Incidence of variations in human cadaveric renal vessels.
Awareness of discrepancies of renal vasculature is crucial for some medical procedures. The present study investigated origin and course of aberrant and accessory renal vessels and any associated variations. Renal blood vessels of 63 cadavers were examined. Number of renal veins and arteries, arrangement, location where the vasculature attached to the kidneys, and presence of variations were recorded. Incidence of renal vasculature variations was determined, and associations were tested with age at death, sex, and cause of death and whether variations were more common on a specific side. Variations were found in 7 (11%; 95% confidence interval [CI] 5-22%) cadavers. For renal veins, double, triple, and quadruple veins unilaterally (5; 8%) and veins that drained the superior pole (1; 2%) or inferior pole only (5; 8%) were found. For renal arteries, double and triple arteries unilaterally (3; 5%) and arteries attached to the superior pole only (1; 2%) or inferior pole only (2; 3%) were found. Other variations (polycystic kidney, variations in the common iliac or gonadal veins) were observed. Only renal failure as a cause of death was different between those with or without variations (4/7 [57%] vs. 1/56 [2%]; p < 0.001). The present study found many variations in renal vasculature. Awareness of such variations may be useful for physicians concerned with this region.


One billion years of bZIP transcription factor evolution: conservation and change in dimerization and DNA-binding site specificity.
The genomic era has revealed that the large repertoire of observed animal phenotypes is dependent on changes in the expression patterns of a finite number of genes, which are mediated by a plethora of transcription factors (TFs) with distinct specificities. The dimerization of TFs can also increase the complexity of a genetic regulatory network manifold, by combining a small number of monomers into dimers with distinct functions. Therefore, studying the evolution of these dimerizing TFs is vital for understanding how complexity increased during animal evolution. We focus on the second largest family of dimerizing TFs, the basic-region leucine zipper (bZIP), and infer when it expanded and how bZIP DNA-binding and dimerization functions evolved during the major phases of animal evolution. Specifically, we classify the metazoan bZIPs into 19 families and confirm the ancient nature of at least 13 of these families, predating the split of the cnidaria. We observe fixation of a core dimerization network in the last common ancestor of protostomes-deuterostomes. This was followed by an expansion of the number of proteins in the network, but no major dimerization changes in interaction partners, during the emergence of vertebrates. In conclusion, the bZIPs are an excellent model with which to understand how DNA binding and protein interactions of TFs evolved during animal evolution.


A selectionist approach to reinforcement.
We describe a principle of reinforcement that draws upon experimental analyses of both behavior and the neurosciences. Some of the implications of this principle for the interpretation of behavior are explored using computer simulations of adaptive neural networks. The simulations indicate that a single reinforcement principle, implemented in a biologically plausible neural network, is competent to produce as its cumulative product networks that can mediate a substantial number of the phenomena generated by respondent and operant contingencies. These include acquisition, extinction, reacquisition, conditioned reinforcement, and stimulus-control phenomena such as blocking and stimulus discrimination. The characteristics of the environment-behavior relations selected by the action of reinforcement on the connectivity of the network are consistent with behavior-analytic formulations: Operants are not elicited but, instead, the network permits them to be guided by the environment. Moreover, the guidance of behavior is context dependent, with the pathways activated by a stimulus determined in part by what other stimuli are acting on the network at that moment. In keeping with a selectionist approach to complexity, the cumulative effects of relatively simple reinforcement processes give promise of simulating the complex behavior of living organisms when acting upon adaptive neural networks.


IgG4 Levels in Bile for Distinguishing IgG4-Associated Cholangiopathy from Other Biliary Disorders: A Single Blinded Pilot Study.
Immunoglobulin G4 (IgG4)-associated cholangiopathy (IAC) is an inflammatory disease and may mimic primary sclerosing cholangitis (PSC), cholangiocarcinoma (CCA), or pancreatic cancer on cholangiography. We investigated whether IgG4 levels in bile aspirated during endoscopic retrograde cholangiopancreatography (ERCP) can distinguish IAC from PSC, CCA, and pancreatic cancer. Bile was aspirated directly from the common bile duct during ERCP in patients with IAC prior to steroid therapy. For control purposes, bile was obtained from patients with PSC, CCA, pancreatic cancer, and benign biliary conditions (sphincter of oddi dysfunction/choledocholithiasis). Biliary IgG4 levels were measured in 54 patients. The median bile IgG4 levels were markedly elevated in patients with IAC (5.5 mg/dL; interquartile range [IQR], 5.1 to 15.6) as compared to patients with benign biliary conditions (0 mg/dL; IQR, 0 to 0.1; p=0.003). The median biliary IgG4 levels in PSC, CCA, and pancreatic cancer were 1.2 (IQR, 0.2 to 3.8), 0.9 (IQR, 0.2 to 3.4), and 0.2 mg/dL (IQR, 0.1 to 0.8), respectively. A cutoff value of 3.8 mg/dL distinguished IAC from PSC and CCA patients with 100% and 76.9% sensitivity and specificity, respectively. The results of this pilot study suggest that measurement of biliary IgG4 levels may have clinical value in distinguishing patients with IAC from biliary disorders that can mimic IAC.


Causes of Neonatal Acute Renal Injury during Critical Illnesses.
The aim of the study was to assess acute kidney injury (AKI) and its contributing risk factors among neonates to reduce morbidity and mortality. The study included 310 neonates who were admitted to the neonatal intensive care unit (NICU). Serum creatinine (SCr) was elevated at admission, after 48 h, and before discharge or death. AKI was defined by either an acute rise in SCr of at least 0.3 mg/dL within 48 h or an increasing or persistently high level of SCr >1.5 mg/dL after 48-72 h of life. The patients who developed AKI were studied regarding the most common risk factors and outcomes. The prevalence of AKI in these neonates was 11.9%. Nephrotoxic drugs were the highest risk factor among patients with AKI, but this was not statistically significant different from patients without AKI. Perinatal asphyxia (59.5%), respiratory distress syndrome (48.6%), shock (43.2%), prematurity (40.5%), and sepsis (37.8%) were the main risk factors of AKI following the nephrotoxic drugs (64.9%). The mortality rate for cases with AKI was 62.1%, with a statistically significant difference from non-AKI neonates. The death rate was higher among neonates born before 36 weeks' gestation. There was no statistical difference between oliguric and non-oliguric neonates with AKI regarding the outcome. The overall incidence of AKI in sick neonates admitted to the NICU was 11.9%. Nephrotoxic drugs, perinatal asphyxia, shock, and prematurity were the main risk factors for developing AKI.


Radiologic-Pathologic Correlation for Benign Results After MRI-Guided Breast Biopsy.
The majority of MRI-guided breast biopsies yield benign pathology. The purpose of this article is to provide a comprehensive overview of benign pathologic entities commonly encountered at MRI-guided breast biopsy. Proper radiologic-pathologic correlation is an integral component of MRI-guided breast biopsy. Familiarity with the spectrum of MRI findings and key histopathologic features of common benign entities will enhance the radiologist's confidence in determining concordance and lead to improved patient management recommendations.


7-oxygenated derivatives of dehydroepiandrosterone and obesity.
7-hydroxy/oxo derivatives of dehydroepiandrosterone are potential regulators of the local cortisol activity due to their competition in the cortisolcortisone balance mediated by 11ß-hydroxysteroid dehydrogenase. 7-hydroxy-dehydroepiandrosterone is marketed as anti-obesity medication, though no clinical study aimed at the benefit of administering 7-oxygenated derivatives of dehydroepiandrosterone has appeared until now. We tried to show whether there exist differences in levels of circulating 7-hydroxy/oxo-dehydroepiandrosterone derivatives between lean and obese boys and girls. From a cohort of adolescents investigated within the frame of anti-obesity programme 10 obese boys and 10 obese girls were compared with age-matched lean boys and girls in their anthropometric data, and concentrations of both epimers of 7-hydroxy-dehydroepiandrosterone and 7-oxo-dehydroepiandrosterone were determined by the RIA method. The basal levels of 7α-hydroxy-dehydroepiandrosterone were significantly higher in obese boys than in lean boys but not in girls. The association was found for anthropometric parameters and 7α-hydroxy-dehydroepiandrosterone, however again only in boys and not in girls. Higher levels of 7α-hydroxy-dehydroepiandrosterone its positive association with anthropometric data in obese boys may serve as a sign that, at least in boys, 7-oxygenated 5-ene-steroids may take part in regulating the hormonal signal for fat formation or distribution.


Chemoprophylaxis for patients with colorectal cancer. Prospective study with five-year follow-up.
The effectiveness of a short-term fluorouracil chemopophylaxis regimen commencing four to six weeks after "curative" surgery was evaluated in a homogeneous group of 213 patients with colorectal cancer. In stage III disease (Dukes class C), five-year survival with no evidence of disease (NED) was 24.3% when treated by surgery alone but was 57.5% when a prophylactic regimen of fluorouracil was added (P less than .01), an increase of 33.2%. In stage II disease (Dukes class B), five-year NED survival was raised from 58.5% to 81.6%, an increase of 23.1% (P less than .02). More striking are the one-, two-, and three-year NED survivals in stage III. The one-, two-m and three-year NED survivals for the chemoprophylaxis group are 100%, 95%, and 75%, respectively, in contrast to 70.7%, 48.8%, and 34.1% in the group with surgery alone. The present data indicate that fluorouracil chemoprophylaxis offers a significant improvement of five-year cure rate of patients with stage II and III disease, an overall increase of 28.1% (P less than .01).


Efficacy and safety of splenectomy in adult autoimmune hemolytic anemia.
Autoimmune hemolytic anemia (AIHA) is a rare hematologic disease, primarily affecting adults or children with immunodeficiency disease. First-line therapy consists of long course of steroids administration, with an early complete response rate (CRr) of 75-80%, but up to 20-30% of patients requires a second-line therapy. Rituximab is the first choice in refractory old AIHA patients, because of its safety and efficacy (early CRr at 80-90% and at 68% at 2-3 years). For this reason, splenectomy is even less chosen as second-line therapy in elderly, even though laparoscopic technique decreased complication and mortality rates. However, splenectomy can be still considered a good therapeutic option with a CRr of 81% at 35.6 months in patients older than 60 year-old, when rituximab administration cannot be performed.


