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13-cis-retinoic acid plus interferon-alpha: a phase II clinical study in squamous cell carcinoma of the lung and the head and neck. Retinoids and interferon-alpha (IFN-alpha) have been shown to have a synergetic antiproliferative and differentiative effect on many cell lines, and in combination they have already been tested with some success in the treatment of some tumors. We investigated the tolerance and efficacy of high dose 13-cis-retinoic acid (2 mg/kg/day) and IFN-alpha in the treatment of advanced squamous cell carcinoma of the lung and of the head and neck. No partial or complete response was observed in the 10 patients treated. The toxicity was unusual and mild to moderate considering the dose of retinoid given. This observation leads us to suspect that IFN-alpha may alleviate some of the side effects of the retinoid, and is of interest in the design of future clinical trials.

Lack of correlation between the induction of donor class I and class II major histocompatibility complex antigens and graft rejection. The induction of donor major histocompatibility complex (MHC) antigens on nonrejected and rejected rat renal allografts was compared at various times after transplantation in two strain combinations, DA-to-PVG and LEW-to-DA. Graft rejection was prevented by preoperative donor-specific blood transfusion (DST). Quantitative absorption analysis and immunohistology were performed using monoclonal antibodies specific for donor class I and class II MHC antigens. A significant increase in the expression of donor MHC antigens, both class I and class II, was demonstrated on nonrejected as well as rejected kidneys after transplantation. A kinetic analysis showed that induction of donor class I antigens was accelerated on the nonrejected grafts, and by day 5 the nonrejected kidneys showed increased expression of class I antigen when compared with the rejected grafts (a 37- vs. a 25-fold increase in expression). Increased expression of donor class I antigens persisted on the nonrejected grafts and was still detectable on long-term-surviving kidneys, 50 days after transplantation. The magnitude of class II antigen induction was similar on both rejected and nonrejected grafts (8-fold by 5 days after transplantation). Immunohistology demonstrated that class I and class II antigens were induced on identical structures in the kidney in both situations. In particular the vessel endothelia, which do not express class II antigens in normal kidney, become strongly positive in both rejected and nonrejected grafts 5 days after transplantation. Although renal allograft rejection is completely suppressed in rats given a single donor-specific blood transfusion before transplantation, graft survival cannot be explained by the lack of induction of donor MHC antigens. Donor MHC antigens are induced on these nonrejected kidney grafts, and therefore they could act as target molecules for the effector cells that mediate graft destruction. Thus the induction of donor MHC antigens on tissue allografts should not be considered as indicative of a rejection response resulting in graft destruction.

A method for coronary artery calcium scoring using contrast-enhanced computed tomography. Limitations to the coronary calcium score include its requirement for noncontrast imaging and radiation exposure that approaches current methods for contrast-enhanced CT angiography. We sought to derive and validate a method of measuring the coronary artery calcium score (CACS) from standard contrast-enhanced CT, obviating the need for a second non-contrast calcium scan. The volume of intramural calcium of >320 HU in major coronary vessels was measured in 90 contrast-enhanced and traditional non-contrast calcium scan pairs. An empiric conversion factor was derived to convert the small voxel contrast-enhanced calcium volume to an Agatston calcium score. The accuracy of this technique was then prospectively validated in 120 consecutive patients undergoing clinical calcium scans and contrasted-enhanced coronary CT. Eleven patients were excluded from analysis because of the prespecified criteria of excessive noise in the contrast-enhanced CT or total coronary artery occlusion. The Pearson correlation of the contrast scan-derived calcium score with the measured CACS was r2 = 0.99. With standard CACS risk bands, agreement of the contrast-enhanced calcium score estimate with the measured CAC by quadratic weighted κ was 0.96. The 95% limits of agreement (Agatston units) were given by ±(3.2 + 0.14 × CACS + 4.44 mean square root of CACS). Inter-observer and intra-observer reliability with the intraclass correlation was 0.99. The calcium score can be accurately measured from contrast-enhanced cardiac CT scans with the use of a Hounsfield unit threshold of 320.

Isolation and preliminary characterization of a novel Helicobacter species from swine. To determine whether a Helicobacter sp similar to Helicobacter pylori in the stomachs of humans could be isolated from the stomachs of pigs. 4 young conventionally reared and 21 gnotobiotic pigs. Gastric mucosal homogenates (10% wt/vol) from 4 young conventionally reared pigs were cultured on Skirrow medium under microaerophilic conditions to assess the presence of Helicobacter spp. Colonies with morphologic features compatible with Helicobacter organisms were selected, tested for urease activity, and subpassaged on Skirrow medium. Isolates were examined via SDS-PAGE electrophoresis and reciprocal western blot analyses involving convalescent sera from monoinfected gnotobiotic pigs. Urease- and catalase-positive, gram-negative, microaerophilic, small, curved rod bacteria were isolated from the gastric mucosa of young healthy pigs. The first isolate (2662) was structurally and immunologically closely related to H pylori isolated from humans. The second isolate (1268) displayed an SDS-PAGE profile dissimilar to that of H pylori and isolate 2662, yet it shared limited immunologic cross-reactivity with these microbes. Findings of this study indicate that development of gastric mucosal ulcers and ulceration of the nonglandular pars esophagea in pigs may be associated with gastric colonization by swine-origin Helicobacter spp, which are similar to H pylori isolated from humans.

Analysis of the domain structure of elongation factor-2 kinase by mutagenesis. A number of elongation factor-2 kinase (eEF-2K) mutants were constructed to investigate features of this kinase that may be important in its activity. Typical protein kinases possess a highly conserved lysine residue in subdomain II which follows the GXGXXG motif of subdomain I. Mutation of two lysine residues, K340 and K346, which follow the GXGXXG motif in eEF-2K had no effect on activity, showing that such a lysine residue is not important in eEF-2K activity. Mutation of a conserved pair of cysteine residues C-terminal to the GXGXXG sequence, however, completely inactivated eEF-2K. The eEF-2K CaM binding domain was localised to residues 77-99 which reside N-terminal to the catalytic domain. Tryptophan 84 is an important residue within this domain as mutation of this residue completely abolishes CaM binding and eEF-2K activity. Removal of approximately 130 residues from the C-terminus of eEF-2K completely abolished autokinase activity; however, removal of only 19 residues inhibited eEF-2 kinase activity but not autokinase activity, suggesting that a short region at the C-terminal end may be important in interacting with eEF-2. Likewise, removal of between 75 and 100 residues from the N-terminal end completely abolished eEF-2K activity.

The outcomes of cementless total ankle arthroplasty - pilot study. Since new generation ankle endoprostheses came into common use, total ankle arthroplasty has become an alternative to arthrodesis in the treatment of advanced osteoarthritis. The aim of paper was present preliminary results of cementless total ankle arthroplasty in patients with osteoarthritis. In 2012-2014, 12 cementless total arthroplasties of the ankle joint with a Mobility implant were conducted at the Department of Orthopaedics and Traumatology of the Central Clinical Hospital of the Ministry of Interior in Warsaw. The patients were 7 women and 5 men aged 27-72 years. Nine of the patients had the arthroplasty procedure due to severe post-traumatic degenerative changes while 3 patients had haemophilic arthropathy. Clinical assessment was based on the AOFAS scale and the VAS pain scale. The patients were followed up for at least 6 months. All patients improved considerably. After surgery, the AOFAS score improved by 43.0 (± 7.5) points against baseline while the VAS score improved by 5.2 (± 0.8) points. Imaging studies revealed an anatomical position of the endoprosthesis in all patients and no evidence of implant loosening. 1. Cementless total ankle arthroplasty currently seems to be an optimal solution in the treatment of osteo arthritis of the ankle joint. 2. Correct qualification for surgery is a prerequisite for successful treatment.

Sublingual isosorbide dinitrate-stimulated tilt test for diagnosis of vasovagal syncope in children and adolescents. Vasovagal syncope is the most likely cause of syncope in the young. Head-up tilt-table test (HUT) provides the ability to provoke vasovagal syncope under controlled laboratory settings. In adult populations, pharmacologic stimulation with intravenous/sublingual isosorbide dinitrate (ISDN) has been shown to be an alternative to isoproterenol for increasing the diagnostic yield of HUT. In this study, 40 patients aged 9-18 years with unexplained syncope and 12 healthy age-matched children were evaluated by HUT to 70 degrees for 45 minutes. If tilting alone did not induce symptoms (syncope and presyncope), 0.1 mg/kg ISDN was given while the patient lay supine. After 5 min, the table was tilted to 70 degrees for 15 min or until the symptoms occurred. The control group consisted of 12 healthy age-matched children studied in a similar manner. Six patients (15%) had a positive basal tilt test. Twenty-five patients (62.5%) lost consciousness following ISDN administration. In the control group, nobody had a syncopal episode during the basal tilt test. However, ISDN administration resulted in 1 positive response (8.3%). The sensitivity of the test was 77.5% and its specificity was 91.6%. It is concluded that sublingual nitroglycerin HUT is suitable for routine clinical practice in children and adolescents with unexplained syncope.

Prostacyclin synthesis elicited by endothelin-1 in rat aorta is mediated by an ETA receptor via influx of calcium and is independent of protein kinase C. The purpose of this study was to characterize the receptor(s) and second messenger systems involved in prostacyclin (prostaglandin [PG] I2) synthesis elicited by endothelin (ET)-1 in the rat aorta. PGI2 synthesis, measured as immunoreactive 6-keto-PGF1 alpha, was assessed in aortic rings exposed to endothelin receptor agonists in the presence and absence of selective ETA and ETB receptor antagonists. ET-1, which has equal affinity for both endothelin receptor subtypes, and ET-3, a preferential ETB receptor agonist, enhanced 6-keto-PGF1 alpha synthesis in a time- and concentration-dependent manner. ET-1 was more potent than ET-3 in increasing 6-keto-PGF1 alpha synthesis. Moreover, the selective ETB receptor agonists IRL-1620 and sarafotoxin S6c did not significantly increase 6-keto-PGF1 alpha synthesis. Furthermore, ET-1-induced 6-keto-PGF1 alpha synthesis was attenuated by an ETA receptor antagonist, BQ-123, in a dose-dependent manner but not by an ETB receptor antagonist, BQ-788. Depletion of extracellular Ca2+ or addition of Ca2+ channel blockers (nifedipine, verapamil, SK&F 96365) attenuated ET-1-mediated 6-keto-PGF1 alpha synthesis, while a Ca2+ channel agonist, S(-)-Bay K 8644, potentiated this effect of ET-1. Selective protein kinase C inhibitors (bisindolylmaleimide I, calphostin C) did not alter ET-1-induced 6-keto-PGF1 alpha synthesis. These data suggest that PGI2 synthesis elicited by ET-1 in the rat aorta is mediated primarily through influx of extracellular Ca2+ via activation of an ETA receptor and is independent of protein kinase C.

Silicone oil removal combined with macular pucker dissection: a retrospective review of 14 cases. Silicone oil must be removed from the eye to avoid late complications after the surgical management of proliferative vitreoretinopathy (PVR). Macular pucker, frequently observed after retinal detachment surgery, is responsible for visual impairment. The safety of a procedure combining epimacular membrane peeling and silicone oil removal was retrospectively evaluated. Fourteen eyes that had previously undergone vitrectomy and silicone oil tamponade for rhegmatogenous retinal detachment with severe PVR, penetrating or blunt trauma, and intraocular foreign bodies were included. Silicone oil tamponade was maintained for a mean period of 30 weeks (range, 12-108 weeks). The removal of silicone oil was combined with the peeling of an epimacular membrane. Mean follow-up after silicone oil removal was 86 weeks (range, 13-234 weeks). The final retinal reattachment rate was 78%. Macular pucker recurred in one eye after a 24-month period. Best-corrected visual acuity improved two lines or more in eight eyes (57%) and reached 20/200 or better in eight eyes (57%) at last follow-up. Macular pucker dissection and silicone oil removal can be safely combined. This single procedure can obviate the need for further surgery in eyes that have already undergone multiple operations and allows good visual recovery.

Short-term feeding of vitamin D3 improves color but does not change tenderness of pork-loin chops. The objective of this study was to determine the effect of short-term feeding of vitamin D3 (D3) on blood plasma calcium concentrations and meat quality of pork-loin chops. Three experiments were carried out to meet this objective. Experiment 1 used 250,000 IU and 500,000 IU/d to determine the effective dose of dietary D3 to raise blood plasma calcium concentration. Experiment 2 used 500,000 IU D3/d to determine the appropriate length of feeding time to elevate blood plasma calcium prior to harvest. Experiment 3 used 500,000 IU D3/d to determine the effectiveness of increased blood plasma calcium in improving postmortem quality and tenderness of pork-loin chops. Pigs fed 500,000 IU D3/d in Exp. 1 exhibited higher (P < 0.05) and more stable plasma calcium concentration over a 14-d feeding trial compared with pigs fed 250,000 IU D3/d and control pigs. Therefore, 500,000 IU D3/d was the dose chosen for Exp. 2, in which pigs fed 500,000 IU D3/d for 3 d prior to harvest exhibited elevated and stable plasma calcium concentrations; this length of time was deemed sufficient in which to observe differences in postmortem meat tenderness in Exp. 3. Vitamin D3 supplementation resulted in lower (P < 0.02) L* values and higher (P < 0.03) a* values of loin chops at 7 and 14 d of shelf storage. Vitamin D3 supplementation did not affect quality characteristics (measured by use of subjective scores) or tenderness (quantified via Warner-Bratzler shear force or Star probe values). On the basis of these findings, feeding 500,000 IU D3/d to finishing pigs improved most Hunter color values at 14 d of storage but did not improve pork-loin chop tenderness at 1 to 21 d of retail shelf storage.

Altered bile acid metabolism in primary biliary cirrhosis. Selected aspects of bile acid metabolism were assessed in six women with primary biliary cirrhosis and varying degrees of cholestasis. Urinary bile acid excretion was markedly increased and correlated highly with serum levels. In three patients in whom urinary bile acids were separated by chromatography, the majority of urinary bile acids were monosulfated (34%, 42%, 32%) or polysulfated and/or glucuronidated (30%, 20%, 38%). The monosulfates of chenodeoxycholic acid were conjugated at either the 3 position (67%, 68%, 73%) or the 7 position (33%, 32%, 27%); similarly, the monosulfates of cholic acid were conjugated at the 3 position (65%, 58%, 68%) or the 7 position (35%, 42%, 32%). The position of sulfation was not markedly influenced by the mode of amidation with glycine or taurine. Chenodeoxycholic exchangeable pool size, turnover rate, and synthesis were measured by isotope dilution and found to be well within normal limits, despite the cholestasis. The fraction of chenodeoxycholic acid synthesis excreted in urine ranged from 9 to 48%; 4--38% of chenodeoxycholic acid synthesis was sulfated. These data indicate that the major abnormalities in bile acid metabolism in patients with cholestasis secondary to primary biliary cirrhosis are formation of sulfated bile acids in greatly increased amounts, elevation of blood levels of primary bile acids, and a shift to renal excretion as a major mechanism for bile acid elimination. Chenodeoxycholic acid synthesis continues at its usual rate despite cholestasis. Whether these changes, including the formation of 7-monosulfated bile acids, occur in other forms of cholestasis and whether either the persistance of unchanged chenodeoxycholic acid synthesis or the formation of such novel conjugates has any pathophysiological significance remain to be investigated.