Influence of climate factors on population density and damage of the leopard moth, Zeuzera pyrina L., in walnut orchards, Iran.
The effect of climate factors (temperature, humidity, precipitation, and frost days) on the population changes, damage, and infestation area of the leopard moth, Zeuzera pyrina L., was studied during 2006-2018 in four parts of Iran including Saman, Arak, Najaf-abad, and Baft. For trend analysis, the Mann-Kendall test was run on time series data of both climate and pest population. According to the results, the annual mean (Kendall's statistics, T = 0.64 and 0.48), annual minimum (T = 0.60 and 0.42), and January mean (T = 0.64 and 0.61, respectively) temperatures showed increasing trends in Saman and Najaf-abad. Moreover, the annual mean minimum and January temperatures (T = 0.41 and 0.45, respectively) in Arak and the annual mean maximum temperature (T = 0.79) in Baft showed increasing trends. The number of frost days/year (Kendall's statistics, T = -0.63, -0.53, -0.32 and -0.37) and annual mean relative humidity (T = -0.43, -0.63, -0.64 and -0.42, respectively) showed decreasing trends in Saman, Arak, Baft, and Najaf-abad stations. Trend analysis indicated significant increases in the mean number of moths caught (T = 0.59, 0.76 and 0.90), the percentage of infested branches/tree (T = 0.66, 0.58, and 0.90), the number of active holes/tree (T = 0.79, 0.55, and 0.68) and the infested areas (T = 0.99, 0.73, and 0.98, respectively) in Saman, Arak and Najaf-abad stations. According to stepwise regression, the mean temperatures of January, autumn, and winter were the most effective variables for increasing Z. pyrina damage and population, while relative humidity and the number of frost days played the major role in reducing it.


Estrogenic effect of leachates and soil extracts from lysimeters spiked with sewage sludge and reference endocrine disrupters.
Several experiments were conducted to evaluate the behavior and performance of some potential endocrine disrupters (ECDs). Two in vitro screening assays, one based on MCF7-cell proliferation (E-screen test) and the other on estrogenic receptor activity [enzyme-linked receptor assay (ELRA)], were used for the tests, which were done in lysimeters 80 cm in diameter with depth of 30 cm (shallow) or 90 cm (deep). A sandy soil was used to fill in all lysimeters, which were spiked on the surface with either: (a) a sewage sludge (SS) at a dose equivalent to 20 tons ha-1; (b) a mixture of reference ECDs, comprising 17 alpha- and 17 beta-estradiol (E2), nonylphenol, octylphenol, and bisphenol A at doses 100 times higher than the maximum concentrations respectively found in the applied SS; or (c) a mixture of ECDs and SS. After percolation of the lysimeters with rain and/or artificial water, five leachates were sampled from each lysimeter during a period of 210 days. Immediately after the lysimeter percolation experiments, four and six soil fractions were dissected from, respectively, the 30-cm and 90-cm lysimeters and extracted by water. Both the leachate and soil extract samples were analyzed for their estrogenicity using the assays indicated above. The E-screen assay was highly sensitive only for some leachate and extract samples but gave no response for most leachates and soil extracts. The results of the ELRA assay suggests a significantly higher estrogenicity of leachate samples from shallow lysimeters compared with that of leachates from deep lysimeters. In contrast, the estrogenic effect measured for soil extracts of shallow lysimeters was lower than that measured for soil extracts of deep lysimeters. The results of the E-screen assay suggests the occurrence of a fast mobilization of applied ECDs and a moderate retardation effect of native ECDs contained in applied SS in the sandy soil used in the lysimeters. In lysimeters spiked with a mixture of SS and ECDs, the washing-out effect of ECDs in the first leachate fraction decreased, but the distribution of ECDs in the lysimeters increased. The relatively high estrogenic impact measured for soil water extracts suggests that the ECDs were mostly associated with water-soluble fractions of organic matter and/or water-suspended fractions of the mineral soil matrix. The application of SS to agricultural and forest fields may determine the immobilization of ECDs in soil or their movement to surface and/or groundwater. Therefore, an endocrine risk of exposure exists for the water and soil organisms.


Substrate recognition and channeling of monomodules from the pikromycin polyketide synthase.
The unique ability of the pikromycin (Pik) polyketide synthase to generate 12- and 14-membered ring macrolactones presents an opportunity to explore the fundamental processes underlying polyketide synthesis, specifically the mechanistic details of the chain extension process. We have overexpressed and purified PikAIII (module 5) and PikAIV (module 6) and assessed the ability of these proteins to generate tri- and tetraketide lactone products using N-acetylcysteamine-activated diketides and (14)C-methylmalonyl-CoA as substrates. Comparison of the stereochemical specificities for PikAIII and PikAIV and the reported values for the DEBS modules reveals significant differences between these systems.


Over-the-Scope Clip Closure of Persistent Gastrocutaneous Fistula After Percutaneous Endoscopic Gastrostomy Tube Removal: A Report of Two Cases.
Persistent gastrocutaneous fistulas have conventionally been treated surgically. Over-the-scope clip (OTSC) was developed as an endoscopic closure device for full-thickness gastrointestinal defects and has become one of the treatment options for gastrocutaneous fistula. Herein, we report two cases of gastrocutaneous fistulas treated using OTSC. Case 1 was a 71-year-old woman and case 2 was an 88-year-old man, both of whom had severe frailty and had a persistent gastrocutaneous fistula after removal of the percutaneous endoscopic gastrostomy (PEG) tube. OTSC closure was chosen over surgical closure to reduce invasiveness. In case 1, OTSC was deployed using a suction method, which was technically successful. However, the fistula reopened two days later, indicating clinical failure of the OTSC. The cause of the failure may be due to an inadequate suction of the fistula into the applicator cap. Based on the experience of OTSC failure in case 1, OTSC in case 2 was deployed using the Anchor to pull the fistula into the cap more reliably. Fistula did not recur during the 30-month follow-up, indicating the clinical success of OTSC in case 2. The use of Anchor may increase the success rate of OTSC, but there is a dilemma that the use of Anchor increases cost. In summary, OTSC has the advantage of being less invasive compared to conventional surgery; however, the application of OTSC for chronic fistulas remains challenging due to issues regarding clinical success rate and cost.


[Brachial plexitis and myelitis and herpes-zoster lumbar plexus disorder in patient treated with infliximab].
Infliximab, a chimeric monoclonal antibody, is a TNF-a inhibitor approved for use in refractory rheumatoid arthritis and Crohn s disease. We present the case of a patient affected by severe rheumatoid arthritis who was successfully treated with infliximab. She suffered diverse neurological complications: brachial plexitis, asymptomatic thoracic myelitis with extensive lesions in MRI study, and herpes zoster lumbar plexitis. We review the neurological adverse effects of infliximab (aseptic meningitis, opportunistic germs infections, disseminated herpes zoster) and focus in their potential adverse effect to induce central and peripheral nervous system demyelination.


Pain management at home. Struggle, comfort, and mission.
This article presents findings from an exploratory, descriptive study that investigated the experiences of pain in the home from the perspective of the patient, the primary family caregiver, and the home care nurse. The following research questions are addressed: What are the special problems associated with pain management at home as identified by patients, caregivers, and nurses? What are the similarities and differences among patients, caregivers, and nurses regarding issues of managing pain at home? Qualitative techniques were used to collect and analyze data. The sample included 10 cancer patients with pain and their respective caregivers and nurses. After the in-depth interviews were transcribed, a multidisciplinary research team performed content analysis on the data. Overall, the findings suggest that patients approach pain management with a struggle for control, whereas self-denying caregivers seek to provide comfort, and nurses attempt to fulfill an urgent mission to eradicate pain.


Smartphone for smart living: Using new technologies to cope with everyday limitations in semantic dementia.
New technologies have considerable potential to support people with semantic dementia-a form of progressive aphasia-in their everyday lives, but evidence is still sparse. The first objective of the study was to document day-to-day compensation strategies, including the use of a smartphone, in ND, a 56-year-old man with semantic dementia. The second objective was to explore if, 5 years after receiving his diagnosis, ND could still learn new smartphone functions. Results for objective 1 showed that ND had adopted a large number of compensation mechanisms in his everyday life, and expanded the use of one application he had learned 4 years earlier. Results for objective 2 showed that, with an errorless learning approach, he learnt to effectively use 10 smartphone functions. He was also able to verbalise semantic knowledge about those functions and still used 40% of them in daily life 6 months post-intervention. He particularly appreciated note-taking, and spontaneously expanded his abilities in using this function's features in order to reduce his semantic difficulties. This study shows the potential of new mobile technologies for semantic dementia, how they can be adapted and modified as the disease progresses, and how some patients can creatively use external technological aids.


Mass spectrometry in clinical proteomics - from the present to the future.
MS is an important analytical tool in clinical proteomics, primarily in the disease-specific discovery, identification and characterisation of proteomic biomarkers and patterns. MS-based proteomics is increasingly used in clinical validation and diagnostic method development. The latter departs from the typical application of MS-based proteomics by exchanging some of the high performance of analysis for the throughput, robustness and simplicity required for clinical diagnostics. Although conventional MS-based proteomics has become an important field in clinical applications, some of the most recent MS technologies have not yet been extensively applied in clinical proteomics. In this review, we will describe the current state of MS in clinical proteomics and look to the future of this field.


An innovative method for preparation of hydrophobic ion-pairing colistin entrapped poly(lactic acid) nanoparticles: Loading and release mechanism study.
Hydrophobic ion-pairing (HIP) complexation has emerged as an efficient approach to enhance the entrapment of therapeutic peptides in the biodegradable polymer matrix. In the present study, we developed an innovative extraction method for preparation of HIP-colistin (CST, a polycationic peptide) using various water-insoluble anionic lipids. To determine the loading mechanism of HIP-CST entrapped poly(lactic acid) (PLA) nanoparticles (HIP-CST-PLA-NPs), the effects of anionic lipids and PLA molecular weight (Mw) on the unentrapped fraction (uf) of CST in PLA-NPs were investigated. And CST release mechanism from HIP-CST-PLA-NPs was also investigated by evaluating their release behavior and NP swelling. It is showed that HIP-CST retention in the PLA-NPs was imposed by their physical localization in the networks of the PLA chains, rather than the electrostatic attraction between anionic lipid and CST in serum. And HIP-CST-PLA-NPs in serum exhibited the swelling-controlled release behavior with a substantially accelerated release and NP swelling observed in comparison with that in phosphate buffer. Our results can effectively guide the preparation of biodegradable polymer based modified drug release systems with desired properties for peptides delivery.


The progressive outer retinal necrosis syndrome: successful treatment with combination antiviral therapy.
To assess a two-drug combination of antiviral therapy for the progressive outer retinal necrosis syndrome (PORN), given the current poor outcome with acyclovir alone. A retrospective review was performed on six consecutive patients who were diagnosed with PORN and were treated with various combinations of intravenous or oral plus intravenous antiviral therapy. The relative efficacies of these modalities were compared. Six eyes of six patients showed active retinitis at the time of presentation. Three patients had unilateral retinitis, and the remaining patients had necrotic, end-stage disease in their fellow eye. All the patients were treated with combination therapy, consisting of either ganciclovir and acyclovir (three patients), foscarnet and ganciclovir (two patients), or foscarnet and acyclovir (one patient). Standard induction doses were employed. During the combination therapy, all six eyes showed resolution of the retinitis, manifested by complete fading of the original retinal lesions and an absence of new lesion formation. At the final follow-up, the areas of prior active retinitis had resolved and remained quiescent. A mild recurrence developed in one eye when ganciclovir and foscarnet were both tapered to a single daily dose. This recurrence promptly resolved with reinduction (twice daily) dosing. Two patients maintained a visual acuity of 20/50 or better in their involved eye for the duration of follow-up (38 and 27 weeks, respectively). One patient maintained a visual acuity of 20/40 for 14 weeks. The remaining three patients had macula-off retinal detachments despite resolution of active retinitis. In addition, for the duration of follow-up, one of the three patients with unilateral disease had retinitis in the uninvolved eye; all three uninvolved fellow eyes maintained a visual acuity of 20/20. One patient had progressive optic atrophy. Prolonged combination antiviral therapy for PORN may successfully arrest the progression of retinitis, maintain remission, and prevent involvement of the fellow eye. Furthermore, if aggressive therapy is begun early, good vision may be preserved.


Severity of Hypoxemia and Other Factors That Influence the Response to Aerosolized Prostacyclin in ARDS.
ARDS is characterized by decreased functional residual capacity (FRC), heterogeneous lung injury, and severe hypoxemia. Tidal ventilation is preferentially distributed to ventilated alveoli. Aerosolized prostaglandin I2 exploits this pathophysiology by inducing local vasodilation, thereby increasing ventilation-perfusion matching and reducing hypoxemia. Therefore, aerosolized prostaglandin I2 efficacy may depend upon FRC. Both PaO2 /FIO2 and compliance of the respiratory system (CRS) are indirect signifiers of FRC and thus may partly determine the response to aerosolized prostaglandin I2. We reviewed the records of 208 ARDS subjects who received aerosolized prostaglandin I2 and had arterial blood gases done before and after the initiation of therapy, without other ventilator manipulations. Subjects were grouped according to baseline PaO2 /FIO2 (lowest: < 60, intermediate: 60-90, highest: > 90 mm Hg) and CRS (< 20, 20-29, 30-39, and ≥ 40 mL/cm H2O) and by other factors, such as sepsis. Comparisons were analyzed by paired t tests, or Kruskal-Wallis and Dunn post-tests. Multivariate logistic regression modeling was done to determine which of 18 clinically relevant factors were most predictive for responding to aerosolized prostaglandin I2. α was set at .05. Mean PaO2 /FIO2 increased by 33 mm Hg (42%) upon initiation of prostaglandin I2, with a responder rate of 62%. PaO2 /FIO2 increased significantly in all oxygenation groups. The highest baseline PaO2 /FIO2 group had the greatest improvement and responder rate (51 ± 63 mm Hg, and 82%). In addition, those with sepsis had a smaller improvement in PaO2 /FIO2 compared with those without sepsis (18 ± 35 vs 40 ± 55 mm Hg, P = .002). Both PaO2 /FIO2 and responder rate increased as CRS improved, but between-group improvements were not as consistent. In the final model, the only factors that predicted a positive response to aerosolized prostaglandin I2 were baseline PaO2 /FIO2 (odds ratio 1.10 [1.004-1.205], P = .042) and CRS (odds ratio 1.04 [1.01-1.08], P = .02). Aerosolized prostaglandin I2 improves oxygenation in approximately 60% of ARDS cases. A favorable response was most strongly associated with baseline PaO2 /FIO2 and CRS.


Possible new antiaging strategies related to neuroendocrine-immune interactions.
The aging process demonstrates gradual and spontaneous changes, resulting in maturation through childhood, puberty and young adulthood, and then decline through middle and late age. However, animals and humans are capable of reaching the extreme limit of life span characteristic for the species with a very efficient network of antiaging mechanisms. Among them, neuroendocrine-immune interactions play a pivotal role. The loss of the capacity of the organism in remodeling the neuroendocrine-immune response leads to the appearance of age-associated pathologies. We herein report some substances which can be proposed as new antiaging strategies because of their capacity to remodel some biological functions in old animals and humans. These substances are: L-deprenyl, leptin, ghrelin, carnosine and NO donors. Their role as possible antiaging strategies in healthy people in relation to neuroendocrine-immune responses and zinc ion bioavailability is reported and discussed.


Effectiveness of graded motor imagery in subjects with frozen shoulder: a pilot randomized controlled trial.
Subjects with frozen shoulder (FS) might not be comfortable with vigorous physical therapy. Clinical trials assessing the effect of graded motor imagery (GMI) in FS are lacking. The aim of this study was to determine the effect of GMI as an adjunct to conventional physiotherapy in individuals with painful FS. Twenty subjects aged 40-65 years having stage I and II of FS were randomly divided into two study groups. The conventional physiotherapy group (n = 10) received electrotherapy and exercises while the GMI group (n = 10) received GMI along with the conventional physiotherapy thrice a week for 3 weeks. Pre- (Session 1) and post- (Session 9) intervention analysis for flexion, abduction, and external rotation range of motion (ROM) using a universal goniometer, fear of movement using the fear avoidance belief questionnaire (FABQ), pain with the visual analogue scale, and functional disability using the shoulder pain and disability index (SPADI) was done by a blinded assessor. Statistically significant difference was seen within both the groups for all the outcomes. In terms of increasing abduction ROM as well as reducing fear of movement, pain, and functional disability, the GMI group was significantly better than control group. However, both groups were equally effective for improving flexion and external rotation ROM. Addition of GMI to the conventional physiotherapy proved to be superior to conventional physiotherapy alone in terms of reducing pain, kinesiophobia, and improving shoulder function for stage I and II of FS.


Elliptic flow at large transverse momenta from quark coalescence.
We show that hadronization via quark coalescence enhances hadron elliptic flow at large p(perpendicular) relative to that of partons at the same transverse momentum. Therefore, compared to earlier results based on covariant parton transport theory, more moderate initial parton densities dN/deta(b=0) approximately 1500-3000 can explain the differential elliptic flow v(2)(p(perpendicular)) data for Au+Au reactions at sqrt[s]=130 and 200A GeV from BNL RHIC. In addition, v(2)(p(perpendicular)) could saturate at about 50% higher values for baryons than for mesons. If strange quarks have weaker flow than light quarks, hadron v(2) at high p(perpendicular) decreases with relative strangeness content.


Ribocyclophanes A-E, Glycosylated Cyclophanes with Antiproliferative Activity from Two Cultured Terrestrial Cyanobacteria.
The cell extracts of two cultured freshwater Nostoc spp., UIC 10279 and UIC 10366, both from the suburbs of Chicago, showed antiproliferative activity against MDA-MB-231 and MDA-MB-435 cancer cell lines. Bioassay-guided fractionation led to the isolation of five glycosylated cylindrocyclophanes, named ribocyclophanes A-E (1-5) and cylindrocyclophane D (6). The structure determination was carried out by HRESIMS and 1D and 2D NMR analyses and confirmed by single-crystal X-ray crystallography. The structures of ribocyclophanes A-E (1-5) contain a β-d-ribopyranose glycone in the rare 1 C4 conformation. Among isolated compounds, ribocyclophane D (4) showed antiproliferative activity against MDA-MB-435 and MDA-MB-231 cancer cells with an IC50 value of less than 1 μM.


The role of SRGN in the survival and immune infiltrates of skin cutaneous melanoma (SKCM) and SKCM-metastasis patients.
Skin cutaneous melanoma (SKCM) is one of most aggressive type of cancers worldwide. Serglycin (SRGN) is an intracellular proteoglycan that playing an important role in various tumors. However, its effect on immune infiltrates and whether it associates with survival of SKCM and SKCM-metastasis patients has not been explored. We evaluated SRGN expression via the databases of Oncomine, Tumor Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA). The influence of SRGN expression on survival of SKCM and SKCM-metastasis patients was analyzed using TIMER database. Furthermore, the correlations between SRGN expression and immune infiltrates or gene marker sets of immune infiltrates were also analyzed via TIMER database. We found that the expression of SRGN in SKCM and SKCM-metastasis tissues was significantly increased compared to the normal skin tissues (P < 0.001). Interestingly, it was showed that lower level of SRGN expression and lower immune infiltrates of B cell, CD8+ T cell, Neutrophil, and Dendritic cell were correlated with poor survival rate of SKCM and SKCM-metastasis patients (P < 0.001) but not SKCM primary patients. We also demonstrated that SRGN expression was positively associated with the immune infiltrates and diverse immune marker sets in SKCM and SKCM-metastasis. Our findings indicated that SRGN was associated with the survival of SKCM and SKCM-metastasis patients. SRGN may be a new immune therapy target for treating SKCM and SKCM-metastasis.


[The development of an intelligent four-channel aggregometer].
The paper introduces the hardware and software design of the instrument. We use 89C52 single-chip computer as the microprocessor to control the amplifier, AD and DA conversion chip to realize the sampling, data process, printout and supervision. The final result is printed out in form of data and aggregation curve from PP40 plotter.


Minimally invasive procedures. Interventional MR image-guided functional neurosurgery.
Intraoperative MR imaging techniques have the potential to greatly improve the stereotactic methods used for functional neurosurgery. No longer are neurosurgeons and patients always constrained by uncomfortable head frames and conventional stereotaxy. Accuracy and complication avoidance are improved by intraoperative imaging. Safety of operative machinery and equipment in an MR imaging operative suite is attainable, even with deep brain stimulating electrodes in depth electrodes for epilepsy. Although cost-effectiveness remains to be determined (see article by Kucharczyk et al in this issue), the minor inconveniences of operating within an iMRI environment seem to be significantly outweighed by the benefits.