Role of atrial peptide in the acute natriuretic response to uninephrectomy. Unilateral nephrectomy (UNX) is associated with an immediate natriuretic response of the remaining kidney. The role of atrial natriuretic peptide (ANP), as assessed by right atrial appendectomy (APX), was investigated in euvolemic anaesthetized rats. In sham APX rats, UNX resulted in a twofold increase in urinary sodium and potassium excretion (1.03 +/- 0.11 to 2.08 +/- 0.17 and 1.39 +/- 0.05 to 2.26 +/- 0.08 mueq/min, respectively) and a doubling of urinary excretion of guanosine 3',5'-cyclic monophosphate (cGMP). No significant change in glomerular filtration rate, renal plasma flow, and lithium clearance occurred in response to UNX. APX totally prevented the UNX-induced natriuresis and diuresis as well as the rise in urinary cGMP. Post-UNX plasma concentration of ANP was higher in sham-operated compared with APX rats (45 +/- 9 vs. 20 +/- 2 fmol/ml). In sham APX rats, UNX was associated with a transient (less than 15 min) rise in arterial pressure; in APX rats, this immediate increase in arterial pressure was of similar magnitude but of longer (greater than 30 min) duration. The observed stimulation of ANP release after UNX and the blunting of the natriuretic response to UNX by APX suggest that ANP may be an important mediator of the renal response to contralateral renal ablation.

Infantile wheeze: rethinking dogma. Wheeze is a common symptom in young children and is usually associated with viral illnesses. It is a major source of morbidity and is responsible for a high consumption of healthcare and economic resources worldwide. A few children have a condition resembling classical asthma. Rarer specific conditions may have a wheezy component and should be considered in the differential diagnosis. Over the last half century, there have been many circular discussions about the best way of managing preschool wheeze. In general, intermittent wheezing should be treated with intermittent bronchodilator therapy, and a controller therapy should be prescribed for a young child with recurrent wheezing only if positively indicated, and only then if carefully monitored for efficacy. Good multidisciplinary support, attention to environmental exposition and education are essential in managing this common condition. This article analyses the pathophysiological basis of wheezing in infancy and critically discusses the evolution of the scientific progress over time in this unique field of respiratory medicine.

Influence of some dopaminergic agents on antinociception produced by quinine in mice. 1. The analgesic effect of quinine and the influence of some dopaminergic agents on it were studied in mice. 2. Quinine (25-130mg/kg, ip) effectively elicited antinociceptive effect in a dose related manner. 3. D-Amphetamine (2.5-4mg/kg, ip), L-dopa (25mg/kg, sc), L-dopa (25mg/kg, sc) plus benserazide (12.5mg/kg, sc), alpha-methyl-p-tyrosine (50mg/kg, ip) plus L-dopa (25mg/kg, sc) and pargyline (50mg/kg, ip) significantly attenuated the antinociceptive effect of quinine (50mg/kg, ip), while DOPS (4mg/kg, ip) did not affect quinine antinociception. 4. Pimozide (4mg/kg, ip), L-sulpiride (40mg/kg, ip), SCH 23390 (0.2mg/kg, sc) and alpha-methyl-p-tyrosine (50mg/kg, ip) effectively potentiated the antinociceptive effects of quinine (50mg/kg, ip). 5. Pimozide (4mg/kg, ip) also antagonised the antagonistic effect of d-amphetamine (4mg/kg, ip) on the antinociceptive effect of quinine (50mg/kg, ip). 6. These data indicate that quinine elicited antinociception dose dependently. Furthermore, the influence of pimozide, L-sulpiride and SCH 23390 on quinine antinociception suggests the involvement of dopaminergic mechanisms.

A histochemical study of alkaline and acid phosphatase activity in osteoarthritic synovial membrane. In order to determine the localization and activity of alkaline and acid phosphatase in the synovial membrane of osteoarthritic hip joints, enzymo-histochemical analyses were performed using Burstone's and Barka & Anderson's methods. Frozen sections of synovial biopsy material from 12 osteoarthritic and 6 control hip joints were studied. Alkaline phosphatase was found located in fibroblasts below the lining cells and in capillaries and precapillary arterioles. Acid phosphatase was seen in the lysosomes in the lining cells. Semiquantitative evaluation by means of initial time determination showed significantly greater activity in osteoarthritic synovia than in the control group. Whilst the increased activity of lysosomal enzymes is presumably implicated in the joint cartilage damage seen in osteoarthritis, the significance of elevated alkaline phosphatase levels is not yet clear.

Isolation of a mycoplasma from three patients with lepromatous leprosy. Using a modified cell-free culture medium and modern microscopic equipment, a mycoplasma was isolated from scrapings of skin lesions of three patients with lepromatous leprosy. Three specimens were taken from the first patients. All five isolates were arginine-positive and their antibiotic sensitivity was identical with only one slight exception.

Bradykinin-mediated hypotension after infusion of plasma-protein fraction. In patients who required volume expansion during extracorporeal circulation, the plasma bradykinin concentration was monitored simultaneously with the mean arterial pressure during infusion of either albumin solution or PPF. The PKA content of the PPF and the albumin solution was 29 and 3 U/L, respectively, measured spectrophotometrically. In six patients receiving 250 ml of PPF, the mean arterial pressure decreased 22% to 54% within 1.5 min after infusion, whereas the plasma bradykinin concentration, measured by radioimmunoassay, increased significantly (p less than 0.0005) during the first minute. In six patients receiving 250 ml of 4% albumin solution, no blood pressure changes were found, and the plasma bradykinin concentration rose only slightly. In vitro, linear correlation (r = 0.94, p less than 0.0005) was observed between the level of PKA of 26 different lots of PPF and the concentrations of bradykinin that were generated in Hageman factor-deficient plasma after incubation with PPF. It is concluded that the hypotensive reactions observed after PPF infusion during extracorporeal circulation are caused by the PKA-induced bradykinin generation.

Tumor-infiltrating lymphocytes and perforation in colon cancer predict positive response to 5-fluorouracil chemotherapy. The major pathologic markers of prognosis in colorectal cancer include vascular invasion by tumor cells, invasion of adjacent lymph nodes, and perforation of the serosal wall. Recent work suggests that a high density of tumor-infiltrating lymphocytes (TIL) is associated with good outcome independently of these established prognostic markers. The aim of the present study was to investigate the prognostic significance of TILs and other routinely reported pathologic features in colon cancer, particularly in relation to the use of adjuvant chemotherapy. Pathologic markers, disease-specific survival, and the use of adjuvant chemotherapy were recorded in a retrospective, population-based series of 1,156 stage III colon cancer patients with a median follow-up time of 52 months. In patients treated by surgery alone (n = 851), markers with significant prognostic value included poor histologic grade, T4 stage, N2 nodal status, vascular invasion, and perforation, but not the presence of TILs. In patients treated with 5-fluorouracil-based chemotherapy (n = 305), TILs were associated with significantly improved survival [hazard ratio (HR), 0.52; 95% confidence interval, 0.30-0.91; P = 0.02] and perforation with a trend for improved survival (HR, 0.67; 95% confidence interval, 0.27-1.05; P = 0.16). Patients with TILs or perforation seemed to gain more survival benefit from chemotherapy (HR, 0.22 and 0.21, respectively) than patients without these features (HR, 0.84 and 0.82, respectively). The apparent survival advantage from 5-fluorouracil associated with TILs and perforation requires confirmation in prospective studies. Because the presence of TILs reflects an adaptive immune response and perforation is associated with inflammatory response, these results suggest that there may be interactions between the immune system and chemotherapy leading to improved survival of colon cancer patients.

Structural and functional properties of proteasomes purified from the human kidney. Proteasomes are 'proteolytic machineries' implicated in many cellular functions, including protein turnover, inflammatory response and immunosurveillance. They exist in various forms sharing the same catalytic core - the 20S proteasome. This core consists of 28 subunits codified by 14 different genes, 3 of which - beta 1, beta 2 and beta 5 - are catalytically active and show peptidyl-glutamyl peptide hydrolyzing (PGPH), trypsin-like and chymo-trypsin-like activities, respectively. Under IFN- delta and TNF- alfa stimuli, the 3 active constitutive subunits are replaced by the corresponding ones - i.e., LMP2, MECL-1, LMP7 - known as inducible subunits, thus resulting in the constitution of the 'immunoproteasome' that is specifically implicated in MHC class I-presented peptide generation. This process is enhanced when the proteasome is associated with the polymeric protein 11S regulator/PA28 made up of 4 alfa and 3 beta subunits. The 20S proteasome was purified from post mortem specimens of human kidney cortex by chromatographic and ultracentrifugation techniques. It was then characterized on the basis of (i) multicatalytic activity evaluated using specific fluorogenic peptides, (ii) electrophoretic mobility on non-denaturating polyacrylamide gels followed by in-gel visualization by fluorogenic peptide overlaying and Coomassie blue staining and (iii) subunit composition as ascertained by SDS-PAGE and 2-dimensional electrophoresis followed by silver staining or Western immunoblotting using specific antibodies against the proteasome subunits. The 20S proteasome was also studied for its association with the 11S regulator by Western immunoblotting using an antibody to the regulator alfa subuniT. T he purified proteasome was shown to have PGPH, trypsin-like and chymotrypsin-like activities. Furthermore, it incorporated the inducible subunits and was associated with the 11S regulator. The features we observed make renal cells susceptible to an over-expression of inflammatory response to immunological challenges.

Effective flow performances and dialysis doses delivered with permanent catheters: a 24-month comparative study of permanent catheters versus arterio-venous vascular accesses. Permanent venous catheters have emerged as a long-term vascular access option for renal replacement therapy in end-stage renal disease patients. The design and venous location of catheter devices bear intrinsic flow limitations that may negatively affect the adequacy of dialysis and the patient outcome. There is limited data comparing the long-term dialysis adequacy delivered with permanent catheters vs arterio-venous vascular accesses (AVA). To explore this problem, we conducted a prospective 24-month trial comparing the flow performances and dialysis dose (Kt/Vdp) deliveries of both access options in a group of 42 haemodialysis patients during two study phases. During the first 12 months the patients completed a treatment period by means of permanent dual silicone catheters (DualKT). Then they were transferred to an AVA (40 native arterio-venous fistulas and two PTFE grafts) and monitored for an additional 12-month period. Assessments of flow adequacy and dialysis quantification were performed monthly. Dialysis adequacy was achieved in all cases. No patient had to be transferred prematurely to the AVA because of catheter failure. Three catheters had to be replaced due to bacteraemia in three patients. The mean effective blood flow rates achieved were 316+/-3.5 ml/min and 340+/-3.3 ml/min with DualKT and AVA, respectively, for a pre-set machine blood flow of 348+/-2.2 ml/min. Recirculation rates evaluated with the 'slow blood flow' method were 8.6+/-0.6 and 12.1+/-0.8% for DualKT and AVA using mean values of the solute markers urea and creatinine. Due to the possibility of a comparison veno-venous vs arterio-venous blood circulation, a corrected arterio-venous access recirculation could be derived from the difference between the two, which was around 3%. The blood flow resistance of the DualKT was slightly higher than with AVA as indicated by venous pressure differences. Kt/Vdp delivered was 1.37+/-0.02 and 1.45+/-0.02 with DualKT and AVA access respectively. The loss of dialysis efficacy using catheters was estimated at 6%. However, in all cases Kt/Vdp values remained above the recommended values (Kt/Vdp > or = 1.2). Protein nutritional state, as well as conventional clinical and biochemical markers of dialysis adequacy, remained in the optimal range. Permanent venous catheters provide adequate haemodialysis on a long-term basis. Flow performances and dialysis doses are slightly reduced (5-6%) when compared with AVA. Regular assessment of dialysis performance is strongly recommended to assure dialysis adequacy. Lengthening dialysis time may represent a simple and efficient tool to compensate for reduced flow performances with catheter use.

A family epidemiological model: a practice and research concept for family medicine. Drawing on knowledge from various behavioral science disciplines and epidemiology, a conceptual model for use in practice, education, and research in family medicine has been developed. This model uses three overlapping circles of a Venn diagram to represent the host (family system), the environmental, and the agent (stressor) systems. The central overlapping area of the three circles is the "resultant adjustment" of all the multiple interacting variables, and reflects the current state of the family. This concept has been designated the Family Epidemiological Model and is an interactive, multisystem, multivariate model. Some of the educational and practical implications of its comprehensive and exhaustive approach are discussed.

Cell-type-specific and projection-specific brain-wide reconstruction of single neurons. We developed a dual-adeno-associated-virus expression system that enables strong and sparse labeling of individual neurons with cell-type and projection specificity. We demonstrated its utility for whole-brain reconstruction of midbrain dopamine neurons and striatum-projecting cortical neurons. We further extended the labeling method for rapid reconstruction in cleared thick brain sections and simultaneous dual-color labeling. This labeling system may facilitate the process of generating mesoscale single-neuron projectomes of mammalian brains.

[Cancer of the penis in Cambodia]. The prevalence of penis cancer in Cambodia is comparable with some Far-East and Latino-American countries. Circumcision performed as a religious observance among Jews or undergone as a regular practice among older Moslems children (the Islam Kmers in Cambodia) might provide an indirect protection against this kind of cancer. It indeed helps in ensuring proper personnal hygiene and in improving the detection, the treatment and the aftercare of all the mild lesions which possibly can pave the way to cancer. Out of of 253 observed cases recorded during a 10 years period (from 1960 to 1970), 164 were treated and followed up by the same surgical team from 1964 to 1970. They stress on those etiopathogenic factors and make possible a description of the reported "anatomoclinical" forms. The use of radiumtherapy either by contact or by means of needles is quite effective; however, when corpora cavernosa are involved, it will be often necessary to perform either a partial amputation or to an emasculation in case of entirely overspreading lesions. As metastases are of rare occurence, it is regarded as a "mild cancer"; however the sequelae due to the treatment are far from small importance. Through better personnal hygiene, detection, treatment, and surveillance of inflammations and benign tumors, with the renforcement of circumcision as a regular practice for every case of phimosis or chronic lesions, an effective prevention of this kind of cancer will expectedly be carried out in Cambodia and its prevalence will be reduced to a rate similar to that in European countries.

Cattell's Scree Test In Relation To Bartlett's Chi-Square Test And Other Observations On The Number Of Factors Problem. It is demonstrated that Cattell's scree test and Bartlett's chi-square test for the number of factors are both based on the same rationale, so the former reflects statistical (subject sampling) variability and the latter usually involves psychometric (variable sampling) influences. If the alpha-level (implicit in the scree test) is set the same, the two tests should lead to the same conclusions. Analyses with some examples suggest that if the alpha-level for the Bartlett test is set (explicitly) in the neighborhood of .0003 for sample Ns of 100 to 150, the results from applications of this test will indicate approximately the same number of factors as estimated on the basis of a scree test determined on a much larger (N ≃ 600) sample. Used in this way, the Bartlett test may yield fairly good "population" estimates of the number of factors. Relationships between the Bartlett test, hence the scree test, and tests for a common factor model and for the significance of a correlation matrix are explicated.

Oriented growth behavior of Ag nanoparticles using SDS as a shape director. We report a chemical approach for synthesizing shape-controlled Ag nanoparticles by using the surfactant SDS as a soft template. The experimental approach includes a two-step reaction: the first step is quickly generating Ag seed clusters by a chemical reaction using sodium borohydride as a reducing reagent; the second is the slow growth of controllable Ag nanoparticles by a mild chemical reaction using hydroxylamine hydrochloride as a reducing reagent. Spherical, polyhedral, and fibrous Ag nanoparticles are synthesized successfully in aqueous solution having SDS concentrations of 0.01, 0.02, and 0.2 wt.%, respectively. Size, morphology, and dispersion stability of these Ag nanoparticles depend on the concentrations of both SDS and AgNO(3).

Molecular weights of poly(butyl cyanoacrylate) nanoparticles determined by mass spectrometry and size exclusion chromatography. Matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS) and size exclusion chromatography (SEC) were employed to elucidate the chemical composition, mean number average molecular weight (M(n)), mean weight average molecular weight (M(w)), and polydispersity (PD) of poly(butyl cyanoacrylate) (PBCA) manufactured by emulsion polymerisation. Both methods gave similar results for M(n), but substantial differences were observed for M(w) and PD, with MALDI producing consistently lower values which could not be improved by off-line coupling of SEC and MALDI. MALDI gave a more detailed view on the chemical composition of the cyanoacrylate and revealed the presence of two additional polymer series with different end groups besides the expected PBCA series, which showed different retention in SEC. Their formation is explained by the secession/addition of formaldehyde from/to the regular polymer via (reverse) Knoevenagel reaction. In additional experiments, the influence of different pH on PBCA-NP during polymerisation was examined by comparison of polymerisation yield and particle diameter to their chemical composition as revealed by the MALDI spectra. The most uniform nanoparticles, with the highest polymerisation yield, narrowest particle size, and mass distribution were produced at pH 1.

Integrating phenotypic plasticity within an Ecological Genomics framework: recent insights from the genomics, evolution, ecology, and fitness of plasticity. E.B. Ford's 1964 book Ecological Genetics was a call for biologists to engage in multidisciplinary work in order to elucidate the link between genotype, phenotype, and fitness for ecologically relevant traits. In this review, we argue that the integration of an ecological genomics framework in studies of phenotypic plasticity is a promising approach to elucidate the causal links between genes and the environment, particularly during colonization of novel environments, environmental change, and speciation. This review highlights some of the questions and hypotheses generated from a mechanistic, evolutionary, and ecological perspective, in order to direct the continued and future use of genomic tools in the study of phenotypic plasticity.

Interactions of alpha-helices with lipid bilayers: a review of simulation studies. Membrane proteins, of which the majority seem to contain one or more alpha-helix, constitute approx. 30% of most genomes. A complete understanding of the nature of helix/bilayer interactions is necessary for an understanding of the structural principles underlying membrane proteins. This review describes computer simulation studies of helix/bilayer interactions. Key experimental studies of the interactions of alpha-helices and lipid bilayers are briefly reviewed. Surface associated helices are found in some membrane-bound enzymes (e.g. prostaglandin synthase), and as stages in the mechanisms of antimicrobial peptides and of pore-forming bacterial toxins. Transmembrane alpha-helices are found in most integral membrane proteins, and also in channels formed by amphipathic peptides or by bacterial toxins. Mean field simulations, in which the lipid bilayer is approximated as a hydrophobic continuum, have been used in studies of membrane-active peptides (e.g. alamethicin, melittin, magainin and dermaseptin) and of simple membrane proteins (e.g. phage Pf1 coat protein). All atom molecular dynamics simulations of fully solvated bilayers with transmembrane helices have been applied to: the constituent helices of bacteriorhodopsin; peptide-16 (a simple model TM helix); and a number of pore-lining helices from ion channels. Surface associated helices (e.g. melittin and dermaseptin) have been simulated, as have alpha-helical bundles such as bacteriorhodopsin and alamethicin. From comparison of the results from the two classes of simulation, it emerges that a major theoretical challenge is to exploit the results of all atom simulations in order to improve the mean field approach.

Noncomplement fixing, IgG4 autoantibodies predominate in patients with anti-epiligrin cicatricial pemphigoid. This study characterized the specific reactivity, IgG subclass, and complement fixing ability of anti-laminin-5 IgG from 12 patients with anti-epiligrin cicatricial pemphigoid. Circulating IgG from all patients bound the dermal side of 1 M NaCl split skin, immunoprecipitated laminin-5 produced by biosynthetically radiolabeled human keratinocytes, and (in 10 of 12 cases) immunoblotted the laminin-alpha3 subunit. Analysis of the distribution of IgG subclasses in these patients' circulating anti-laminin-5 autoantibodies by semiquantitative indirect immunofluorescence microscopy using the HP series of subclass-specific monoclonal antibodies revealed: (i) IgG4 predominant autoantibodies in seven of 11 sera; (ii) IgG1 and IgG2 at substantially lower levels in a smaller number of sera; and (iii) no specific IgG3 anti-laminin-5 autoantibodies in any patients. The same IgG4-dominant profile of anti-laminin-5 autoantibodies was found in enzyme-linked immunosorbent assay studies of purified human laminin 5. Direct immunofluorescence microscopy of six skin biopsies from three patients found that IgG4 was also the predominant subclass of IgG in epidermal basement membranes in situ. Consistent with these findings, sera from 11 of 11 patients with anti-laminin-5 IgG autoantibodies did not fix C3 to epidermal basement membranes in vitro. These immunochemical studies suggest that complement activation does not play a major role in the pathophysiology of this disease and that subepidermal blisters in these patients may develop via a direct effect of anti-laminin-5 IgG itself.

Relevance and usability of a computerized patient simulator for continuous medical education of isolated care professionals in sub-saharan Africa. to explore the relevance and usability of using a computerized patient simulator as a tool for continuous medical education and decision support for health professionals in district hospitals in Sub-Saharan Africa. based on the diagnosis pathway and decision analysis in uncertainty context, interactive clinical vignettes are developed using VIPS, a computerized patient simulator, taking into account clinical problem situations whose relevance was identified. Vignettes were adapted to take into account local epidemiology, availability of diagnostic and therapeutic resources, and local socio-cultural constraints. The evaluation on VIPS software was made by care professionals and students. a computerized patient simulator can be used to provide initial and continuing medical education in Sub-Saharan Africa. But many challenges exist. further research is needed to measure potential improvements in knowledge, skills, decision-making abilities as well as patient outcome.

The general hospitals' role in the care of the seriously disabled mentally ill. Acute-care general hospitals play an important role in the care of the seriously disabled mentally ill (SDMI), especially in the State of Hawaii. Currently there are 4 private hospitals on the island of Oahu that have acute psychiatric wards: (1) Castle Medical Center has a unit with both locked and unlocked wards; (2) The queen's Medical Center (QMC) has a unit with locked and unlocked wards as well as a 24-hour psychiatric resident physician coverage for the emergency room; (3) St. Francis Hospital has a small unlocked combined medical and psychiatric unit; and (4) Kahi Mohala, a psychiatric hospital, has a large locked and unlocked unit. In addition, Tripler Medical Center serves military-related cases on Oahu and there are 3 Neighbor Island general hospital psychiatric units. The emergency rooms in the acute hospitals are the frequent entryways to the care system for the SDMI. For many such patients, they continue to be the focus for treatment and, for some, they are almost the exclusive source of treatment.

SH479, a Betulinic Acid Derivative, Ameliorates Experimental Autoimmune Encephalomyelitis by Regulating the T Helper 17/Regulatory T Cell Balance. CD4+ T helper cells, especially T helper 17 (TH17) cells, combined with immune regulatory network dysfunction, play key roles in autoimmune diseases including multiple sclerosis (MS). Betulinic acid (BA), a natural pentacyclic triterpenoid, has been reported to be involved in anti-inflammation, in particular having an inhibitory effect on proinflammatory cytokine interleukin 17 (IL-17) and interferon-γ (IFN-γ) production. In this study, we screened BA derivatives and found a BA derivative, SH479, that had a greater inhibitory effect on TH17 differentiation. Our further analysis showed that SH479 had a greater inhibitory effect on TH17 and TH1, and a more stimulatory effect on regulatory T (Treg) cells. To evaluate the effects of SH479 on autoimmune diseases in vivo, we employed the extensively used MS mouse model experimental autoimmune encephalomyelitis (EAE). Our results showed that SH479 ameliorated clinical and histologic signs of EAE in both prevention and therapeutic protocols by regulating the TH17/Treg balance. SH479 dose-dependently reduced splenic lymphocyte proinflammatory factors and increased anti-inflammatory factors. Moreover, SH479 specifically inhibited splenic lymphocyte viability from EAE mice but not normal splenic lymphocyte viability. At the molecular level, SH479 inhibited TH17 differentiation by regulating signal transducer and activator of transcription-3 (STAT3) phosphorylation, DNA binding activity, and recruitment to the Il-17a promoter in CD4+ T cells. Furthermore, SH479 promoted the STAT5 signaling pathway and inhibited the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. Together, our data demonstrated that SH479 ameliorated EAE by regulating the TH17/Treg balance through inhibiting the STAT3 and NF-κB pathways while activating the STAT5 pathway, suggesting that SH479 is a potential novel drug candidate for autoimmune diseases including MS.

Nuclear trafficking during plant innate immunity. Land plants possess innate immune systems that can control resistance against pathogen infection. Conceptually, there are two branches of the plant innate immune system. One branch recognizes conserved features of microbial pathogens, while a second branch specifically detects the presence of pathogen effector proteins by plant resistance (R) genes. Innate immunity controlled by plant R genes is called effector-triggered immunity. Although R genes can recognize all classes of plant pathogens, the majority can be grouped into one large family, encoding proteins with a nucleotide binding site and C-terminal leucine rich repeat domains. Despite the importance and number of R genes present in plants, we are just beginning to decipher the signaling events required to initiate defense responses. Recent exciting discoveries have implicated dynamic nuclear trafficking of plant R proteins to achieve effector-triggered immunity. Furthermore, there are several additional lines of evidence implicating nucleo-cyctoplasmic trafficking in plant disease resistance, as mutations in nucleoporins and importins can compromise resistance signaling. Taken together, these data illustrate the importance of nuclear trafficking in the manifestation of disease resistance mediated by R genes.

Detection of Blastomyces dermatitidis antigen in patients with newly diagnosed blastomycosis. Blastomycosis is a serious and potentially fatal infection, and diagnosis can be difficult at times. We evaluated the diagnostic utility of a commercially available assay for detection of Blastomyces dermatitidis antigen, recently modified to permit quantitation, in subjects with newly diagnosed blastomycosis. Twenty-three of 27 (85.1%) subjects had detectable B. dermatitidis antigenuria. In 2 of these 23, positive results were obtained after concentration of the urine specimen. Nine of 11 (81.8%) subjects had detectable B. dermatitidis antigen in serum, including 3 subjects with negative results before treatment of serum with ethylenediaminetetraacetic acid (EDTA) and positive results after EDTA treatment. B. dermatitidis antigen was not detected in specimens from 50 control subjects but was detected in 15 patients with histoplasmosis. B. dermatitidis antigen was detected in most of the patients with blastomycosis and can be a useful tool for timely diagnosis.

Physicians' attitudes towards patients' rights legislation. Patients' rights laws, bills and charters aim at delineating the patient-physician relationship in regard to consent to medical treatment, confidentiality and related issues. The need to shape such an intimate relationship by way of legislation seems anomalous to some, but imperative to others. We present for the first time an insight into Israeli physicians' attitudes towards Israel's patients' rights laws, in a changing medical and socio-legal environment. The research results suggest that physicians are reluctant to participate in the implementation of such laws, demonstrated by the level of their misunderstanding of the law's norms and regulations, and subjective attitudes and perceptions. In order to ensure the medical community's participation in augmenting patients' rights, efforts should focus on improved legal and ethical education, enhanced cooperation of professional associations and joint action with legislators to assure a productive composition of these important acts.

Cost of Immediate Surgery Versus Non-operative Treatment for Trigger Finger in Diabetic Patients. As health care costs continue to rise, providers must increasingly identify and implement cost-effective practice measures without sacrificing quality of care. Corticosteroid injections are an established treatment for trigger finger; however, numerous clinical trials have documented the limited efficacy of these injections in the diabetic population. Furthermore, the most cost-effective treatment strategy for diabetic trigger finger has not been determined. The purpose of this study was to perform a decision analysis to identify the least costly strategy for effective treatment of diabetic trigger finger using existing evidence in the literature. Four treatment strategies for diabetic trigger finger were identified: (1) 1 steroid injection followed by surgical release, (2) 2 steroid injections followed by surgical release, (3) immediate surgical release in the operating room, and (4) immediate surgical release in the clinic. A literature review was conducted to determine success rates of the different treatment strategies. Costing analysis was performed using our institutional reimbursement from Medicare. One-way sensitivity and threshold analysis was utilized to determine the least costly treatment strategy. The least costly treatment strategy was immediate surgical release in the clinic. In patients with insulin-dependent diabetes mellitus, this strategy results in a 32% and a 39% cost reduction when compared with treatment with 1 or 2 corticosteroid injections, respectively. For 1 or 2 corticosteroid injections to be the most cost-effective strategy, injection failure rates would need to be less than 36% and 34%, respectively. The overall cost of care for immediate surgical release in the clinic was $642. Diabetic trigger finger is a common problem faced by hand surgeons, with a variety of acceptable treatment algorithms. Management of diabetic trigger finger with immediate surgical release in the clinic is the most cost-effective treatment strategy, assuming a corticosteroid injection failure rate of at least 34%. Economic/decision III.

Dehydration and clearing of whole mouse brains and dissected hippocampi for ultramicroscopy. This protocol describes the preparation of whole mouse brains and dissected hippocampi for ultramicroscopy (UM), a powerful imaging technique that achieves precise and accurate three-dimensional (3D) reconstructions of intact macroscopic specimens with micrometer resolution. In UM, a specimen in the size range of ∼1-15 mm is illuminated perpendicular to the observation pathway by two thin counterpropagating sheets of laser light. Thus, specimens for UM need to be sufficiently transparent, which requires chemical clearing in most cases. In this protocol, mouse brains and hippocampi are carefully dissected and dehydrated, and then cleared in a solution of benzyl benzoate and benzyl alcohol.