Withania somnifera prevents acquisition and expression of morphine-elicited conditioned place preference.
Previous studies have reported that some of the central effects of morphine are counteracted by the administration of the methanolic extract of the root of Indian ginseng, Withania somnifera Dunal (WSE). The present study sought to determine whether WSE affects acquisition and expression of morphine-elicited conditioned place preference (CPP) in CD-1 mice. In CPP acquisition experiments, WSE (0, 25, 50, and 100 mg/kg) was administered, during conditioning, 30 min before morphine (10 mg/kg), whereas in expression experiments, WSE (0, 25, 50, and 100 mg/kg) was administered 30 min before the postconditioning test. The results demonstrate (i) that WSE was devoid of motivational properties; (ii) that WSE (100 mg/kg) was devoid of effects on spontaneous and morphine-stimulated motor activity and on spatial memory; and (iii) that WSE (50 and 100 mg/kg) significantly prevented the acquisition and expression of CPP. Further, to characterize the receptor(s) involved in these effects, we studied, by receptor-binding assay, the affinity of WSE for µ-opioid and γ-aminobutyric acid B receptors. These experiments revealed a higher affinity of WSE for γ-aminobutyric acid B than for µ-opioid receptors. Overall, these results point to WSE as an interesting alternative tool, worthy of further investigation, to study opiate addiction.


The Structural Basis for Activation and Inhibition of ZAP-70 Kinase Domain.
ZAP-70 (Zeta-chain-associated protein kinase 70) is a tyrosine kinase that interacts directly with the activated T-cell receptor to transduce downstream signals, and is hence a major player in the regulation of the adaptive immune response. Dysfunction of ZAP-70 causes selective T cell deficiency that in turn results in persistent infections. ZAP-70 is activated by a variety of signals including phosphorylation of the kinase domain (KD), and binding of its regulatory tandem Src homology 2 (SH2) domains to the T cell receptor. The present study investigates molecular mechanisms of activation and inhibition of ZAP-70 via atomically detailed molecular dynamics simulation approaches. We report microsecond timescale simulations of five distinct states of the ZAP-70 KD, comprising apo, inhibited and three phosphorylated variants. Extensive analysis of local flexibility and correlated motions reveal crucial transitions between the states, thus elucidating crucial steps in the activation mechanism of the ZAP-70 KD. Furthermore, we rationalize previously observed staurosporine-bound crystal structures, suggesting that whilst the KD superficially resembles an "active-like" conformation, the inhibitor modulates the underlying protein dynamics and restricts it in a compact, rigid state inaccessible to ligands or cofactors. Finally, our analysis reveals a novel, potentially druggable pocket in close proximity to the activation loop of the kinase, and we subsequently use its structure in fragment-based virtual screening to develop a pharmacophore model. The pocket is distinct from classical type I or type II kinase pockets, and its discovery offers promise in future design of specific kinase inhibitors, whilst mutations in residues associated with this pocket are implicated in immunodeficiency in humans.


Giant epidermal cyst of the foot.
Epidermoid inclusion cysts are usually composed of epidermal elements implanted into the dermal layers. Patients are seen in the outpatient clinics with a mass. Most of the complaints are mechanical and cosmetic problems. A 34-year-old female patient was admitted to our clinic because of swelling and pain in her right foot. A palpable mass was detected in the first web. On the x-rays of the foot no osseous lesion was detected.There was a soft tissue mass in the first web according to MRI report. Soft tissue mass was excised and sent to pathology. According to pathology report the mass was an epidermoid cyst 5 x 2 x 1.5 cm in size.There were no problems during follow-up of the patient for 6 months after surgery. The patient had no swelling in the foot and had no additional complaints on checkup. In the differential diagnosis, we should take into consideration epidermoid cyst of large soft tissue masses of the foot. Surgical excision should be done within the appropriate limits.


Portal hypertension in a dog due to circumscribed fibrosis of the wall of the extrahepatic portal vein.
A two-and-a-half-year-old German shepherd dog with ascites and a high concentration of blood ammonia was investigated. Sonographically, its liver was normal but the portal vein was dilated and the flow of blood within it was slow. A liver biopsy showed that the liver was normal, and did not reveal any possible cause of portal hypertension or ascites. Postmortem, the cranial part of the portal vein was dilated with a cross-striped internal surface, but the caudal part looked normal; there was a stenotic ring between the normal and dilated parts. Histology of the dilated segment revealed marked hypertrophy of both the internal circular and the external longitudinal smooth muscle layers. At the site of the stenosis, the longitudinal muscular layer was replaced by connective tissue. Circumscribed fibrosis in the wall of the portal vein was responsible for the stenosis and the subsequent prehepatic portal hypertension. The cross-striped pattern in the dilated part of the vein was the result of hypertrophy of the inner circular smooth muscle layer.


[Urticarial vasculitis as a symptom of Muckle-Wells syndrome?].
A patient is reported with a history of several years of chronic urticaria, transient fever, arthralgias and secondary systemic amyloidosis. A biopsy of an urticarial lesion showed necrotizing vasculitis and amyloid deposits in the eccrine sweat glands. Amyloid A deposits were also detected in kidney and rectum biopsies. This patient is likely to represent a variant of the Muckle-Wells syndrome (chronic relapsing urticaria, fever, arthralgia, deafness and renal amyloidosis). Hitherto undescribed is the presence of a necrotizing vasculitis as cause of the urticarial rash; further investigation will determine whether or not this finding represents the rule rather than an exception.


Pediatric trigger thumb in identical twins: congenital or acquired?
Pediatric trigger thumb is an uncommon condition with a calculated incidence of 3 per 1000 live births or less. Some reports have suggested a congenital etiology while others could not find a single case of pediatric trigger thumb at birth. This article reports the occurrence of bilateral trigger thumbs in identical twins, age 3 years and 9 months, affecting their thumbs to similar extents, which may suggest a congenital etiology.Congenital etiology for trigger thumb has been proposed for many reasons: occurrence in infants, occurrence in twins, occasional bilaterality, possible presence of triggering at birth, and absence of history of trauma. The occurrence of pediatric trigger thumb in twins has been reported 3 times in the literature; all reported cases were bilateral, as in our case.The mean age at presentation of pediatric trigger thumb is 2 years. The thumb is usually held in a fixed flexion position (mimicking a fracture). Examination usually reveals a palpable nodule in the flexor pollicis longus tendon at the metacarpal joint. This is an important clinical sign. Triggering in children, however, is rare. Macroscopically, there is a nodular thickening of the tendon itself. Pathological changes can be found in the tendon, tendon sheath, or both. A specimen taken from one of the nodules in our case showed degenerative changes while those from both pulleys were normal.Pediatric trigger thumb responds predictably to A1 pulley release, preferably before age 4 years, although milder cases may resolve spontaneously.


Fractional Brownian motion with a reflecting wall.
Fractional Brownian motion, a stochastic process with long-time correlations between its increments, is a prototypical model for anomalous diffusion. We analyze fractional Brownian motion in the presence of a reflecting wall by means of Monte Carlo simulations. Whereas the mean-square displacement of the particle shows the expected anomalous diffusion behavior 〈x^{2}〉∼t^{α}, the interplay between the geometric confinement and the long-time memory leads to a highly non-Gaussian probability density function with a power-law singularity at the barrier. In the superdiffusive case α>1, the particles accumulate at the barrier leading to a divergence of the probability density. For subdiffusion α<1, in contrast, the probability density is depleted close to the barrier. We discuss implications of these findings, in particular, for applications that are dominated by rare events.


A glucose kinase from Mycobacterium smegmatis.
Carbon metabolism and regulation is poorly understood in mycobacteria, a genus that includes some major pathogenic species like Mycobacterium tuberculosis and Mycobacterium leprae. Here, we report the identification of a glucose kinase from Mycobacterium smegmatis. This enzyme serves in glucose metabolism and global carbon catabolite repression in the related actinomycete Streptomyces coelicolor. The gene, msmeg1356 (glkA), was found by means of in silico screening. It was shown that it occurs in the same genetic context in all so far sequenced mycobacterial species, where it is located in a putative tricistronic operon together with a glycosyl hydrolase and a putative malonyl-CoA transacylase. Heterologous expression of glkA in an Escherichia coli glucose kinase mutant led to the restoration of glucose growth, which provided in vivo evidence for glucose kinase function. GlkA(Msm) was subsequently overproduced in order to study its enzymatic features. We found that it can form a dimer and that it efficiently phosphorylates glucose at the expense of ATP. The affinity constant for glucose was with 9 mM about eight times higher and the velocity was about tenfold slower when compared to the parallel measured glucose kinase of S. coelicolor. Both enzymes showed similar substrate specificity, which consists in an ATP-dependent phosphorylation of glucose and no, or very inefficient, phosphorylation of the glucose analogues 2-deoxyglucose and methyl alpha-glucoside. Hence, our data provide a basis for studying the role of mycobacterial glucose kinase in vivo to unravel possible catalytic and regulatory functions.


Reactions to patient death: the lived experience of critical care nurses.
A qualitative study using phenomenological descriptive design was conducted to explore critical care nurses' experiences with patient death. Several themes emerged as a result of this study: coping, personal distress, emotional disconnect, and inevitable death. Understanding critical care nurses' reactions to patient death may help to improve the care provided to critically ill dying patients and their families and to meet the needs of the nurses who care for them.


Textile Electronics with Laser-Induced Graphene/Polymer Hybrid Fibers.
The concept of wearables is rapidly evolving from flexible polymer-based devices to textile electronics. The reason for this shift is the ability of textiles to ensure close contact with the skin, resulting in comfortable, lightweight, and compact "always with you" sensors. We are contributing to this polymer-textile transition by introducing a novel and simple way of laser intermixing of graphene with synthetic fabrics to create wearable sensing platforms. Our hybrid materials exhibit high electrical conductivity (87.6 ± 36.2 Ω/sq) due to the laser reduction of graphene oxide and simultaneous laser-induced graphene formation on the surface of textiles. Furthermore, the composite created between graphene and nylon ensures the durability of our materials against sonication and washing with detergents. Both of these factors are essential for real-life applications, but what is especially useful is that our free-form composites could be used as-fabricated without encapsulation, which is typically required for conventional laser-scribed materials. We demonstrate the exceptional versatility of our new hybrid textiles by successfully recording muscle activity, heartbeat, and voice. We also show a gesture sensor and an electrothermal heater embedded within a single commercial glove. Additionally, the use of these textiles could be extended to personal protection equipment and smart clothes. We achieve this by implementing self-sterilization with light and laser-induced functionalization with silver nanoparticles, which results in multifunctional antibacterial textiles. Moreover, incorporating silver into such fabrics enables their use as surface-enhanced Raman spectroscopy sensors, allowing for the direct analysis of drugs and sweat components on the clothing itself. Our research offers valuable insights into simple and scalable processes of textile-based electronics, opening up new possibilities for paradigms like the Internet of Medical Things.


[Role of leptin in immunodeficiency in children with protein-calorie malnutrition].
The article based on current literature, reviews physiological properties of leptin and the influence of nutritional state on its production. Leptin is the pleiotropic hormone secreted by adipocytes. Besides participation in the regulation of energy balance, it influences the immunological system and improves the state of immunity, both inborn and acquired. In protein-caloric malnutrition leptin secretion is reduced which may cause immunity deficit, especially of the cellular type. The authors also discuss the usefulness of measuring leptin serum concentration for evaluation of treatment of malnourished children.