Multilocular cystic renal cell carcinoma is a subtype of clear cell renal cell carcinoma. Multilocular cystic renal cell carcinoma is an uncommon low grade renal cell carcinoma with unique morphologic features. Its cytogenetic characteristics have not been fully investigated. Its relationship to typical clear cell renal cell carcinoma is uncertain. We evaluated 19 cases of multilocular cystic renal cell carcinoma diagnosed by strict morphologic criteria using the 2004 WHO classification system. The control group consisted of 19 low grade (Fuhrman grades 1 or 2) clear cell renal cell carcinomas. Chromosome 3p deletion status was determined by dual color interphase fluorescence in situ hybridization analysis. Chromosome 3p deletion was identified in 17 out of 19 (89%) of the clear cell renal cell carcinoma cases and 14 out of 19 (74%) of the multilocular cystic renal cell carcinoma cases, respectively. There was no difference in the status of chromosome 3p deletion between clear cell renal cell carcinoma and multilocular cystic renal cell carcinoma (P=0.40). These results support the concept that multilocular cystic renal cell carcinoma as a subtype of clear cell renal cell carcinoma.

Two new species of Ergasilus Nordmann, 1832 (Copepoda: Ergasilidae) and a redescription of Ergasilus salmini Thatcher & Brazil-Sato, 2008 from Salminus brasiliensis Cuvier and S. franciscanus Lima & Britsky (Teleostei: Characidae) in Brazil. Three species of Ergasilus Nordmann, 1832 are reported from the gills of Salminus spp. in Brazil. Ergasilus salmini Thatcher & Brazil-Sato, 2008 from Salminus brasiliensis Cuvier is redescribed, based on examination of paratypes. The study revealed morphological differences from the original description, especially in the morphology of the cephalothorax and the ornamentation of antenna, antennule and legs. Ergasilus lacusauratus n. sp. described from S. brasiliensis in lake Lagoa Dourada (Paraná) differs from the only known species from this host group, E. salmini, in the shape and size of the cephalothorax and the general morphology of the egg-sacs. Ergasilus sinefalcatus n. sp. from S. franciscanus Lima & Britsky in River São Francisco (Minas Gerais) closely resembles E. pitalicus, E. coatiarus and E. leporinidis in the lack of a pectinate seta on the first exopodal segment, a feature common in species of Ergasilus in the Neotropics. Ergasilus sinefalcatus n. sp. differs from these species in the presence of a spiniform process on the coxae of legs 2, 3 and 4, an ornament never reported from freshwater species of Ergasilus in South America.

Lipodystrophy: a case report of partial lipodystrophy of the face. Lipodystrophy is a disorder of the subcutaneous adipose tissue. It can occur in two forms--partial and total. Gorlin and Goldman (1970) suggested that facial lipodystrophy can only occur bilaterally, and should it occur unilaterally, then it is hemifacial atrophy. A case is reported to illustrate that partial lipodystrophy can occur unilaterally.

Coupling of multiple opioid receptors to GTPase following selective receptor alkylation in brain membranes. Opioid agonists of the mu, kappa and delta types stimulated low-Km guanosine triphosphatase (GTPase) in membranes, from the brain of the rat by up to 34%, with potencies the rank order of which corresponded to the respective binding affinities to opioid receptor. In general, kappa ligands stimulated GTPase to a lesser degree than mu or delta opiates. The coupling of a given type of opioid receptor to GTPase was resolved by direct or protective alkylation of the other receptors. Treatment of the membranes with beta-funaltrexamine abolished the stimulation of GTPase by sufentanil and levorphanol (mu), but not by bremazocine (kappa) or DSLET (delta). On the other hand, prior incubation with Superfit, an alkylating agent with selectivity for the delta opioid receptor, specifically eliminated the effect of DSLET. Partial alkylation by increasing concentrations of Superfit gradually reduced the extent of stimulation of GTPase by DSLET. The successive treatment of membranes with Superfit and beta-funaltrexamine blocked the actions of DSLET, sufentanil and levorphanol, but had no effect on the stimulation of the GTPase by bremazocine. Selective coupling of an opioid receptor to GTPase was also obtained after incubation of membranes with beta-chlornaltrexamine in the presence of protective concentrations of mu, kappa or delta opioid ligands. Alkylation resolved the coupling of the non-selective opiate etorphine: the sum of stimulation of GTPase in the receptor-selective membranes equalled maximal stimulation of enzyme in untreated membranes. Naloxone blocked the stimulation of GTPase by mu, kappa or delta agonists, but ICI-174,864 specifically inhibited the effect of DSLET.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular calcification in nondialyzed patients with chronic kidney disease. Chronic kidney disease (CKD) has become a major health-care problem of global proportions. Progression to end-stage renal disease (ESRD), the need for renal replacement therapy, and the high annual death rate of dialysis patients are the most noticeable outcomes of CKD. Less appreciated, however, is the fact that most patients with CKD actually die mainly from cardiovascular disease, rather than progress to ESRD. Coronary artery calcification (CAC), a surrogate marker of atherosclerosis, is common in dialysis and CKD patients. Coronary artery calcium scores, as measured by ultrafast computed tomography, is an independent predictor of future cardiac events. Using this technique, several studies have documented extensive calcification in dialysis patients, a subject of several exhaustive reviews. Unfortunately, much less attention has been paid to calcification in nondialyzed patients with CKD. In this review, I will emphasize the fact that CVC is common in patients with CKD not yet on dialysis, develops early in the course of CKD, and worsens with the decline in renal function particularly among diabetics who progressed to ESRD. I will also discuss the pathogenesis of CVC in CKD patients and highlight the lack of a major role for abnormalities of mineral metabolism in the pathogenesis of calcification in CKD patients. In addition to the high prevalence of traditional risk factors for CAD, the presence of proteinuria, reduced renal function, diabetic nephropathy, and the rate of progression to ESRD may represent the main uremia-related factors that increase the risk for calcification in CKD. Finally, I will review the protective role of inhibitors of calcification in CKD.

Effect of ultraviolet (UV) A, UVB or ionizing radiation on the cell cycle of human melanoma cells. One important component of the cellular response to irradiation is the activation of cell cycle checkpoints. It is known that both ultraviolet (UV) radiation and ionizing radiation (IR) can activate checkpoints at transitions from G(1) to S phase, from G(2) phase to mitosis and during DNA replication. To evaluate the effects of irradiation with different wavelengths on cell cycle alterations. p53-deficient IPC-298 melanoma cells were irradiated with 10 J cm(-2) UVA, 40 mJ cm(-2) UVB, or with 7.5 Gy IR. Cell cycle effects were then determined by DNA/5-bromodeoxyuridine dual-parameter flow cytometry. IPC-298 cells irradiated in G(1) with UVA were not arrested at the G(1)/S transition, but at the G(2)/M transition. Despite p53 deficiency, the cells showed a G(1) arrest after UVB exposure. Furthermore, IR did not affect G(1) or S phase, but induced G(2) phase arrest. Hence, the effects of UVA, but not of UVB, on the cell cycle in p53-deficient melanoma cells are comparable with those of IR. UVA and IR induce radical-mediated strand breaks and DNA lesions, and UVB essentially induces thymine dimers that lead to excision repair-related strand breaks. Different cell cycle effects may be a consequence of different types of DNA damage. The results showed that UVB-irradiated p53-deficient cells are arrested in G(1). Irradiation with the solar radiation component UVB can therefore result in a beneficial retardation of tumour promotion in human skin carrying p53-mutated cell clones.

Nature of M-Ga bonds in dihalogallyl complexes (η5-C5H5)(Me3P)2M(GaX2) (M = Fe, Ru, Os) and (η5-C5H5)(OC)2Fe(GaX2) (X = Cl, Br, I): a DFT study. Density functional theory (DFT) calculations have been performed on the terminal dihalogallyl complexes of iron, ruthenium, and osmium (η(5)-C(5)H(5))(Me(3)P)(2)M(GaX(2)) (M = Fe, Ru, Os; X = Cl, Br, I) and (η(5)-C(5)H(5))(OC)(2)Fe(GaX(2)) (X = Cl, Br, I) at the BP86/TZ2P/ZORA level of theory. On the basis of analyses suggested by Pauling, the M-Ga bonds in all of the dihalogallyl complexes are shorter than M-Ga single bonds; moreover, on going from X = Cl to X = I, the optimized M-Ga bond distances are found to increase. From the perspective of covalent bonding, however, π-symmetry contributions are, in all complexes, significantly smaller than the corresponding σ-bonding contribution, representing only 4-10% of the total orbital interaction. Thus, in these GaX(2) complexes, the gallyl ligand behaves predominantly as a σ donor, and the short M-Ga bond lengths can be attributed to high gallium s-orbital character in the M-Ga σ-bonding orbitals. The natural population analysis (NPA) charge distributions indicate that the group 8 metal atom carries a negative charge (from -1.38 to -1.62) and the gallium atom carries a significant positive charge in all cases (from +0.76 to +1.18). Moreover, the contributions of the electrostatic interaction terms (ΔE(elstat)) are significantly larger in all gallyl complexes than the covalent bonding term (ΔE(orb)); thus, the M-Ga bonds have predominantly ionic character (60-72%). The magnitude of the charge separation is greatest for dichlorogallyl complexes (compared to the corresponding GaBr(2) and GaI(2) systems), leading to a larger attractive ΔE(elstat) term and to M-Ga bonds that are stronger and marginally shorter than in the dibromo and diiodo analogues.

Clinical effects of buprenorphine on open field behaviour and gait symmetry in healthy and lame weaned piglets. Lameness in pigs decreases animal welfare and economic profit for the farmer. An important reason for impaired welfare in lame animals is pain due to lameness. No direct measurement of pain is possible in animals, and methods to indirectly detect and quantify the amount of pain an animal is experiencing are urgently needed. In this study, two methods to assess pain associated with lameness in pigs were evaluated to determine if they were sensitive enough to detect a lameness reduction as an effect of an experimental analgesic medication. Asymmetry associated with lameness was objectively quantified using pressure mat kinetic parameters: peak vertical force (PVF), load rate (LR), vertical impulse (VI) and peak vertical pressure (PVP). Locomotor activity was assessed in an open field test. A dose of 0.04 mg/kg buprenorphine, a strong analgesic, was used to treat 10 lame pigs, while eight other lame pigs, treated with physiological saline solution, served as controls. Buprenorphine decreased lameness-associated asymmetry for pressure mat LR (P = 0.002), VI (P = 0.003) and PVP (P = 0.001) and increased activity of the lame pigs in the open field (P = 0.023), while saline-treated animals did not show any changes in asymmetry and became less active in the open field (P <0.001). It was concluded that measurement of gait asymmetry by pressure mat analysis and locomotor activity in an open field test are both sensitive enough to detect the analgesic effects of buprenorphine when used to treat moderate to severe clinical pain in a relatively small group of affected pigs. The methods used in this study may also provide promising additional tools for future research into early pain recognition and lameness treatment in pigs.

Clinical research in family medicine: quantity and quality of published articles. Publication of clinical research in peer-reviewed journals is an important measure of scholarly productivity. This study determined the quantity and quality of original clinical research published by family physicians. We surveyed clinical research papers published in the year 2000 in four leading family medicine research journals and research originating in a family practice institution but published in 16 non-family medicine journals. All were selected on the basis of relevance to family physicians and "impact factor." The relevance and validity of papers was assessed using previously established criteria. The survey of family medicine journals revealed a total of 170 original research articles. Ninety eight were from academic family practice programs, and the remaining 72 were from other medical specialties or health care institutions. Most of the papers were cross-sectional surveys. There were seven qualitative studies, six randomized controlled trials, and no systematic reviews from family practice programs in these journals. Eight of the articles were from practice-based research networks. A total of 79 articles were considered relevant or highly relevant, and 22 of these were also considered valid (Patient-oriented Evidence That Matters or POEMs). The survey of 16 non-family medicine journals revealed 37 clinical research papers: 16 surveys, nine prospective cohort studies, seven randomized controlled trials, three systematic reviews/meta-analysis, one qualitative study, and one case-control study. There were nine "highly relevant" papers--seven could be classified as POEMs. Most clinical family medicine research uses less-rigorous study designs, such as the cross-sectional survey. The majority of papers do not meet established criteria for relevance and validity. There are no standards or comparable studies to compare these results to prior years or to other disciplines.

Percutaneous transluminal angioplasty of a large septal artery. A severely stenotic, large-caliber, first septal artery was successfully dilated in a patient with refractory angina and nonsurgical, multivessel coronary artery disease. The success of this dilatation was related to favorable coronary anatomy and to the availability of a guidewire-directed dilatation catheter. Septal artery stenosis with or without surgically accessible stenoses in other coronary vessels represents a potential indication for percutaneous transluminal coronary angioplasty.

Ultrastructural characteristics and lysozyme content in hypergranular and variant type of acute promyelocytic leukaemia. We investigated the electronmicroscopic (EM) features and cellular lysozyme (LZ) content in 16 cases of acute promyelocytic leukaemia (APL): 11 cases of the hypergranular form (M3) and five cases of the microgranular variant (M3-V). The main EM features in all cases were: irregular, folded or bilobed nuclei, many cytoplasmic granules, distended rough endoplasmic reticulum (RER) cisternae which, in some cases, presented as stellate forms (more frequent in M3-V), and bundles of cytoplasmic microfilaments. Many Auer rods were present in M3 cases and few in M3-V; most of these disclosed parallel tubular arrays (PTA) with a varied periodicity ranging from 13 to 26 nm. There was a significant difference between M3 and M3-V (P<0.0001) in both the number of granules per cell section (62.9 +/- 34.5 v 38.0 +/- 23.6) and in the granule section area (0.044 +/- 0.033 v 0.026 +/- 0.015 microm2). In some cases, mainly in M3-V, we found cells with large granules containing PTA which probably represent poorly developed Auer rods. Intracellular LZ content assayed by a post-embedding immunogold method, showed high granular LZ density (in the range of that found in M4 and M5) in M3 cells and very low granular LZ content in M3-V. This study adds new objective parameters for the diagnosis of these two types of APL and provides new information on their LZ pattern of expression.

Fantastic beasts and how to find them-Molecular identification of the mitochondrial ATP-sensitive potassium channel. Despite reported sightings over many years, certain mitochondrial-specific channels have proven to be elusive beasts, evading molecular identification. However, combining modern genetics with a wave of their ion-sensing wand, researchers have managed to capture first the mitochondrial calcium uniporter, and now that semi-mythological beast, the mitochondrial ATP-sensitive potassium (mitoKATP) channel.