Nonintracranial fatal firearm injuries in children: implications for treatment.
Understanding the injury characteristics of nonintracranial fatal (NIF) gunshot wounds in children treated in a statewide trauma system will help guide effective treatment strategies. This study was a retrospective analysis of children fatally injured with firearms. The review included demographic information, firearm injury characteristics, and outcome. The setting included trauma centers participating in a statewide trauma registry. Patients were all children (age < 18 years) treated in trauma centers for NIF gunshot wounds from January 1988 through December 2000. The main outcome measures were characteristics of fatal firearm injuries in children. Over the 13-year period, there were 1,954 children with firearm injuries including 368 (18.8%) children with fatal wounds. Of the fatally wounded children, 177 (48.1%) had no intracranial injury. The NIF injury population was 90.4% male, with a mean age of 14.9 years (range, <1-17 years) and an Injury Severity Score of 38.2 (range, 9-75). Over 95% of deaths in this group occurred within 24 hours of admission. Although injuries to the thorax were most common (78.5%), 48.6% of the NIF cohort had injuries to multiple body regions, including 31% with injuries in both the abdomen and thorax. Compared with all children wounded by firearms, NIF firearm injury patients had, on average, more body regions injured (1.6 vs. 1.1, p < 0.001) and a greater total number of injuries (6.0 vs. 3.5, p < 0.001). Patients with an NIF injury were more likely to suffer a major vascular injury (54.8% vs. 13.8%, p < 0.001), lung injury (56.5% vs. 12.9%, p < 0.001), or cardiac injury (44.6% vs. 4.6%, p < 0.001) than all children with a firearm injury. Most children who arrive at trauma centers alive and subsequently die from NIF firearm injuries do so rapidly from major vascular and thoracic injury. Almost half of these children have injuries to multiple body regions, further complicating management. Innovative, aggressive treatment approaches should be sought to improve survival in this extremely injured cohort of children.


Artemisinin Therapy for Malaria in Hemoglobinopathies: A Systematic Review.
Artemisinin derivatives are widely used antimalarial drugs. There is some evidence from in vitro, animal and clinical studies that hemoglobinopathies may alter their disposition and antimalarial activity. This review assesses relevant data in α-thalassemia, sickle cell disease (SCD), β-thalassemia and hemoglobin E. There is no convincing evidence that the disposition of artemisinin drugs is affected by hemoglobinopathies. Although in vitro studies indicate that Plasmodium falciparum cultured in thalassemic erythrocytes is relatively resistant to the artemisinin derivatives, mean 50% inhibitory concentrations (IC50s) are much lower than in vivo plasma concentrations after recommended treatment doses. Since IC50s are not increased in P. falciparum cultures using SCD erythrocytes, delayed post-treatment parasite clearance in SCD may reflect hyposplenism. As there have been no clinical studies suggesting that hemoglobinopathies significantly attenuate the efficacy of artemisinin combination therapy (ACT) in uncomplicated malaria, recommended artemisinin doses as part of ACT remain appropriate in this patient group.


Analysis of the impact of secondary prophylaxis on Clostridioides difficile recurrence in critically ill adults.
Clostridioides (formerly Clostridium) difficile infection recurrence in patients re-exposed to antibiotics for treatment of a non-Clostridioides difficile infection is high at approximately 33%. Low-dose per os vancomycin (e.g. 125 mg q12 h) or metronidazole (e.g. 500 mg intravenous/per osq8 h) may help prevent recurrences, but study of secondary prophylaxis in critically ill patients is needed. To determine whether critically ill adults receiving low-dose per os vancomycin for secondary Clostridioides difficile infection prophylaxis have fewer recurrences of Clostridioides difficile infection in 90 days compared with patients receiving metronidazole for secondary Clostridioides difficile infection prophylaxis or control (no secondary prophylaxis). This was a retrospective, two-center, observational study in a large academic medical center and affiliated community hospital. Included patients had a history of Clostridioides difficile infection within 1 year of receiving antibiotics for clinical care. We compared patients receiving secondary prophylaxis with vancomycin or metronidazole and control patients; in addition, an unplanned fourth group (vancomycin/metronidazole combination) was identified and analyzed. The primary outcome was Clostridioides difficile infection recurrence within 90 days of a course of broad-spectrum antibiotic therapy. Fisher's exact, analysis of variance, and Kruskal-Wallis tests were used to compare Clostridioides difficile infection recurrence with prophylaxis group and additional contributing factors. Eighty-two patients were included: 38 control (46.3%), 20 metronidazole (24.4%), 17 vancomycin (20.7%), and 7 combination (8.5%). Ten of 82 patients (12.2%) had at least one Clostridioides difficile infection recurrence; 8/38 patients in the control group (21.1%), 1/7 patients in the combination group (14.3%), 1/17 patients in the per os vancomycin group (5.9%), and 0/20 in the metronidazole group (0%; p = 0.073). As a post hoc secondary analysis, the three prophylaxis groups were coalesced into one group and compared with control (4.5% vs 21%; p = 0.039). Additional factors (e.g. age, obesity, immunosuppression, acid suppression) were not significantly associated with Clostridioides difficile infection recurrence or with prophylaxis group. There was no difference in Clostridioides difficile infection recurrence between prophylaxis groups, however, given the low recurrence rate, prospective evaluation with a larger sample of critically ill patients is necessary.


Long-term prospective randomized study comparing two different regimens of oxybutynin as a treatment for detrusor overactivity.
Prospective randomized trial to compare two low starting doses of oxybutynin, using an incremental regimen to assess patient compliance and treatment efficacy in the long-term. Women with detrusor overactivity were included. Oxybutynin was randomly prescribed with a starting dose of either 2.5 mg bd or 5 mg nocte. Instructions were given to increase oxybutynin up to 5 mg tds over a period of 6 weeks fortnightly. After two years we re-contacted all the women, using a specific questionnaire to assess the efficacy, acceptability and compliance with these two different regimens. Twenty-two women in each group were calculated to show a 5% difference with a significance of 0.05 and a power of 0.9. The chi2-test was used to compare the two groups and a P-value < 0.05 was considered significant. Ninety-six women were included; 66 (68.75%) (mean age 57.5 years) responded to our questionnaire. Twenty-seven had a starting dose of 2.5 mg oxybutynin twice a day and 39 of 5 mg nocte. 34.8% complained of side effects. Only 19 (43.2%) out of the 44, not on medication anymore abandoned oxybutynin for adverse reactions. Most of the patients stopped oxybutynin within 4 months. 53.0% reported improvement or cure. 39.4% denied any benefit and 7.6% (none still on oxybutynin) did not answer. The two groups did not differ for duration of treatment, improvement with oxybutynin, maximum dose they reached, the present dose, and the present urinary symptoms. This study did not show any advantage in efficacy or compliance with oxybutynin when two different regimens of low starting were used. Two-thirds of patients discontinued the therapy within 4-6 months. Therefore, patients on anticholinergics should be reassessed after 6 months in clinical practice.


Allergy immunotherapy for primary care physicians.
Allergic diseases affect a large proportion of the population of the United States. Although there are many effective pharmacologic therapies available, only allergen-specific immunotherapy has been shown to have significant and long-lasting therapeutic and immunomodulatory effects for the management of allergic rhinitis, allergic asthma, and venom hypersensitivity. Allergen immunotherapy requires a build-up phase as the dose of the vaccine is increased until a therapeutic (maintenance) level is achieved. This maintenance dose is usually continued for 3 to 5 years. Most patients tolerate immunotherapy well, but local reactions are not uncommon. Immunotherapy should only be administered in a physician's office because some patients may experience systemic anaphylactic reactions requiring immediate therapy. Even with newer therapies on the horizon, allergen immunotherapy will continue to have an important role in the treatment of allergic diseases.


The major amino acid transporter superfamily has a similar core structure as Na+-galactose and Na+-leucine transporters.
The sodium solute symporters (SSS) and neurotransmitter sodium symporters (NSS) are two families of secondary transporters that are not related in amino acid sequence. Nonetheless, recent crystal structures showed that the Na(+)/galactose (SSS) and Na(+)/leucine (NSS) transporters have similar core structures. The structural relatedness highlights the need for classification methods for membrane protein structures based on other criteria than amino acid similarity. Here, we demonstrate that a method based on hydropathy profile alignments convincingly identifies structural similarity between the NSS and SSS families. Most importantly, the method shows that one of the largest transporter families for which a crystal structure is elusive (the amino acid/polyamine/organocation or APC superfamily), also shares the similar core structure observed for the Na(+)/galactose and Na(+)/leucine transporters. The APC superfamily contains the major amino acid transporter families that are found throughout life. Insight into their structure will significantly facilitate the studies of this important group of transporters.


Cerebral infarcts related to isolated middle cerebral artery stenosis.
The clinical presentation of middle cerebral artery (MCA) stenosis, a rarely diagnosed condition, is not well known. The aim of this study was to analyze the stroke patterns of patients with isolated MCA stenosis. Twenty-two patients with cerebral infarcts due to isolated MCA stenosis were analyzed with respect to their clinical syndrome, and cerebral lesions were assessed by neuroimaging. MCA stenosis was diagnosed by transcranial Doppler sonography (TCD) in 16, by TCD and digital subtraction angiography (DSA) in 4, and by DSA alone in 2 patients. Ten patients (45.5%) had lacunar syndromes, suggesting small-vessel disease, and 12 patients (55.5%) showed signs and symptoms of cortical dysfunction. Cerebral CT or MRI showed no lesion in 2 patients, small deep infarcts in 10, large striatocapsular infarcts in 2, combined piomedullary and striatocapsular infarcts in 4, piomedullary branch infarcts in 3, and MCA trunk infarct in 1. The results suggest an association between MCA stenosis and (1) lacunar infarcts and (2) the occurrence of piomedullary MCA branch infarcts alone or in combination with subcortical infarcts. The clinical syndromes and the radiological findings correspond in most cases.


Perceptions of Community-Dwelling Patients and Their Physicians on OxyContin® Discontinuation and the Impact on Chronic Pain Management.
OxyContin, formerly one of the most commonly prescribed medications for chronic pain in Canada, was discontinued, delisted from the Ontario Drug Formulary, and replaced by a tamper-resistant formulation in 2012. The impact of discontinuing OxyContin on patients formerly prescribed it to treat chronic pain was unreported. Patients with chronic pain aged 45 years and over (n = 13) were recruited from two primary care and one specialty practice sites and interviewed using a semistructured guide to capture their experiences with discontinuing OxyContin, the efficacy of alternate medications, and relationships with physicians. Additional interviews were conducted with their physicians (n = 7) to obtain physician perceptions on discontinuation and to expand understanding of the patients' experiences. Aspects of patients' pain and medical care through the discontinuation process revealed emergent themes that both converge and diverge from that of treating physicians. Areas of divergence include the motive for discontinuation, which was condemned by most patients but supported by all physicians, and the perceived impact of discontinuance on pain control, with the majority of patients experiencing a negative impact and most physicians describing it as insignificant. Perceptions of patients and physicians coincided on the need to optimize pain management practices.


An increase in human cases of spotted fever rickettsiosis in Yucatan, Mexico, involving children.
The first human case of infection caused by Rickettsia in Yucatan was detected in 1996, and it was determined that the species was R. felis. Since then, passive epidemiologic surveillance was implemented to search for human cases in the public hospitals of the state, and in 2005, the first human case of Rocky Mountain spotted fever was detected. During the following 2 years, eight new confirmed cases and one probable case were identified. Seven cases involved children younger than 12 years of age, with a fatal outcome in three of the cases. Children are a particularly vulnerable population for this serious emerging infection.


Continuous irradiation with a 633-nm light-emitting diode exerts an anti-aging effect on human skin cells.
Accumulating evidence has indicated that the light source emitted from light‑emitting diode (LED) has a potential anti-aging effect on human skin. Studies using single and interval LED irradiation have documented such effects; however, to the best of our knowledge, the anti-aging effects of continuous LED irradiation have not yet been investigated. In the present study, we demonstrated that continuous irradiation with a 633±3-nm LED exerted anti-aging effects in both in vitro and ex vivo experiments. More specifically, irradiation with a 633-nm LED for 2 days increased the synthesis of type 1 procollagen and decreased the expression of matrix metalloproteinase (MMP)1 and MMP2 in skin fibroblasts. In addition, irradiation with a 633-nm LED decreased the expression levels of inflammatory genes, such has cyclooxygenase-2 (COX-2), and interleukin-1-α (IL-1α) in keratinocytes. Furthermore, a 14-day LED irradiation moderately increased keratinocyte proliferation. Using human skin explants, we confirmed the safety of this 633-nm LED irradiation, which resulted in unaltered morphology and allergy-free potential in human tissue. Overall, these data provide insight into the anti-aging effects of continuous LED irradiation on human skin.


HPCO-A Phosphorus-Containing Analogue of Isocyanic Acid.
We describe the isolation and spectroscopic characterization of the heavier phosphorus-containing analogue of isocyanic acid (HPCO), and its isotopologue (DPCO). This fundamental small molecule, which has been postulated to exist in interstellar space, has thus far only been observed at low gas phase concentrations or in inert gas matrices. In this report we describe its synthesis, spectroscopic properties, and reactivity in solution.


Characterization of hemoglobin immobilized on gamma-zirconium phosphate.
The fact that different gamma-zirconium phosphate (gamma-ZrP) preintercalation method induced varied degree and type of conformational change of the adsorption protein was confirmed by characterization techniques including circular dichroism (CD), fourier transform infrared spectroscopy (FTIR) and X-ray powder diffraction (XRD) analysis. The results indicated that the association of hemoglobin with gamma-ZrP preintercalated using butylamine was correlated with conformational change in the secondary structure of the protein. gamma-ZrP which was preintercalated with tetra (n-butylammonium) hydroxide caused the conformational change of Hemoglobin in both the secondary structure and the tertiary structure. X-ray powder diffraction analysis was used to analyze the crystalline structure of the nanocomposites prepared by relamination. The adsorption isotherms of Hemoglobin on different matrices were set up and fitted with Langmuir and Freundlich equations.


In vitro and In vivo Model Systems for Hemophilia A Gene Therapy.
Hemophilia A is a hereditary disorder caused by various mutations in factor VIII gene resulting in either a severe deficit or total lack of the corresponding activity. Recent success in gene therapy of a related disease, hemophilia B, gives new hope that similar success can be achieved for hemophilia A as well. To develop a gene therapy strategy for the latter, a variety of model systems are needed to evaluate molecular engineering of the factor VIII gene, vector delivery efficacy and safety-related issues. Typically, a tissue culture cell line is the most convenient way to get a preliminary glimpse of the potential of a vector delivery strategy. It is then followed by extensive testing in hemophilia A mouse and dog models. Newly developed hemophilia A sheep may provide yet another tool for evaluation of factor VIII gene delivery vectors. Hemophilia models based on other species may also be developed since hemophiliac animals have been identified or generated in rat, pig, cattle and horse. Although a genetic nonhuman primate hemophilia A model has yet to be developed, the non-genetic hemophilia A model can also be used for special purposes when specific questions need to be addressed that cannot not be answered in other model systems. Hemophilia A is caused by a functional deficiency in the factor VIII gene. This X-linked, recessive bleeding disorder affects approximately 1 in 5000 males [1-3]. Clinically, it is characterized by frequent and spontaneous joint hemorrhages, easy bruising and prolonged bleeding time. The coagulation activity of FVIII dictates severity of the clinical symptoms. Approximately 50% of all cases are classified as severe with less than 1% of normal levels of factor VIII detected [4]. This deficiency may lead to spontaneous joint hemorrhages or life-threatening bleeding. In contrast, patients with 5-30% of normal factor VIII activity exhibit mild clinical manifestations.


Calcific discitis in children: vertebral body involvement (possible insight into etiology).
The aim of the study was to present our cases of calcific discitis, analyze the imaging findings, and review the literature in an attempt to formulate a possible etiology. We reviewed the imaging and clinical findings in nine patients with calcific discitis and accomplished a literature review of the condition. There were nine patients, five males and four females. Age range was 5-13 years with a mean of 9.7 years. Twenty-three discs were involved, nine cervical and fourteen thoracic. Four cervical discs were not calcified but merely swollen. One patient presented with abnormal magnetic resonance (MR) signal changes within a vertebral body. Our literature search revealed another such patient and brought up the possibility that the insult to the disc might be secondary to vertebral body involvement and disruption of the tenuous vascular/nutritional support of the intervertebral disc from the adjacent vertebral body. In the early stages of calcific discitis, only swelling and expansion of the disc are seen. More recently, with MR imaging, vertebral body involvement has been demonstrated to also occur. As a result, it may be that the initial insult (vascular compromise) is to the vertebral body (nutritional support for the disc) rather than to the disc.


Self-directed care for adults with serious mental illness: the barriers to progress.
The President's New Freedom Commission on Mental Health identified self-directed care as one service innovation that could create a more consumer- and family oriented mental health system. Four years later, there are still fewer than 400 consumers in five states accessing self-directed care in the public mental health system. This Open Forum identifies three main barriers to explain this lack of progress: the absence of a strong evidence base to support the effectiveness of self-directed care for serious mental illness, uncertainty over the appropriate scope of self-directed care, and the absence of a sustainable source of funding. The introduction of the 1915(i) provision of the Social Security Act in 2007 appears to partly address the funding barrier to self-directed care. There is also a strong case for a large-scale evaluation of self-directed care for persons with serious mental illness to address the two remaining barriers to progress.


Mucosal expression signatures of two Cathepsin L in channel catfish (Ictalurus punctatus) following bacterial challenge.
The mucosal surfaces of fish are the first line of host defense against various pathogens. The mucosal immune responses are the most critical events to prevent pathogen attachment and invasion. Cathepsins are a group of peptidases that involved in different levels of immune responses, but the knowledge of the roles of Cathepsin in mucosal immune responses against bacterial infection are still lacking. Therefore, in the present study we characterized the Cathepsin L gene family in channel catfish, and profiled their expression levels after challenging with two different Gram-negative bacterial pathogens. Here, two Cathepsin L genes were identified from channel catfish and were designated CTSL1a and CTSL.1. Comparing to other fish species, the catfish CTSL genes are highly conserved in their structural features. Phylogenetic analysis was conducted to confirm the identification of CTSL genes. Expression analysis revealed that the CTSL genes were ubiquitously expressed in all tested tissues. Following infection, the CTSL genes were significantly induced at most timepoints in mucosal tissues. But the expression patterns varied depending on both pathogen and tissue types, suggesting that CTSL genes may exert disparate functions or exhibit distinct tissue-selective roles in mucosal immune responses. Our findings here, clearly revealed the key roles of CTSL in catfish mucosal immunity; however, further studies are needed to expand functional characterization and examine whether CTSL may also play additional physiological roles in catfish mucosal tissues.


Metagenomic approach reveals variation of microbes with arsenic and antimony metabolism genes from highly contaminated soil.
Microbes have great potential for arsenic (As) and antimony (Sb) bioremediation in heavily contaminated soil because they have the ability to biotransform As and Sb to species that have less toxicity or are more easily removed. In this study, we integrated a metagenomic method with physicochemical characterization to elucidate the composition of microbial community and functional genes (related to As and Sb) in a high As (range from 34.11 to 821.23 mg kg-1) and Sb (range from 226.67 to 3923.07 mg kg-1) contaminated mine field. Metagenomic analysis revealed that microbes from 18 phyla were present in the 5 samples of soil contaminated with high As and Sb. Moreover, redundancy analysis (RDA) of the relationship between the 18 phyla and the concentration of As and Sb demonstrated that 5 phyla of microbes, i.e. Actinobacteria, Firmicutes, Nitrospirae, Tenericutes and Gemmatimonadetes were positively correlated with As and Sb concentration. The distribution, diversity and abundance of functional genes (including arsC, arrA, aioA, arsB and ACR3) were much higher for the samples containing higher As and Sb concentrations. Based on correlation analysis, the results showed a positive relationship between arsC-like (R2 = 0.871) and aioA-like (R2 = 0.675) gene abundance and As concentration, and indicated that intracellular As(V) reduction and As(III) oxidation could be the dominant As detoxification mechanism enabling the microbes to survive in the environment. This study provides a direct and reliable reference on the diversity of microbial community and functional genes in an extremely high concentration As- and Sb-contaminated environment.