Climatic change and its ecological implications at a subantarctic island. Marion Island (47°S, 38°E) has one of the most oceanic climates on earth, with consistently low air temperatures, high precipitation, constantly high humidity, and low incident radiation. Since 1968 mean surface air temperature has increased significantly, by 0.025° C year-1. This was strongly associated with corresponding changes in sea surface temperature but only weakly, or not at all, with variations in radiation and precipitation. We suggest that changing sealevel (atmospheric and oceanic) circulation patterns in the region underlie all of these changes. Sub-Antarctic terrestrial ecosystems are characterized by being species-poor and having a simple trophic structure. Marion Island is no exception and a scenario is presented of the implications of climatic change for the structure and functioning of its ecosystem. Primary production on the island is high and consequently the vegetation has a large annual requirement for nutrients. There are no macroherbivores and even the insects play only a small role as herbivores, so most of the energy and nutrients incorporated in primary production go through a detritus, rather than grazing, cycle. Ameliorating temperatures and increasing CO2 levels are expected to increase productivity and nutrient demand even further. However, most of the plant communities occur on soils which have especially low available levels of nutrients and nutrient mineralization from organic reserves is the main bottleneck in nutrient cycling and primary production. Increasing temperatures will not significantly enhance microbially-mediated mineralization rates since soil microbiological processes on the island are strongly limited by waterlogging, rather than by temperature. The island supports large numbers of soil macro-arthropods, which are responsible for most of the nutrient release from peat and litter. The activities of these animals are strongly temperature dependent and increasing temperature will result in enhanced nutrient availability, allowing the potential for increased primary production due to elevated temperature and CO2 levels to be realized. However, housemice occur on the island and have an important influence on the ecosystem, mainly by feeding on soil invertebrates. The mouse population is strongly temperature-limited and appears to be increasing, possibly as a result of ameliorating temperatures. We suggest that an increasing mouse population, through enhanced predation pressure on soil invertebrates, will decrease overall rates of nutrient cycling and cause imbalances between primary production and decomposition. This, along with more direct effects of mice (e.g. granivory) has important implications for vegetation succession and ecosystem structure and functioning on the island. Some of these are already apparent from comparisons with nearby Prince Edward Island where mice do not occur. Other implications of climatic change for the island are presented which emphasize the very marked influences that invasive organisms have on ecosystem structure and functioning. We suggest that changing sealevel circulation patterns, by allowing opportunities for colonization by new biota, may have an even more important influence on terrestrial sub-Antarctic ecosystems than is suggested merely on the basis of associated changes in temperature or precipitation.

A fatal case of transfusion-transmitted babesiosis in the State of Delaware. Most cases of human babesiosis in North America are caused by Babesia microti, which is endemic in the northeastern and upper midwestern United States. Although the disease is usually transmitted by a tick bite, there has been an increase in the number of transfusion-transmitted cases reported. We describe a fatal case of transfusion-transmitted babesiosis in a nonendemic state, Delaware. The patient was a 43-year-old Caucasian woman with history of transfusion-dependent Diamond-Blackfan syndrome, hepatitis C, and splenectomy. She was admitted initially for presumptive pneumonia. The next day, a routine examination of the peripheral blood smears revealed numerous intraerythrocytic ring forms, consistent with Babesia. The parasitemia was approximately 5% to 6%. The diagnosis was confirmed by positive polymerase chain reaction (PCR) for B. microti DNA and high titer of antibody to B. microti (1:2048). Despite aggressive therapy including clindamycin and quinine antibiotics, the patient expired 3 days after admission. Subsequently, 13 blood donors were tested for B. microti. All tested donors were negative by PCR. However, one donor living in New Jersey had a significant elevated B. microti antibody titer (1:1024). We believe that this is the first reported case of transfusion-transmitted babesiosis in Delaware, a nonendemic state. Our case illustrates that clinicians should consider babesiosis in the differential diagnosis of immunocompromised patients who have fever and recent transfusion history, even in areas where babesiosis is not endemic. It also demonstrates the need for better preventive strategies including more sensitive, specific, and rapid blood donor screening tests to prevent transfusion-transmitted babesiosis.

Eosinophil cationic protein as a serological marker of disease activity in childhood bronchial asthma. To study the value of eosinophil cationic protein (ECP) as a serological marker of disease activity in childhood bronchial asthma, ECP levels were measured in 20 healthy control children and 25 asthmatic children, during and 2 weeks after acute exacerbation. The mean serum ECP level of all asthmatic patients, during and after exacerbation, was significantly higher than the control group and was significantly higher during attacks than 2 weeks after their termination. ECP levels were highest in severe attacks, but did not differ between mild and moderate attacks. ECP levels in asthmatic patients 2 weeks after mild and moderate attacks were comparable to normal; after severe attacks levels remained higher than normal. Measurement of serum ECP will be helpful in determining asthma activity and deciding the use of anti-asthma drugs.

MR imaging and MR spectroscopy in prostate cancer management. Currently, endorectal coil MR imaging has the ability to improve accuracy in staging of localized prostate cancer. The addition of MR spectroscopic imaging has further improved the sensitivity of MR imaging for intraprostatic tumor localization. Additional refinements and techniques are expected to further improve the performance of MR imaging for prostate cancer imaging and to aid in patient management. Further studies are required to identify the ideal role for MR imaging in the diagnosis and management of prostate cancer.

A Nanobionic Light-Emitting Plant. The engineering of living plants for visible light emission and sustainable illumination is compelling because plants possess independent energy generation and storage mechanisms and autonomous self-repair. Herein, we demonstrate a plant nanobionic approach that enables exceptional luminosity and lifetime utilizing four chemically interacting nanoparticles, including firefly luciferase conjugated silica (SNP-Luc), d-luciferin releasing poly(lactic-co-glycolic acid) (PLGA-LH2), coenzyme A functionalized chitosan (CS-CoA) and semiconductor nanocrystal phosphors for longer wavelength modulation. An in vitro kinetic model incorporating the release rates of the nanoparticles is developed to maximize the chemiluminescent lifetimes to exceed 21.5 h. In watercress (Nasturtium officinale) and other species, the nanoparticles circumvent limitations such as luciferin toxicity above 400 μM and colocalization of enzymatic reactions near high adenosine triphosphate (ATP) production. Pressurized bath infusion of nanoparticles (PBIN) is introduced to deliver a mixture of nanoparticles to the entire living plant, well described using a nanofluidic mathematical model. We rationally design nanoparticle size and charge to control localization within distinct tissues compartments with 10 nm nanoparticles localizing within the leaf mesophyll and stomata guard cells, and those larger than 100 nm segregated in the leaf mesophyll. The results are mature watercress plants that emit greater than 1.44 × 1012 photons/sec or 50% of 1 μW commercial luminescent diodes and modulate "off" and "on" states by chemical addition of dehydroluciferin and coenzyme A, respectively. We show that CdSe nanocrystals can shift the chemiluminescent emission to 760 nm enabling near-infrared (nIR) signaling. These results advance the viability of nanobionic plants as self-powered photonics, direct and indirect light sources.

Safety of retigabine in adults with partial-onset seizures after long-term exposure: focus on unexpected ophthalmological and dermatological events. Retigabine is an antiepileptic drug developed for the adjunctive treatment of adults with epilepsy and partial-onset seizures (POS). Following its approval in 2011, reports of ophthalmological/dermatological pigmentation/discoloration led to a restriction of the indication in 2013, and in 2017, retigabine was voluntarily withdrawn from the market because of its limited usage. Here, data are reported from four open-label extension studies focusing on long-term safety with particular emphasis on ophthalmological and dermatological events. Studies 113413 (NCT01336621), 114873 (NCT01777139), 115097 (NCT00310388), and 115098 (NCT00310375) were multicenter, open-label extension studies of retigabine (300-1200 mg/day) for the adjunctive treatment of adults with POS. Safety assessments included monitoring treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). When new safety issues were identified, protocols were amended to include additional on-treatment safety evaluations, including ophthalmological and dermatological examinations. Patients who had abnormal retinal pigmentation, unexplained vision change, pigmentation of nonretinal ocular tissue, or abnormal discoloration of skin, lips, nails, and/or mucosa at the end of the treatment phase were asked to enter a safety follow-up continuation phase comprising 6-monthly ophthalmological/dermatological assessments. The safety population (patients receiving ≥1 dose of retigabine in the open-label phase) comprised 98, 30, 376, and 181 patients for studies 113413, 114873, 115097, and 115098, respectively. Mean (standard deviation) treatment exposure ranged from 529 (424) to 1129 (999) days. In total, 68%-96% and 4%-27% of patients across the studies experienced TEAEs and TE SAEs, respectively. There were seven on-treatment deaths and two after discontinuation. Overall, 14%-73% of patients had an on-treatment eye examination, of whom 8/53, 4/22, 17/54, and 14/36 had abnormal retinal pigmentation and 15/53, 7/22, 15/54, and 11/36 had nonretinal ocular pigmentation in studies 113413, 114873, 115097, and 115098, respectively. Four patients had confirmed acquired vitelliform maculopathy. In patients with unresolved events at discontinuation and ≥1 posttreatment follow-up, retinal pigmentation resolved completely in 1/3, 0/3, 0/10, and 1/7 patients and nonretinal ocular pigmentation in 1/4, 0/3, 8/10, and 4/6 patients, respectively. Overall, 12%-83% of patients had an on-treatment dermatological examination, of whom 11/58, 0/25, 23/46, and 23/37 had any-tissue discoloration, respectively. In patients with unresolved events at discontinuation and ≥1 posttreatment follow-up, discoloration of skin, lips, nails, and/or mucosa resolved completely in 2/3, 0/0, 7/13, and 1/11 patients, respectively. The safety profile of retigabine in adults with POS across four open-label studies was generally consistent with data from previous placebo-controlled studies. Discoloration of various tissues occurred in a proportion of patients treated with retigabine and resolved completely in a small number of these patients following treatment discontinuation. In addition, comprehensive eye examination identified a new adverse reaction of acquired vitelliform maculopathy in a limited number of patients.

Effects of oral zinc supplementation on serum leptin levels in Ache males of eastern Paraguay. Significant population variation has been demonstrated in serum leptin levels, independent of adiposity. Included within these populations, Ache males have significantly lower leptin levels compared to American subjects with comparable adiposity. The underlying causes of these differences are not understood but zinc has been shown to be an important regulator of leptin in humans and rodents. Zinc deficiency is associated with somatic wasting and significant declines in circulating leptin levels. Zinc deficiency is common in underdeveloped regions and may therefore contribute to low leptin levels among Ache men. To ascertain the potential role of zinc on Ache male leptin profiles, zinc supplementation was conducted to observe leptin responsiveness. Ache males were given daily oral zinc supplementation (50mg zinc gluconate) (n = 8) or placebo (n = 6) for 10 days. Serum leptin levels were measured on the first and last days of the treatment/placebo period. Despite supplementation exceeding triple the USDA recommended daily requirements, serum leptin levels did not change in the zinc-supplemented group (P = 0.61) and were not significantly different from males receiving placebo (P = 0.72). It is concluded that zinc is not likely to be a contributing factor in male Ache leptin profiles and that other sources of variation such as chronic energetic stresses affecting leptin production and perhaps receptor number or sensitivity should be considered.

Brain cytokine synthesis induced by an intraparenchymal injection of LPS is reduced in MCP-1-deficient mice prior to leucocyte recruitment. We have previously shown that ischaemic lesions are smaller in monocyte chemoattractant protein-1-deficient (MCP-1(-/-)) mice than in wild-type (wt) controls. In addition to its role as a monocyte chemoattractant, monocyte chemoattractant protein-1 (MCP-1) has been proposed to contribute to lesion progression after focal ischaemia by driving local cytokine synthesis by resident glia. To investigate this hypothesis we injected lipopolysaccharide (LPS) into the brain parenchyma of MCP-1(-/-) mice and compared the resulting inflammatory response and production of proinflammatory cytokines to those in wt mice. Microglial and astrocyte morphological activation was the same in the two strains, but MCP-1(-/-) mice showed significantly lower levels of proinflammatory cytokine synthesis; interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha) levels were up to 50% lower than in wt controls after 6 h. This reduced synthesis of proinflammatory cytokines occurred well before leucocyte recruitment to the central nervous system (CNS) is observed in this model of acute inflammation and thus cannot be attributed to lower numbers of recruited monocytes at the site of injury. We propose that MCP-1 contributes to acute CNS inflammation by pleiotropic mechanisms. In addition to being a potent chemoattractant for monocytes, we provide evidence here that MCP-1 can modify the responsiveness of CNS glia to acute inflammatory stimuli prior to leucocyte recruitment, thereby acting as a priming stimulus for cytokine synthesis in cells such as microglia.

The role of IFN in the development of NAFLD and NASH. Non-alcoholic fatty liver disease (NAFLD) and its progressive inflammatory form non-alcoholic steatohepatitis (NASH) are major health challenges due to a significant increase in their incidence and prevalence. While NAFLD is largely benign, the chronic liver inflammation in NASH patients may cause progression to liver cirrhosis and hepatocellular carcinoma. There is an urgent need for a better understanding of the factors, which drive the progression from NAFLD to NASH and how to use this information both to improve diagnostic and to develop new treatment strategies. Increasing evidence points to interferons (IFNs) as key players in NAFLD and particular in the progression to NASH. IFNs crucial role in disease development is supported by both genetic evidence and animal studies. In this review, we describe the involvement of both type I and type III IFNs in the development and progression of NAFLD and NASH.

Clinical comparison of monophasic oral contraceptive preparations of gestodene/ethinyl estradiol and desogestrel/ethinyl estradiol. Latin American Oral Contraceptive Study Group. The efficacy, cycle control, subjective complaints, and safety of monophasic preparations of the oral contraceptives containing gestodene 75 mcg plus ethinyl estradiol 30 mcg versus desogestrel 150 mcg plus ethinyl estradiol 30 mcg were compared in a 6-cycle, open-label, parallel, randomized, multicenter phase IV clinical study in Latin America. Of a total of 176 women in each group, 163 in the gestodene group and 160 in the desogestrel group completed 6 cycles, providing data for 1,015 and 1,006 cycles, respectively. Subject compliance was excellent; pills were missed during only 6.9% of the cycles in each group. No woman became pregnant during the study. Gestodene group exhibited significantly better cycle control as evidenced by the lower incidence of breakthrough bleeding and spotting. Spotting in some cycles was reported by 11.9% of women taking the gestodene-combination compared with 21% of women taking the desogestrel-combination. Based on number of women, 86.4% of the gestodene group reported all cycles were normal (no BTB) compared with 76.7% of the desogestrel group. Also, the women in the gestodene group reported a significantly lower incidence of nuisance side effects during treatment cycles. No amenorrhea was observed for either group. There were no clinically significant differences between groups with respect to body weight, blood pressure, or laboratory evaluations. Seven women withdrew from the gestodene group and 8 women withdrew from the desogestrel group because of adverse reactions. The results of this study indicate that, although both OCs provided effective contraception, in comparison to the desogestrel-combination, the gestodene-containing OC is associated with better cycle control, less bleeding, and fewer subjective complaints.