Comparison of drug abuse in Germany and China.
Drug abuse has a long, but also different history in Germany and China. The Opium War largely influenced the history of China in 19th century; however, China was once recognized as a drug-free nation for 3 decades from the 1950s to the 1980s. Drug abuse has spread quickly since re-emerging as a national problem in China in the late 1980s. The number of registered drug abusers increased from 70 000 in 1990 to more than 1 million by the end of 2005. In past decades, illicit drug trafficking and production have swept most provinces in China, and drug abuse has caused many problems for both abusers and the community. One major drug-related problem is the spread of HIV, which has caused major social and economic damage in China. Germany, the largest developed European country, also faces the drug and addiction problem. Germany has about 150 000 heroin addicts, for whom HIV/AIDS has become a serious threat since the mid 1980s. To control the drug problem, the German Government adopted the pAction Plan on Drugs and Addictionq in 2003; the China Central Government approved a similar regulation in the antidrug campaign in 2005. Germany has experience in reducing drug-related harm. The methadone maintenance treatment (MMT) program has run for more than 20 years and the public has become more tolerant of addicts. In 2003, China began the MMT program for controlling the spread of HIV/AIDS. It is necessary for China to learn from developed countries to acquire success in its antidrug campaign. In this review, we will go over the differences and similarities in drug abuse between Germany and China. The differences are related to history, population and economics, drug policy context, drug laws, HIV/hepatitis C virus infection, the MMT program and so on. These 2 nations have drug abuse problems with different histories and currently use different approaches to handle illicit drug marketing and use. The legal penalties for illicit drug offences reflect the social differences of these 2 nations with respect to the seriousness of particular types of crimes. The characteristics of the MMT program may also influence patterns of drug abuse in these 2 nations and China should improve the MMT program based on the successful model in Europe, the USA, and Australia. We recommend more dialogue and collaboration between Germany and China.


Comprehensive evaluation of the response of genes to the administration of the antitumor drug S-1 using a low density array.
S-1 is a newly developed dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine that exhibits high clinical efficacy against non-small cell lung cancers. To identify genes that may be associated with chemosensitivity to the antitumor drug S-1, we used a low density array representing 93 genes to analyze expression profiles in 4 orthotopically implanted lung cancers derived from human lung cancer cell lines (Lu99, Lu130, LC6 and A549). The tumor growth inhibition (TGI) rates of S-1 in orthotopically implanted tumors of the Lu99, Lu130, LC6 and A549 cell lines were 34.6, 37.5, 32.1 and 3.6%, respectively. The expression of the PRSS3, ABCC4, TXN, SHMT1 and CMPK genes was significantly promoted in the orthotopically implanted SCID mouse model of the 4 lung cancer cell lines by the administration of S-1, while the expression of the LMO7 and FOLH1 genes was significantly suppressed. The expression of the ABCC1, 2 and TST genes was negatively correlated with TGI. The expression of the TK1 and ERCC2 genes was positively correlated with TGI. The results of the present study suggest that the expression of the ABCC1, 2, TST, TK1 and ERCC2 genes is related to resistance to the antitumor drug S-1.


On the evolution of the DyNiO3 perovskite across the metal-insulator transition though neutron diffraction and Mössbauer spectroscopy studies.
The structural changes of polycrystalline DyNiO3 perovskite across the metal-insulator transition (TMI = 564 K) have been studied by high resolution neutron diffraction techniques together with Mössbauer spectroscopy, in a sample doped with 1.5 at.% 57Fe. In the insulating (semi-conducting) regime, below T(MI), the perovskite is monoclinic, space group (SG) P21/n, and the crystal structure contains two chemically different Ni1 and Ni2 cations, as a result of the charge disproportionation of Ni3+ cations. The beta parameter, characterizing the low-temperature monoclinic distortion, is smaller than 90.04 degrees for T < TMI, indicating a strongly pseudo-orthorhombic symmetry, although the internal monoclinic symmetry, implying the splitting and shifts of oxygen positions around the two Ni sites is perfectly detected by neutrons. Above TMI, DyNiO3 becomes orthorhombic, SG Pbnm. Upon heating across TMI, there is an abrupt convergence of the two sets (Ni1 and Ni2) of three Ni-O bond lengths, in the monoclinic-insulating phase, to three unique Ni-O distances in the orthorhombic-metallic phase upon entering the metallic region. The 57Fe Mössbauer spectra of an iron-doped (1.5 at.%) DyNiO3 sample recorded in the insulating, paramagnetic temperature range (TN < T < TMI) are discussed by supposing that the Fe3+ probe cations replace nickel in the two octahedral Ni1 and Ni2 sites. Electric field gradient calculations have shown that the 57Fe hyperfine parameters of Fe1 and Fe2 subspectra reflect a specificity of local structure corresponding to large (Ni1O6) and small (Ni2O6) octahedra. At T > TMI, the 57Fe spectrum gives clear evidence for the formation of an unique state for iron probe atoms and could, therefore, imply that the charge disproportionation in the (NiO6) subarray completely vanishes at the insulator-->metal transition.


EPR investigation of in vivo inhibitory effect of guanidine compounds on nitric oxide production in rat tissues.
The aim of the present study was to evaluate in vivo effects on NO production of pharmacologically widely used, commercially available NOS inhibitors, structurally related to guanidine. We compared the NO inhibitory potency and selectivity of L-NAME, aminoguanidine and guanabenz in tissues of normal and LPS-stimulated rats using ex vivo EPR measurements of the NO radical in its complex with dithiocarbamate-Fe(II). The tissues studied were the brain cortex, kidney, liver, heart and testis. Differential inhibitory effects were seen for L-NAME, aminoguanidine and guanabenz when applied during basal or LPS-stimulated conditions. Aminoguanidine exerted inhibition of NO only after stimulation with LPS. Guanabenz had little effect on NO in liver, kidney, testis and heart under normal conditions, while it reduced the basal NO in brain cortex. After stimulation with LPS guanabenz afforded a partial inhibition of the NO formation in all tissues studied. L-NAME was a potent inhibitor of NO synthesis in all tested tissues, both during basal and LPS stimulated conditions. Our results show that compounds containing a guanidine moiety might possess different NOS inhibitory profiles in vivo.


A glutamine 67--> histidine mutation in homotetrameric R67 dihydrofolate reductase results in four mutations per single active site pore and causes substantial substrate and cofactor inhibition.
R67 dihydrofolate reductase (DHFR) is a type II DHFR produced by bacteria as a resistance mechanism to increasing clinical use of the antibacterial drug trimethoprim. Type II DHFRs are not homologous in either sequence or structure with chromosomal DHFRs. The crystal structure of R67 DHFR shows a single active site pore that spans the length of the homotetramer. Related sites (due to a 222 symmetry element at the center of the pore) are used to bind ligands, i.e. each half of the pore can accommodate either the substrate, dihydrofolate (DHF), or the cofactor, NADPH, although DHF and NADPH are bound differently. To evaluate the role of glutamine 67 (and its symmetry-related Q167, Q267 and Q367 residues which occur at the center of the active site pore), a Q67H mutation was constructed. Binary binding of dihydrofolate (DHF; monitored by isothermal titration calorimetry) displays two identical sites with a Kd value of 0.04 microM, while binding of NADPH shows two sites possessing negative cooperativity with Kd values of 0.027 and 0.62 microM. A comparison of ligand binding in Q67H versus wild-type (wt) R67 DHFR indicates both ligands bind more tightly (80-6000-fold) and DHF binding in Q67H R67 DHFR no longer displays positive cooperativity as seen in wt R67 DHFR. Ternary complex binding in the Q67H mutant indicates a total of two ligands can bind per pore. Substantial substrate and cofactor inhibition are observed during catalysis, consistent with non-productive binding of either two DHF or two NADPH molecules in Q67H R67 DHFR. Because of the symmetry-related binding sites in the active site pore, the accumulation of potentially positive mutations in R67 DHFR is limited by the balance between tighter binding of ligands (and thus potentially increased catalytic efficiency) and inhibition that arises upon tighter binding of two identical ligands at symmetry-related sites.


Optic Neuropathy As the Initial Presenting Sign of N-methyl-d-aspartate (NMDA) Encephalitis.
A 52-year-old woman presented with painless vision loss for 3 months. She was in custody for allegedly robbing a bank and had recently been diagnosed with paranoid schizophrenia. She had 20/100 VA OD, a 2+RAPD, and optic atrophy. Extensive diagnostic workup including MRI, Fluorescein Angiography, Infectious Disease Panel, lumbar puncture, and leptomeningeal biopsy were unrevealing. Vision in her right eye declined to NLP and her left eye declined to 20/200 VA. Anti N-methyl-D-aspartate (NMDA) Autoimmune Encephalitis was diagnosed based on CSF serology and clinical suspicion. Her clinical course improved as she was treated with corticosteroids and rituximab.


Syntheses and biological evaluation of indolocarbazoles, analogues of rebeccamycin, modified at the imide heterocycle.
A series of 10 indolocarbazole derivatives, analogues to the antitumor antibiotic rebeccamycin, bearing modifications at the imide heterocycle were synthesized. They bear an N-methyl imide, N-methyl amide, or anhydride function instead of the original imide. Their inhibitory potencies toward topoisomerase I were examined using a DNA relaxation assay and by analyzing the drug-induced cleavage of 32P-labeled DNA. Protein kinase C (PKC) inhibition and interaction with DNA were also studied together with the in vitro antiproliferative activities against B16 melanoma and P388 leukemia cells. The antimicrobial activities against two Gram-positive bacteria (Bacillus cereus and Streptomyces chartreusis), a Gram-negative bacterium (Escherichia coli), and a yeast (Candida albicans) were tested as well as their antiviral activities toward HIV-1. The efficiency of the anhydride compounds was compared to that of the parent compound rebeccamycin and its dechlorinated analogue. All the compounds studied were inactive against PKC. The structural requirements for PKC and topoisomerase I inhibition are markedly different. In sharp contrast with the structure-PKC inhibition relationships, we found that an anhydride function does not affect topoisomerase I inhibition, whereas a methyl group on the indole nitrogen prevents the poisoning of topoisomerase I. The compounds exhibiting a marked toxicity to P388 leukemia cells had little or no effect on the growth of P388CPT5 cells which are resistant to the topoisomerase I inhibitor camptothecin. This study reinforces the conclusion that the DNA-topoisomerase I cleavable complex is the primary cellular target of the indolocarbazoles and significantly contributes to their cytotoxicity and possibly to their weak but noticeable anti-HIV-1 activities. The structure-activity relationships are also discussed.


Visual behavior and motor responses of novice and experienced wheelchair tennis players relative to the service return.
The purpose of this study was to determine visual behavior and motor responses between experienced and novice wheelchair tennis players relative to the return in tennis. Novice (n = 7) and Experienced (n = 5) wheelchair tennis players took part in the study. Two series of serves performed to the forehand and the backhand sides were examined in both groups. One series was performed in a video-based setting (two dimensional) and the other one on court (three dimensional). Experienced participants focused initially on the head/shoulders and the free-arm, while novice players focused on the expected ball toss area or followed the ball from the toss to the apex. Results suggest that the experienced players obtain useful information from racket-arm cues during the stroke phase. They also performed faster motor responses as well.