Crystal Structure of Cleaved Serp-1, a Myxomavirus-Derived Immune Modulating Serpin: Structural Design of Serpin Reactive Center Loop Peptides with Improved Therapeutic Function. The Myxomavirus-derived protein Serp-1 has potent anti-inflammatory activity in models of vasculitis, lupus, viral sepsis, and transplant. Serp-1 has also been tested successfully in a Phase IIa clinical trial in unstable angina, representing a "first-in-class" therapeutic. Recently, peptides derived from the reactive center loop (RCL) have been developed as stand-alone therapeutics for reducing vasculitis and improving survival in MHV68-infected mice. However, both Serp-1 and the RCL peptides lose activity in MHV68-infected mice after antibiotic suppression of intestinal microbiota. Here, we utilize a structure-guided approach to design and test a series of next-generation RCL peptides with improved therapeutic potential that is not reduced when the peptides are combined with antibiotic treatments. The crystal structure of cleaved Serp-1 was determined to 2.5 Å resolution and reveals a classical serpin structure with potential for serpin-derived RCL peptides to bind and inhibit mammalian serpins, plasminogen activator inhibitor 1 (PAI-1), anti-thrombin III (ATIII), and α-1 antitrypsin (A1AT), and target proteases. Using in silico modeling of the Serp-1 RCL peptide, S-7, we designed several modified RCL peptides that were predicted to have stronger interactions with human serpins because of the larger number of stabilizing hydrogen bonds. Two of these peptides (MPS7-8 and -9) displayed extended activity, improving survival where activity was previously lost in antibiotic-treated MHV68-infected mice (P < 0.0001). Mass spectrometry and kinetic assays suggest interaction of the peptides with ATIII, A1AT, and target proteases in mouse and human plasma. In summary, we present the next step toward the development of a promising new class of anti-inflammatory serpin-based therapeutics.

Study on the kinetics of keto-enol tautomerism of p-hydroxyphenylpyruvic acid using capillary electrophoresis. The kinetics of keto-enol tautomerism of p-hydroxyphenylpyruvic acid (pHPP) as a model of alpha-carbonyl compounds in aqueous solution at room temperature (25 degrees C) was first investigated by capillary electrophoresis with UV detection at 200 nm. The two tautomers could be separated and detected within 3 min. Since the ketonization of enolic pHPP varied with the buffer composition and buffer pH, the kinetics of pHPP was studied under different conditions, and relevant distributing fractions of enolic pHPP, ketonization rate constants and half-life were determined. In addition, beta-CD played an important part in the separation of the two tautomers, thus, the interaction between pHPP and beta-CD was also investigated by electrochemical techniques.

Assessment of hemodynamic disturbances in aphasic patients by transcranial Doppler ultrasonography. The author presents a study of Doppler cerebrovascular ultrasonography carried out in 38 aphasie patients (forms ranging from transient speech disturbances to severe, persistent disturbances of motor, sensory or mixed aphasia) after ischemic or hemorrhagic stroke. In these cases, the clinical symptoms were dominated by speech impairment and neurological deficits (mainly pyramidal), of low intensity or transient. The angiographic study revealed stenotic or occlusive disturbances at various levels of the cerebral arterial trunks. The prevalence of some clinical aspects of aphasia correlated with Doppler velocimetric images is discussed and the use of transcranial Doppler method in idiopathic aphasia, possible consequence of a transient ischemic attack, is suggested.

Development and full validation of a liquid chromatography-tandem mass spectrometry method for determination of carbinoxamine in beagle plasma and its application to a pharmacokinetic study. Carbinoxamine maleate is an antihistamine drug with mild sedation effects, which is used to treat seasonal and perennial allergic rhinitis clinically. In order to optimize drug therapy, reduce drug accumulation, lessen the frequency of adverse effects and facilitate clinical research, a high performance liquid chromatography tandem mass spectrometry assay was firstly established and fully validated for the quantitative admeasurements of carbinoxamine. After extraction with ethyl acetate, the chromatographic separation was implemented on a C18 column (Hypersil GOLD, 100 mm × 2.1 mm, 3.0 μm) using gradient elution with water (containing 0.1% formic acid) and methanol at the flow rate of 0.4 mL/min. The analytes were measured under multiple reactions monitoring (MRM) mode with m/z 291.2 → 202.1 for carbinoxamine and m/z 285.0 → 193.2 for diazepam (IS) using electrospray ionization source (ESI) in the positive ion mode. A satisfactory linearity was obtained over the wide extent of 0.1-100.0 ng/mL (r > 0.99). Inter- and intra-day precision and accuracy of the assay were favorably accorded with the currently recognized limits (< 8.9%). The mean extraction recoveries for carbinoxamine ranged from 74.00% to 86.4%. The pharmacokinetic characteristics of carbinoxamine were subsequently evaluated in beagles. Following intragastric administration (0.534 mL/kg), carbinoxamine possessed a large apparent volume of distribution of the central compartment (Vc = 1005.7 ± 945.9 L/kg), oral clearance (Cl = 112.446 ± 53.249 L/h/kg), and a relatively long absorption time (Tmax = 2.38 ± 1.00 h). This analytical method with adequate sensitivity was applicable to pharmacokinetic study and could monitor concentrations of carbinoxamine in beagle plasma. Moreover, the methodology could be used for further bioequivalence determination and addressing metabolism associated with the drug.

Planar Procrustes analysis of tooth shape. Accurate quantification of variation in tooth shape is important in studies of dental development, which typically have involved measuring distances between subjectively identified landmarks, key points of correspondence on teeth. An established statistical framework now exists for the analysis of shape when objects are represented as configurations of landmark coordinates; allowing work with the full geometry of objects, which is otherwise lost. This approach was introduced here to the study of tooth morphology, demonstrating how after optimally matching shapes to account for the unwanted effects of location, scale and rotation, most standard descriptive and inferential statistical techniques can be adapted and applied successfully. The techniques are illustrated using a sample of buccal-surface images of central incisors from patients with hypodontia; a significant difference is found in mean buccal-surface shape (Hotelling's two-sample T(2)-test; P=0.004) when compared to a corresponding control group. Successful implementation of these methods depends on the accuracy and reliability with which the landmarks are collected; issues and problems to be addressed are discussed.

Ranitidine vs metoclopramide in the medical treatment of reflux esophagitis. 45 patients with symptomatic reflux esophagitis were randomly treated with either Ranitidine (150 mg b.i.d.) or Metoclopramide (10 mg t.i.d.) for six weeks. The severity of dyspeptic symptoms and the grade of endoscopic and histological esophagitis were assessed before and after treatment. Both drugs proved significantly effective in inducing symptomatic and endoscopic improvement, but Ranitidine appeared significantly superior in promoting disappearance or improvement of endoscopic esophagitis. Moreover Ranitidine was found to significantly reduce the severity of histological changes, whereas Metoclopramide was unable to do so.

Part III. Molecular changes induced by high nitric oxide adaptation in human breast cancer cell line BT-20 (BT-20-HNO): a switch from aerobic to anaerobic metabolism. Nutrient deprivation and reactive oxygen species (ROS) play an important role in breast cancer mitochondrial adaptation. Adaptations to these conditions allow cells to survive in the stressful microenvironment of the tumor bed. This study is directed at defining the consequences of High Nitric Oxide (HNO) exposure to mitochondria in human breast cancer cells. The breast cancer cell line BT-20 (parent) was adapted to HNO as previously reported, resulting in the BT-20-HNO cell line. Both cell lines were analyzed by a variety of methods including MTT, LDH leakage assay, DNA sequencing, and Western blot analysis. The LDH assay and the gene chip data showed that BT-20-HNO was more prone to use the glycolytic pathway than the parent cell line. The BT-20-HNO cells were also more resistant to the apoptotic inducing agent salinomycin, which suggests that p53 may be mutated in these cells. Polymerase chain reaction (PCR) followed by DNA sequencing of the p53 gene showed that it was, in fact, mutated at the DNA-binding site (L194F). Western blot analysis showed that p53 was significantly upregulated in these cells. These results suggest that free radicals, such as nitric oxide (NO), pressure human breast tumor cells to acquire an aggressive phenotype and resistance to apoptosis. These data collectively provide a mechanism by which the dysregulation of ROS in the mitochondria of breast cancer cells can result in DNA damage.

Directing visual attention with spatially informative and spatially noninformative tactile cues. We investigated the tactile cuing of visual spatial attention using spatially-informative (75% valid) and spatially-noninformative (25% valid) tactile cues. The participants performed a visual change detection task following the presentation of a tactile spatial cue on their back whose location corresponded to one of the four visual quadrants on a computer monitor. The participants were explicitly instructed to use the spatially-informative tactile cues but to ignore the spatially-noninformative cues. In addition to reaction time data, participants' eye-gaze was monitored as a measure of overt visual attention. The results showed that the spatially-informative tactile cues resulted in initial saccades toward the cued visual quadrants, and significantly reduced the visual change detection latencies. When spatially-noninformative tactile cues were used, the participants were largely successful at ignoring them as indicated by a saccade distribution that was independent of the quadrant that was cued, as well as the lack of a significant change in search time as compared to the baseline measure of no tactile cuing. The eye-gaze data revealed that the participants could not always completely ignore the spatially-noninformative tactile cues. Our results suggest that the tactile cuing of visual attention is natural but not automatic when the tactile cue and visual target are not collocated spatially, and that it takes effort to ignore the cues even when they are known to provide no useful information. In addition, our results confirm previous findings that spatially-informative tactile cues are especially effective at directing overt visual attention to locations that are not typically monitored visually, such as the bottom of a computer screen or the rearview mirror in an automobile.

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Adult exposure to diethylstilbestrol induces spermatogenic cell apoptosis in vivo through increased oxidative stress in male hamster. Effects of diethylstilbestrol (DES), an endocrine disrupting chemical, on abnormal spermatogenesis were studied in adult hamster using daily subcutaneous injection of 0.01, 0.1 and 1.0mg/kg body weight for 1 week. Testicular weight and seminiferous tubular area gradually decreased as dosage increased to 1.0mg/kg DES. Germ cells were rarefied and showed irregular distribution in seminiferous tubules. Apoptosis was pronounced among spermatocytes and spermatids at the 1.0mg/kg dose level. Antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and total antioxide capacity (T-AOC) markedly decreased and malondialdehyde (MDA) concentration significantly increased in the testes. These results suggest that DES (1.0mg/kg) induces testicular oxidative stress and spermatogenic apoptosis in adult male hamsters to extend findings shown for prenatal and/or neonatal exposure.

Pseudo-pseudohypoparathyroidism, empty sella syndrome, and hypopituitarism in a young woman. The confluence of pseudo-pseudohypoparathyroidism, empty sella syndrome, and pituitary insufficiency is reported for the first time. The patient, an 18-year-old woman, was evaluated because of primary amenorrhea. Possible relations between the three entities described are discussed and the appearance of pituitary hypofunction in patients with the empty sella syndrome is emphasized.

Biocompatibility and biomechanical characteristics of loofah based scaffolds combined with hydroxyapatite, cellulose, poly-l-lactic acid with chondrocyte-like cells. The current study reports the biocompatibility and biomechanical characteristics of loofah-based scaffolds combined with hydroxyapatite (HA), cellulose, poly-l-lactic acid (PLLA) with chondrocytes-like cells. Scanning electron microscope (SEM) micrographs of the scaffolds showed that the addition of PLLA usually resulted in an increase in cell's attachment on scaffolds. Mechanical and elemental analyzes were assessed using tensile test and Energy Dispersive X-ray spectrometry (EDS), respectively. In summary, we showed that the loofah+PLLA+HA scaffolds perform significantly better than other loofah-based scaffolds employed in terms of increasing a diversity of mechanical properties including tensile strength and Young's modulus. Based on the analysis of the differential scanning calorimetry (DSC) thermograms and EDS spectrums that give an idea about the calcium phosphate (CaP) ratios, the improvement in the mechanical properties could principally be recognized to the strong interaction formed between loofah, PLLA and HA. The viability of chondrocytes on loofah-based scaffolds was analyzed by XTT tests. However, none of the scaffolds have proved to be toxic in metabolic activity. The histological evaluation obtained by hematoxylin and eosin (H&E), Masson trichrome, toluidine blue and immunohistochemistry methods showed that cells in all scaffolds produced extracellular matrix that defined proteoglycan and type I-II collagens. The results of this study suggest that the loofah-based scaffold with desirable properties can be considered as an ideal candidate for cartilage tissue engineering applications.

Muscle strength in knee varus and valgus. The purpose of this study was to investigate the lower-limb muscle strength in knee varus-valgus and its dependence on knee varus-valgus position. The hypothesis was that humans could differentially contract the medial and lateral muscles crossing the knee and generate significant moments in knee valgus-varus. The subjects sat with the knee at full extension and secured from the medial, lateral, anterior, and posterior sides. Both hips were clamped from the lateral sides. The subjects adducted (abducted) the ipsilateral hip during the knee valgus (varus) maximal voluntary contraction with EMG signals recorded from muscles crossing the knee and knee joint moments measured using a six-axis force sensor. Frontal plane tibiofemoral movement was evaluated using a fluoroscope. The subjects differentially contracted the medial and lateral muscles, and fluoroscope images showed the corresponding tibiofemoral movement. The subjects showed considerable strength in knee varus and valgus. The active knee varus strength increased significantly with increasing knee valgus angle, and the valgus strength was significantly higher when the knee was in varus position (P < 0.039). Active valgus muscle strength at 5 degrees knee varus was significantly higher than the active varus strength at 5 degrees valgus (P = 0.002). The passive resistance moment increased linearly with increasing knee valgus and varus angles, and it accounted for 28% and 35% of the total (active plus passive) moment at the 5 degrees varus and 5 degrees valgus, respectively. The significant varus-valgus muscle strength demonstrated in this study may play important roles in performing various functional tasks, maintaining joint stability, and preventing potential injuries, whether the major load and motion at the knee is in the frontal plane or not.

Production of dairy goat embryos, by nuclear transfer, transgenic for human acid beta-glucosidase. Expression of recombinant human lysosomal acid beta-glucosidase (hGCase) by a transgenic animal bioreactor, using somatic cell nuclear transfer (SCNT), would decrease the cost of producing this product. The objective was to establish an effective procedure to prepare hGCase transgenic donor cells and nuclear transfer (NT) embryos to produce hGCase protein in the Saanen dairy goat mammary gland. A mammary-specific expression vector for hGCase was constructed and transfected into HC-11 mammary epithelial cells for bioactivity analysis in vitro; mRNA transcripts and hGCase protein were correctly expressed in transfected HC-11 cells. The hGCase gene was then introduced into fetal fibroblasts (from dairy goats) to prepare competent transgenic donor cells. Transgenic fibroblast clones from a single round of transfection were reliably isolated by 96-well cell culture plates and screened with PCR amplification and chromosomal counting (66.8%). Dairy goat cloned embryos were produced from these hGCase fetal cells by SCNT, the hGCase transgene was successfully detected in these embryos, and there were similar rates (P>0.05) of fusion (83.3% vs. 77.8%), cleavage (89.1% vs. 90.9%), and development to the morula/blastocyst stages (36.4% vs. 38.9%) between NT embryos using transgenic fetal fibroblasts and non-transfected control cells. Moreover, 98 well-developed reconstructed embryos derived from transgenic cells were transferred to 16 recipients; pregnancy was confirmed at 40 d in two goats. Therefore, we achieved functional expression of hGCase in mammary gland cells and normal development to Day 40 of cloned embryos carrying the hGCase gene.

Enterotoxin gene profile of methicillin-resistant Staphylococcus pseudintermedius isolates from dogs, humans and the environment. This study aimed to detect and identify staphylococcal enterotoxin (SE) genes in methicillin-resistant Staphylococcus pseudintermedius (MRSP) strains from different sources, and to investigate the relationship between their sequence types (STs) and SE gene patterns. The profiles of 17 SE genes in 93 MRSP strains isolated from dogs (n=43), humans (n=18) and the environment (n=32) were detected by PCR. Multilocus sequence typing (MLST), SCCmec typing and pulsed-field gel electrophoresis (PFGE) were used to analyse the clonal relatedness between the molecular type and SE gene profiles.Results/Key findings. The human MRSP strains harboured the greatest number of SE genes (12/17; sea, sec, seg, sei, sek, sel, sem, sen, seo, sep, seq and tst-1) compared to those from dogs (5/17; sec, sel, sem, seq and tst-1) and environmental sources (3/17; sec, seq and tst-1). Using MLST and PFGE, different SE gene profiles were found within the same clonal type. We show that isolates of MRSP vary in their virulence gene profiles, depending on the source from which they have been isolated. This insight should encourage the development of appropriate monitoring and mitigation strategies to reduce the transmission of MRSP in veterinary hospitals and households.

Rearrangement of beta-amino alcohols via aziridiniums: a review. This tutorial review focuses on the rearrangement of beta-amino alcohols via aziridinium intermediates. It covers the literature from 1947 to January 2009 (55 references). The rearrangement of beta-amino alcohols can be performed by activation of the hydroxy group followed by the addition of nucleophiles (Nu). In most examples, an aziridinium intermediate is involved in the rearrangement. The ratio of amines resulting from the attack of nucleophiles at either the C-1 or C-2 position of the aziridinium intermediate, depends on the nature of the nucleophiles and the R(2) substituent. In some cases, solvent as well as temperature can influence the ratio of amines.

The effect of vigorous exercise during pregnancy on birth-weight. The aim of this study was to assess the effect on birth-weight of continuing a programme of vigorous exercise into late pregnancy. 'Potential exercisers' were women who had been doing vigorous exercise prior to pregnancy and intended to continue exercising during pregnancy. Controls were healthy pregnant women who did not do regular vigorous exercise. Both groups kept 2, 7-day food +/- exercise diaries at 25 and 35 weeks. The primary outcome variable was birth-weight. Women who continued doing at least 30 minutes of vigorous exercise at least 3 times weekly at 25 weeks and either maintained this minimum level or had delivered by 35 weeks were classified as 'exercisers'. Women doing more than 4 sessions of vigorous exercise weekly at 25 weeks had babies whose mean birth-weight was 315 g lower than the mean birth-weight of babies born to controls.

Differential accumulation of silymarin induced by exposure of Silybum marianum L. callus cultures to several spectres of monochromatic lights. Silybum marianum L. (Milk thistle) is one of the most extensively studied medicinal herbs with well-known hepatoprotective activity. Light is considered as a key abiotic elicitor influencing several physiological processes in plants, including the biosynthesis of secondary metabolites. In this study, we investigated the influence of light quality on morphological and biochemical aspects in in vitro grown leaf-derived callus cultures of S. marianum. Combination of 6-benzylaminopurine (BAP 2.5 mg/L) and α-naphthalene acetic acid (NAA 1.0 mg/L) resulted in optimum callogenic response (97%) when placed under cool-white light with 16 h light and 8 h dark. Red light significantly increased the total phenolic content (TPC), total flavonoid content (TFC), antioxidant and superoxide dismutase (SOD) activities while highest peroxidase (POD) activity was recorded for the dark grown cultures, followed by green light grown cultures. HPLC analysis revealed enhanced total silymarin content under red light (18.67 mg/g DW), which was almost double than control (9.17 mg/g DW). Individually, the level of silychristin, isosilychristin, silydianin, silybin A and silybin B were found greatest under red light, whereas green spectrum resulted in highest accumulation of isosilybin A and isosilybin B. Conversely, the amount of taxifolin was found maximum under continuous white light (0.480 mg/g DW) which was almost 8-fold greater than control (0.063 mg/g DW). A positive correlation was found between the TPC, TFC and antioxidant activities. This study will assist in comprehending the influence of light quality on production of valuable secondary metabolites in in vitro cultures of S. marianum L.

A clinico-pathological study of canine Cushing's disease caused by a pituitary carcinoma. Knowledge of clinico-pathological correlations in canine Cushing's disease is rather poor. Therefore we describe, clinically and pathologically, a case of pituitary tumour-dependent Cushing's disease in an 8-year old female cocker spaniel. Based on our results, the tumour was defined as a non-dexamethasone-suppressive, corticotrophic adenocarcinoma characterized by some new findings such as intracerebral metastases of anti-ACTH-labelled tumour cells and combined alpha-, beta- and gamma 3-MSH immunoreactivity in the tumour.

Clinical experience using intrathecal (IT) bupivacaine infusion in three patients with complex regional pain syndrome type I (CRPS-I). To date, there is no reliable method for treating the severe pain and for modifying the natural evolution of CRPS-I. Therefore, we explored the effect of long-term IT bupivacaine infusion (with or without buprenorphine) on this syndrome. (a) two women and one man, 25, 31 and 42 years old, with CRPS-I of the lower (n=2) or upper (n=1) extremity lasting for 4 and 5 months, and 14 years. (b) insertion of externalized IT catheters; IT infusion of buprenorphine 0.015 mg/ml and bupivacaine 4.75 mg/ml (n=1), or only bupivacaine 5 mg/ml (n=2) from external electronic pumps. The IT treatment lasted for 172, 282 and 668 days. The mean/maximal daily doses of the IT bupivacaine were 39/66, 55/80 and 69/125 mg, respectively. The pain intensity decreased from VASmean =7+/-1 to VASmean =2+/-2. None of the patients had regression of allodynia, edema, and trophic disturbances in the affected extremities. In 2 patients, the IT treatment did not prevent spread of the disease to the opposite extremity or the occurrence of phantom pain and stump allodynia after amputation. The IT catheters were withdrawn as being no longer needed: in 2 patients 56 and 458 days after amputation of the involved extremity, and in another one before replacement of the IT bupivacaine infusion with epidural dorsal column stimulation (EDCS). After termination of the IT treatment, the patients were observed for 1437, 1575, and 2689 days (until September 1, 1998). At that date, all the patients were alive, and still affected by their CRPS-I, either in the amputation stump (n=2), and/or in the opposite or remote extremities (n=2); further, two were unemployed and one worked for 75% of the time. One of them was taking up to 1500 mg of slow-release morphine to cope with pain. The IT pain treatment with bupivacaine (with or without buprenorphine) alleviated the "refractory" pain, but affected neither the associated symptoms and signs of the CRPS-I, nor its natural evolution. Thus, the IT treatment cannot be recommended in preference to other pain treatment regimens for CRPS-I.

Cerebral oxidative metabolism failure in traumatic brain injury: "Brain shock". Shock is a systemic form of acute circulatory failure leading to cellular dysoxia and death. Such a state of aerobic metabolism failure also underlies neuronal cell death in severe traumatic brain injury. It is becoming increasingly recognized that ischemic hypoxia is not the sole mechanism and that multiple alternate cooperating mechanisms may be responsible for compromising neuronal oxidative metabolism. These different mechanisms can be usefully understood via analysis of the classic subdivisions of tissue hypoxia. This approach could lead to an alternative treatment paradigm toward cerebral oxygen metabolic rate targeting instead of the traditional targets of intracranial and perfusion pressures.

A systematic methodology to extend the applicability of a bioconversion model for the simulation of various co-digestion scenarios. Detailed simulation of anaerobic digestion (AD) requires complex mathematical models and the optimization of numerous model parameters. By performing a systematic methodology and identifying parameters with the highest impact on process variables in a well-established AD model, its applicability was extended to various co-digestion scenarios. More specifically, the application of the step-by-step methodology led to the estimation of a general and reduced set of parameters, for the simulation of scenarios where either manure or wastewater were co-digested with different organic substrates. Validation of the general parameter set involved the simulation of laboratory-scale data from three continuous co-digestion experiments, treating mixtures of different organic residues either at thermophilic or mesophilic conditions. Evaluation of the results showed that simulations using the general parameter set fitted experimental data quite well, indicating that it offers a reliable reference point for future simulations of anaerobic co-digestion scenarios.

Narrow band imaging is a new technique in visualization of recurrent respiratory papillomatosis. Recurrent respiratory papillomatosis (RRP) is a rare, benign, wart-like disease for which no curative treatment exists. The goal of treatment is total surgical removal of the epithelial lesions to keep the airway open and the voice sufficient. Therefore, it is essential to visualize all papillomatous lesions. The present study aims to evaluate the sensitivity of additional use of narrow band imaging (NBI) in detecting RRP during microlaryngoscopy. Prospective study. Between January 2011 and July 2011, patients with RRP underwent systematic inspection during microlaryngoscopy using conventional white light (WL) immediately followed by inspection with NBI. Consensus was achieved about the number of lesions and number of RRP suspect lesions. All lesions were subsequently excised and sent for histopathological examination. Eighty-six excisional biopsies were taken in 24 microlaryngoscopies performed in 14 RRP patients. Eleven out of the 13 additional biopsies taken, induced by the second inspection with NBI, proved to be papillomata after histopathological examination. The sensitivity increased from 80% with WL up to 97% with WL + NBI (P < .01), whereas the specificity remained poor (32% and 28%, respectively). NBI is an additional diagnostic tool in increasing the sensitivity of visualizing papillomata during microlaryngoscopy.

[5 years of experience in the treatment of parkinsonism with L-dopa and its combination with Ro4-4602]. Eighty-one Parkinsonic patients were treated with L-dopa alone and/or combined with Ro4-4602, during 27 to 60 months. The results are reported. 7.2% of the patients, who are still being treated, showed good, very good or excellent results. There was a relation between the duration of the illness and the degree of improvement, the most prolonged Parkinsonisms showed the least improvement. The 4:1 proportion of L-dopa and Ro4-4602 was more effective than the 3:2. Adding small amounts of L-dopa to the combinations improvement and secondary effects increased. No advantages were found using high combined dosages. The main secondary effects at the end of treatment were abnormal movements (45% of cases) and distonic attitudes (53%). Patients who stoped the medication showed less sustained improvement and a high degree of Parkinsonism. This reveals that Parkinson's disease continues to envolve in spite of the medication. The "long-term syndrome" includes the late decrease of effectiveness of the drugs and/or the increase of secondary effects.

Modeling ebola virus disease transmissions with reservoir in a complex virus life ecology. We propose a new deterministic mathematical model for the transmission dynamics of Ebola Virus Disease (EVD) in a complex Ebola virus life ecology. Our model captures as much as possible the features and patterns of the disease evolution as a three cycle transmission process in the two ways below. Firstly it involves the synergy between the epizootic phase (during which the disease circulates periodically amongst non-human primates populations and decimates them), the enzootic phase (during which the disease always remains in fruit bats population) and the epidemic phase (during which the EVD threatens and decimates human populations). Secondly it takes into account the well-known, the probable/suspected and the hypothetical transmission mechanisms (including direct and indirect routes of contamination) between and within the three different types of populations consisting of humans, animals and fruit bats. The reproduction number R0 for the full model with the environmental contamination is derived and the global asymptotic stability of the disease free equilibrium is established when R0andlt;1. It is conjectured that there exists a unique globally asymptotically stable endemic equilibrium for the full model when R0andgt;1. The role of a contaminated environment is assessed by comparing the human infected component for the sub-model without the environment with that of the full model. Similarly, the sub-model without animals on the one hand and the sub-model without bats on the other hand are studied. It is shown that bats influence more the dynamics of EVD than the animals. Global sensitivity analysis shows that the effective contact rate between humans and fruit bats and the mortality rate for bats are the most influential parameters on the latent and infected human individuals. Numerical simulations, apart from supporting the theoretical results and the existence of a unique globally asymptotically stable endemic equilibrium for the full model, suggest further that: (1) fruit bats are more important in the transmission processes and the endemicity level of EVD than animals. This is in line with biological findings which identified bats as reservoir of Ebola viruses; (2) the indirect environmental contamination is detrimental to human beings, while it is almost insignificant for the transmission in bats.

Bond strength of fiber posts after the application of erbium:yttrium-aluminum-garnet laser treatment and gaseous ozone to the root canal. The aim of the present study was to investigate the effects of antibacterial agents (erbium:yttrium-aluminum-garnet [Er:YAG] laser or gaseous ozone) intended to disinfect root canals on bond strengths of fiber posts compared with canals that were finally irrigated using chlorhexidine (CHX). One hundred forty-four human anterior teeth were divided into three groups (n = 48); root canal instrumentation was performed, and antimicrobial pretreatment was conducted as follows: control group: CHX, group 2: Er:YAG laser, and group 3: gaseous ozone. In all groups, fiber posts were inserted using Panavia F 2.0 (Kuraray, Osaka, Japan), Variolink II (Ivoclar Vivadent, Schaan, Liechtenstein), RelyX Unicem (3M Espe; Seefeld, Germany), or Ketac Cem (3M Espe) (n = 12 each). Push-out bond strengths to root canal dentin were affected by the type of luting agent but not by the antimicrobial pretreatment regimen. However, significant interactions between the luting agent and pretreatment could be observed, and adhesion of the self-adhesive resin cement RelyX Unicem was significantly reduced after using gaseous ozone.

Shear adhesion strength of thermoplastic gecko-inspired synthetic adhesive exceeds material limits. Natural gecko array wearless dynamic friction has recently been reported for 30,000 cycles on a smooth substrate. Following these findings, stiff polymer gecko-inspired synthetic adhesives have been proposed for high-cycle applications such as robot feet. Here we examine the behavior of high-density polyethylene (HDPE) and polypropylene (PP) microfiber arrays during repeated cycles of engagement on a glass surface, with a normal preload of less than 40 kPa. We find that fiber arrays maintained 54% of the original shear stress of 300 kPa after 10,000 cycles, despite showing a marked plastic deformation of fiber tips. This deformation could be due to shear-induced plastic creep of the fiber tips from high adhesion forces, adhesive wear, or thermal effects. We hypothesize that a fundamental material limit has been reached for these fiber arrays and that future gecko synthetic adhesive designs must take into account the high adhesive forces generated to avoid damage. Although the synthetic material and natural gecko arrays have a similar elastic modulus, the synthetic material does not show the same wear-free dynamic friction as the gecko.

Magnetic resonance techniques in musculoskeletal diseases. Magnetic resonance imaging provides a sensitive technique for detection of musculoskeletal pathology. In order to optimize this information and properly characterize lesions, it is important to select carefully image parameters. Patient selection criteria are also important due to the strength of magnetic fields used for magnetic resonance imaging. These factors must be clearly understood when determining if magnetic resonance imaging is the most appropriate examination for a given musculoskeletal problem.