Prognostic Value of Cancer Stem Cell Markers in Potentially Malignant Disorders of Oral Mucosa: A Meta-analysis.
Oral squamous cell carcinoma (OSCC) is usually preceded by clinically visible changes on oral mucosa categorized as oral potentially malignant disorders (OPMD). The progression of OPMD to OSCC is a multistep process that provides an opportunity for early cancer detection and interception. Recent research suggests that cancer stem cells (CSC) hold the key to unlocking effective strategies to curb initiation and growth of several malignant neoplasms, including OSCC. In this meta-analysis, we evaluated the efficacy of CSC markers CD133, podoplanin, ALDH1, and others in predicting risk of malignant transformation of OPMDs. The PubMed database was systematically reviewed for relevant articles. Quality of eligible studies was assessed as per reporting recommendations for tumor marker (REMARK) criteria. A total of 18 investigations from 12 studies evaluated clinical or prognostic significance of CSC markers in OPMDs. A reasonable number of patients (1,659) were included in this analysis. Positive expression of CSC markers in OPMDs is significantly associated with progression to OSCC [risk ratio (RR), 3.31; 95% confidence interval (CI), 2.72-4.02]. Variability in CSC population makes it difficult to understand exact biology of OPMDs based on single CSC marker investigation. Identifying CSC population is a reliable prognostic indicator in OPMDs with or without dysplasia. Multi-marker panel investigation for CSCs in OPMDs may assist in curtailing new cases of oral cancer to a great extent. The study illustrates that evaluating CSC marker expression in OPMDs is a key tool in identifying high-risk cases to prevent development of OSCC.


Enhanced motivation to self-administer cocaine is predicted by self-grooming behaviour and relates to dopamine release in the rat medial prefrontal cortex and amygdala.
Rats, like humans, show strong individual differences in their response to anxiogenic and stressful stimuli. In the present study we evaluated whether differences in stress-induced self-grooming behaviour may predict an individual's vulnerability to engage in drug self-administration behaviour. From a population of Wistar rats, the lower and upper quartile with respect to time spent self-grooming on an elevated plus maze (EPM) were selected and trained to intravenously self-administer cocaine under fixed and progressive ratio schedules of reinforcement. High grooming (HG) rats reached considerably higher breakpoints than low grooming (LG) rats but showed no differences in acquisition rate and dose-response relationships. Further, EPM exposure elicited higher anxiety levels and enhanced plasma corticosterone secretion in HG rats. In addition, HG rats did not display enhanced novelty-seeking and still spent more time self-grooming during an EPM re-test following the cocaine self-administration procedure, indicating that stress-induced self-grooming is a stable behavioural trait marker. Neurochemically, electrically evoked [(3)H]dopamine release in vitro was profoundly lower in brain slices from the substantia nigra, medial prefrontal cortex and amygdala of naive HG rats as compared to LG rats, whereas no differences were found in the nucleus accumbens shell and core, the ventral tegmental area and caudate putamen. In conclusion, stress-induced self-grooming specifically predicts enhanced motivation to self-administer cocaine rather than sensitivity to its reinforcing effects. Responsiveness of dopaminergic nerve terminals in the medial prefrontal cortex and amygdala may represent pre-existing underlying factors.


The translational clinical practice system: a way to implement the evidence-based approach in the dental office.
Evidence-based decision-making in dental practice is challenging and rewarding. But for many clinicians, the evidence-based approach is an abstract and even theoretical idea that sounds good, but is not very practical. The Translational Clinical Practice System provides an overriding domain and a system within which the evidence-based approach may be more effectively utilized in clinical practice. Most would agree that using good evidence, information, and data as the basis for decisions are the starting points toward reaching the best results for the patient. However, there are clearly insufficiencies in the currently available best scientific evidence for many of the procedures patients need. The good news is that the evidence environment is improving and better quality information is becoming available in the office where it is needed. This article describes a logical and straightforward approach for clinicians to use in order to put together complex and often interwoven factors involved with patient care. Specific clinical examples are provided.


Providencia stuartii: a common cause of antibiotic-resistant bacteriuria in patients with long-term indwelling catheters.
The long-term-catheterized urinary tract may offer a particular niche to Providencia stuartii, which is otherwise an uncommon clinical isolate. Published accounts of bacteriuria in patients catheterized for long periods indicate that P. stuartii has often been found as frequently as familiar uropathogens such as Escherichia coli, Proteus mirabilis, enterococcus, and Pseudomonas aeruginosa. As in most nosocomial infections, the frequency of isolation of a given species has commonly differed among institutions. In the future P. stuartii may be more frequently encountered as a nosocomial pathogen in nursing homes and in acute care hospitals to which bacteriuric patients are transferred. This trend appears likely because of the increasingly large nursing-home population, the predilection of the bacterium for the long-term-catheterized urinary tract, the opportunity for nosocomial transmission from this reservoir, the resistance of the organism to multiple antibiotics, and the occasional systemic illness and bacteremia caused by P. stuartii.


Nanogap effects on near- and far-field plasmonic behaviors of metallic nanoparticle dimers.
In the field of plasmonics, the nanogap effect is often related to one aspect like the near-field enhancement at a single excitation wavelength or the far-field resonance shift. In this study, taking full advantage of finite element method (FEM) calculations, we present a comprehensive and quantitative analysis of the nanogap effect on the plasmonic behaviors of metallic nanoparticle dimers. Firstly, near-field spectroscopy is proposed in order to extract the near-field resonance wavelengths. Focusing on the bonding dipole mode, it is found that the near-field enhancement factors exhibit a weak power-law dependence on the gap size, while the near-field resonance shift decays nearly exponentially as the gap size increases, with a lower decay length than that for the far-field resonance shift. The spectral deviation between these two shifts is suggested to be taken into account for spectroscopy applications of plasmonic devices, although it may be negligible for dimer structures with rather small gaps.


Oxidative Stress and Cellular Protein Accumulation Are Present in Keratoconus, Macular Corneal Dystrophy, and Fuchs Endothelial Corneal Dystrophy.
The aim of the study was to investigate oxidative stress as well as cellular protein accumulation in corneal diseases including keratoconus (KC), macular corneal dystrophy (MCD), and Fuchs endothelial corneal dystrophy (FECD) at their primary affecting sites. Corneal buttons from KC, MCD, and FECD patients, as well as healthy controls, were analyzed immunohistochemically to evaluate the presence of oxidative stress and the function of the proteostasis network. 4-Fydroxynonenal (4-HNE) was used as a marker of oxidative stress, whereas the levels of catalase and heat-shock protein 70 (HSP70) were analyzed to evaluate the response of the antioxidant defense system and molecular chaperones, respectively. Sequestosome 1 (SQSTM1) levels were determined to assess protein aggregation and the functionality of autophagic degradation. Basal epithelial cells of the KC samples showed increased levels of oxidative stress marker 4-HNE and antioxidant enzyme catalase together with elevated levels of HSP70 and accumulation of SQSTM1. Corneal stromal cells and endothelial cells from MCD and FECD samples, respectively, showed similarly increased levels of these markers. All corneal diseases showed the presence of oxidative stress and activation of the molecular chaperone response to sustain protein homeostasis. However, the accumulation of protein aggregates suggests insufficient function of the protective mechanisms to limit the oxidative damage and removal of protein aggregates via autophagy. These results suggest that oxidative stress has a role in KC, MCD, and FECD at the cellular level as a secondary outcome. Thus, antioxidant- and autophagy-targeted therapies could be included as supporting care when treating KC or corneal dystrophies.


Coronary arteries in children up to the age of ten years II. Intimal thickening and its role in atherosclerotic involvement.
The frequency, histologic feature and topographic distribution of the first foci of intimal thickening were investigated in the coronary arteries of 40 fetuses, 40 neonates and 90 children up to the age of ten years. Particular hemodynamic and mechanical stresses seem to be involved in the precocious development of these isolated foci of intimal thickening which appeared in the early fetal life as well as in their progressive extension and fusion which give rise to diffuse thickened intima. After birth the stressed areas with thickened intima might evolve toward fibrosis and the "protected" ones toward degenerative and necrotic processes. These processes were detected in approximately 8% of the 5-10 year-old children and appeared before the development of fatty streaks or other forms of lipid accumulation.


Cyclic-AMP modulates downstream events in CD40-mediated signal transduction, but inhibition of protein kinase A has no direct effect on CD40 signaling.
The role of cAMP/protein kinase A (PKA) in CD40 signal transduction is controversial, with evidence both for and against its importance. In this study we have used a tetracycline-repressible expression system to reversibly express a dominant-negative form of the PKA regulatory subunit type I (PKA-R(G324D)) in a B lymphoma line, M12. Expression of PKA-R(G324D) in M12 lymphomas inhibits both cAMP-mediated growth inhibition and cAMP-mediated induction of B7-2. This inhibition is reversed by tetracycline treatment of the cells to turn off inhibitor expression. In contrast, the expression of the PKA-R(G324D) subunit has no effect on CD40-mediated growth inhibition in M12 cells, nor on CD40-mediated induction of B7-1, CD23, Fas, ICAM-1, or LFA-1. Thus, our data do not support a direct role for cAMP/PKA in CD40-mediated signal transduction. However, we do observe that cAMP can regulate CD40 signaling both positively and negatively. Cyclic-AMP synergizes with CD40-mediated B7-1 induction in M12 lymphomas, while inhibiting CD40-mediated CD23, Fas, and ICAM-1 induction.


Degree of coronary artery disease predicted by exercise testing.
The ability of exercise testing to predict the extent of coronary artery disease was examined in 268 male patients undergoing both coronary angiography and bicycle testing with electrocardiography before coronary artery bypass surgery. When maximal ST-depressions limited by symptoms increased from 0 to 4 mm or more, the percentage of patients with 'serious' coronary disease, defined as either triple vessel disease or left main stem stenosis, increased from 50% to 80% (P = 0.0001). The patients in the lowest third of physical work capacity showed only a slightly increased risk of serious disease. This tendency was abolished in patients who were using beta-blockers, whereas the relationship between ST-depression and disease was not affected by this medication. The probability of finding left main stem stenosis in a patient increased from 5 to 30% with increasing ST-depression: beta-blockers did not affect this relationship, but there was no additional predictive effect of implicating the level of physical work capacity. It is concluded that traditional electrocardiography during exercise is of value when selecting patients for angiography, but that the physical work level obtained during the test does not predict the degree of coronary pathology.