Cardiopulmonary limitations to exercise in restrictive lung disease. Cardiopulmonary limitations to exercise in restrictive lung disease. Med. Sci. Sports Exerc., Vol. 31, No. 1 (Suppl.), pp. S28-S32, 1999. Restrictive lung disease encompasses a large and diverse group of disorders characterized by a diminished lung volume. These disorders exhibit common pathophysiologic features including abnormal gas exchange caused by loss of functioning alveolar-capillary unit, abnormal respiratory muscle energetics caused by altered mechanical ventilatory function, and secondary hemodynamic and cardiac dysfunction. Impaired gas exchange is the most prominent exercise abnormality in interstitial lung disease and eventually develops in other causes of lung restriction as well. Measurements of diffusing capacity (DLCO) and alveolar-arterial oxygen tension gradient during exercise are more sensitive detectors of disease than measurements at rest. Excessive dead space ventilation is common in pulmonary parenchymal, pleural, and thoracic diseases, leading to a higher minute ventilation and ventilatory work during exercise. The associated increase in the metabolic energy requirement of respiratory muscles may exceed 50% of available total body oxygen delivery and result in insufficient energy delivery to nonrespiratory muscles that sustain locomotion. Pulmonary arterial hypertension develops secondarily to an increased pulmonary vascular resistance. In addition, diastolic filling of the ventricles during exercise may be restricted by pulmonary fibrosis or anatomical restriction of the pleura and thorax, contributing to secondary cardiac dysfunction. Examples of heart-lung interaction are illustrated by the patient after unilateral pneumonectomy. These pathophysiologic changes help explain why functional disability in these patients is often out proportion to the impairment in lung function.

Skull Base Chondrosarcoma Caused by Ollier Disease: A Case Report and Literature Review. Ollier disease (OD) is a rare, nonhereditary bone disease that is characterized by the presence of multiple enchondromatosis (3 or more) with a typical asymmetric distribution which is mainly confined to the appendicular skeleton. OD's most serious complication is the transformation of an enchondroma into chondrosarcoma. The most common sites for chondrosarcoma are in the pelvic and shoulder bones, the superior metaphyseal and diaphyseal regions of the extremities. However, the cranium is an extremely rare site for chondrosarcoma because of OD. We report the case of a 27-year-old woman who was admitted to our hospital with paroxysmal headaches over 1 month and left ptosis for 2 weeks. Magnetic resonance imaging (MRI) scan revealed a mass was located at the left side of the parasellar area. The mass was surgically removed, and histopathologic examination confirmed chondrosarcoma grade I. During follow-up, more imaging examinations and pathologic examination confirmed the final diagnosis was OD. Intracranial chondrosarcoma caused by OD is extremely rare but should be considered in the differential diagnosis when primary chondrosarcoma is diagnosed. Preoperative diagnosis is challenging, and definitive diagnosis requires immunohistochemical examination and systematic examination of the body. Surgical resection is the most effective therapy for rapid relief of symptoms. For patients with OD with normal intracranial MRI, long-term follow-up is necessary.

Calf muscle work and segment energy changes in human treadmill walking. The relation between changes in potential and kinetic energy in a seven-segment model of the human body and the work of m. triceps surae was investigated in four subjects walking on a treadmill at speeds between 0.5 and 2.0 m/s. Segment energy levels were determined by means of tachometers attached with strings to various points on the subject's body. Muscle work was assessed by electromyogram to force processing. M. triceps surae is active during stance, first doing negative (eccentric) work and ending with a short period of positive (concentric) work at "push-off". It turned out that in normal walking these muscles provide the major part of positive work for the initiation of swing at push-off. Only at large step lengths, when push-off starts well before contralateral heel contact, is there a minor pushing forward of the trunk. In the negative work phase, m. triceps surae seem to check the forward speed of the trunk. A related decrease of trunk kinetic energy is not present, however, but this may be obscured by the simultaneous action of m. quadriceps femoris and, in a later stage, by a transfer of energy from the decelerating contralateral (swing) leg to the trunk. Energy of the trunk segment shows a sharp decline in double stance and a more gradual increase in the first half of single stance. Evidence is given that this effect is due to quadriceps action in the knee flexion-extension movement during stance. The presented results are incorporated in a general picture of energy flows in human walking.

Twenty-year outcome of cutaneous vesicostomy. Forty cutaneous vesicostomy urinary diversions were done at our hospital from 1958 to 1961. Of these cases 30 patients have been followed every 6 months or until death. The vesicostomy-related failure rate was 8.6 per cent, with new stones forming in 3 additional kidneys. Cutaneous vesicostomy provides long-term preservation of renal function in patients requiring urinary diversion. However, close followup is mandatory to ensure a good result.

Enhanced expression of potassium-chloride cotransporter KCC2 in human temporal lobe epilepsy. Synaptic reorganization in the epileptic hippocampus involves altered excitatory and inhibitory transmission besides the rearrangement of dendritic spines, resulting in altered excitability, ion homeostasis, and cell swelling. The potassium-chloride cotransporter-2 (KCC2) is the main chloride extruder in neurons and hence will play a prominent role in determining the polarity of GABAA receptor-mediated chloride currents. In addition, KCC2 also interacts with the actin cytoskeleton which is critical for dendritic spine morphogenesis, and for the maintenance of glutamatergic synapses and cell volume. Using immunocytochemistry, we examined the cellular and subcellular levels of KCC2 in surgically removed hippocampi of temporal lobe epilepsy (TLE) patients and compared them to control human tissue. We also studied the distribution of KCC2 in a pilocarpine mouse model of epilepsy. An overall increase in KCC2-expression was found in epilepsy and confirmed by Western blots. The cellular and subcellular distributions in control mouse and human samples were largely similar; moreover, changes affecting KCC2-expression were also alike in chronic epileptic human and mouse hippocampi. At the subcellular level, we determined the neuronal elements exhibiting enhanced KCC2 expression. In epileptic tissue, staining became more intense in the immunopositive elements detected in control tissue, and profiles with subthreshold expression of KCC2 in control samples became labelled. Positive interneuron somata and dendrites were more numerous in epileptic hippocampi, despite severe interneuron loss. Whether the elevation of KCC2-expression is ultimately a pro- or anticonvulsive change, or both-behaving differently during ictal and interictal states in a context-dependent manner-remains to be established.

Regulation of interferon-gamma-activated STAT1 by the ubiquitin-proteasome pathway. STAT proteins (signal transducers and activators of transcription) are latent cytoplasmic transcription factors that are phosphorylated by Janus kinases in response to cytokines. Phosphorylated STAT proteins translocate to the nucleus, where they transiently turn on specific sets of cytokine-inducible genes. The mechanism that controls the amounts of activated STAT proteins is not understood. STAT1 proteins activated by interferon-gamma treatment in HeLa cells were shown to be stabilized by a proteasome inhibitor and ubiquitinated in vivo. Thus, the amount of activated STAT1 may be negatively regulated by the ubiquitin-proteasome pathway.

Development of a Tumor-Responsive Nanopolyplex Targeting Pancreatic Cancer Cells and Stroma. Desmoplasia plays a pivotal role in promoting pancreatic cancer progression and is associated with poor clinical outcome. Targeting the desmoplastic tumor microenvironment in combination with chemotherapy is therefore a promising strategy for pancreatic cancer therapy. Here, we report a novel biodegradable copolymer to codeliver LY2109761 (a TGF-β receptor I/II inhibitor) and CPI-613 (a novel chemotherapy agent) to desmoplastic stroma and tumor cells, respectively, in the tumor microenvironment. Hydrophobic CPI-613 is conjugated to the hydrophilic copolymer via a newly designed MMP-2-responsive linker to form a trigger-responsive nanopolyplex. LY2109761 is hydrophobic and encapsulated into the hydrophobic core of the nanopolyplex. The resulting nanopolyplex is modified with a plectin-1-targeting peptide to enhance the accumulation of the nanopolyplex in pancreatic tumors. The nanopolyplex aims to normalize the stroma by blocking the interaction between tumor cells and pancreatic stellate cells to inhibit the activation of pancreatic stellate cells and subsequently reduce the dense extracellular matrix. Normalized stroma increases the penetration of the nanopolyplex into the tumor. The nanopolyplex shows enhanced accumulation in xenograft pancreatic tumors in a biodistribution study. Moreover, the targeted nanopolyplex markedly inhibits tumor growth in an orthotopic pancreatic cancer mouse model by dual-targeting tumor cells and stroma. Overall, the multifunctional nanopolyplex is a promising platform for pancreatic cancer therapy.

Stress in dentistry. Dentists believe their profession is stressful. Research has indicated this belief is generally based upon patient behaviors and economic pressures. A discussion of stress and adaptation is presented. Since stress can lead to both physical and emotional problems, recognition of stress by the practitioner is discussed. While physical symptoms are easily recognized, emotional behaviors are often overlooked. The practitioner should become aware of these behaviors in the self as well as others. Methods to help reduce and control stress are given.

Current scenario and future strategies to fight artemisinin resistance. Despite several setbacks in the fight against malaria such as insecticide and drug resistance as well as low efficacy of available vaccines, considerable success in reducing malaria burden has been achieved in the past decade. Artemisinins (ARTs and their combination therapies, ACTs), the current frontline drugs against uncomplicated malaria, rapidly kill plasmodial parasites and are non-toxic at short exposures. Though the exact mode of action remains unclear, the endoperoxide bridge, indispensable for ART activity, is thought to react with heme released from hemoglobin hydrolysis and generate free radicals that alkylate multiple protein targets, thereby disrupting proteostasis pathways. However, rapid development of ART resistance in recent years with no potential alternatives on the horizon threaten the elimination efforts. The Greater Mekong Subregion in South-East Asia continues to churn out mutants resistant to multiple ACTs and detected in increasingly expanding geographies. Extensive research on ART-resistant strains have identified a potential candidate Kelch13, crucial for mediating ART resistance. Parasites with mutations in the propeller domains of Plasmodium falciparum Kelch13 protein were shown to have enhanced phosphatidylinositol 3-kinase levels that were concomitant with delayed parasite clearance. Current research focused on understanding the mechanism of Kelch13-mediated ART resistance could provide better insights into Plasmodium resistome. This review covers the current proposed mechanisms of ART activity, resistance strategies adopted by the parasite in response to ACTs and possible future approaches to mitigate the spread of resistance from South-East Asia.

Loss of natural dentition: multi-level effects among a geriatric population. To quantify the impact of edentulousness on residual ridge volume, denture stomatitis (DS), as well as oral health behaviours among geriatric denture-wearers. Residual ridge resorption (RRR) is the primary intraoral complication of complete edentulism, but individual variation among geriatric patients has been observed. Data collection relied upon a 10-year retrospective chart review of all complete denture-wearing geriatric patients presenting at the Removable Prosthodontics Clinic, Dental School of Athens, between 1993 and 2002. Analyses relied on descriptive, bivariate, and multivariate methods based on ordinal logistic regression. A total of 873 records of geriatric patients (age mean = 72; median = 70; range = 65-95) comprised our analytical sample. Subjects' mean (SD) time since edentulation was 7.7 (10.2) years. Eleven percent were diagnosed with temporomandibular disorder (TMD). While 28% of patients reported cleaning their dentures at least daily, 6% presented with denture stomatitis (DS). Each added year of edentulism increased the odds of mandibular RRR: OR (95% CI) = 1.05 (1.03, 1.07). Nightly denture wear was the strongest risk factor for DS. Finally, independent of age and sex, each year of being edentulous increased the odds of presenting with TMD: OR (95% CI) = 1.03 (1.01, 1.05). Time since edentulation was strongly associated with mandibular but not maxillary RRR, as well as TMD development.

Ultraviolet radiation-induced ubiquitination and proteasomal degradation of the large subunit of RNA polymerase II. Implications for transcription-coupled DNA repair. We have shown previously that UV radiation and other DNA-damaging agents induce the ubiquitination of a portion of the RNA polymerase II large subunit (Pol II LS). In the present study UV irradiation of repair-competent fibroblasts induced a transient reduction of the Pol II LS level; new protein synthesis restored Pol II LS to the base-line level within 16-24 h. In repair-deficient xeroderma pigmentosum cells, UV radiation-induced ubiquitination of Pol II LS was followed by a sustained reduction of Pol II LS level. In both normal and xeroderma pigmentosum cells, the ubiquitinated Pol II LS had a hyperphosphorylated COOH-terminal domain (CTD), which is characteristic of elongating Pol II. The portion of Pol II LS whose steady-state level diminished most quickly had a relatively hypophosphorylated CTD. The ubiquitinated residues did not map to the CTD. Importantly, UV-induced reduction of Pol II LS level in repair-competent or -deficient cells was inhibited by the proteasome inhibitors lactacystin or MG132. These data demonstrate that UV-induced ubiquitination of Pol II LS is followed by its degradation in the proteasome. These results suggest, contrary to a current model of transcription-coupled DNA repair, that elongating Pol II complexes which arrest at intragenic DNA lesions may be aborted rather than resuming elongation after repair takes place.

[The phenotypic heterogeneity of meningococcal strains by their serogroup trait]. It is shown that heterogeneity of meningococci of the outlined serogroups is formed due to appearance of nonagglutinable individuals in subpopulations but heterogeneity of polyagglutinable strains is characterized by incorporation not only of cross-reacting cells, but also microcommunities of each separate group which make a total feature. Serologically inactive strains either may be homogeneous or may form variants with low (to 20%) and high (to 44%) specific weight of agglutinable colonies. Strains in the centres embrace different concentrations of microcommunities which are identical by their serogroup properties to subpopulations of the meningitis pathogen.

Adenocarcinoma of the head of the pancreas: determination of surgical unresectability with thin-section pancreatic-phase helical CT. This study was conducted to evaluate newly introduced criteria for unresectability of pancreatic cancer with thin-section pancreatic-phase helical CT. Twenty-five patients with adenocarcinoma in the head of the pancreas underwent thin-section pancreatic-phase helical CT. The major peripancreatic vessels were categorized on a scale of 1-4, according to the degree of circumferential involvement by tumor. The maximum diameters of the small peripancreatic veins--gastrocolic trunk, anterosuperior pancreaticoduodenal vein, and posterosuperior pancreaticoduodenal vein--were recorded. Findings on CT were compared with the results of surgery in each patient. Sixteen patients had surgically resectable tumors, and nine patients had surgically unresectable tumors. CT and surgical correlation was available for 98 major peripancreatic vessels; 85 were resectable and 13 were unresectable. Of category 1 vessels, 72 (97%) of 74 were resectable at surgery. Of category 2 vessels, 12 (71%) of 17 were resectable. One (50%) of two category 3 vessels and none (0%) of five category 4 vessels were resectable at surgery. CT showed a dilated gastrocolic trunk in two patients; one of these patients had a surgically resectable tumor, but the other patient had a surgically unresectable tumor. In patients with adenocarcinoma in the head of the pancreas, the degree of circumferential vessel involvement by tumor as shown by CT is useful in predicting which patients will have surgically unresectable tumors. A dilated gastrocolic trunk should not be used as an independent sign of surgical unresectability.