bluuebunny/crossref_metadata_2025 huggingface dataset:
Spontaneous Adrenal Haemorrhage as a Manifestation of Isolated Relapse of Non-Hodgkin’s Lymphoma
Authors: Kartsios Charalambos , Kaloyannidis Panayotis , Yannaki Evangelia , Iordanidis Photios , Penopoulos Vassilios , Sakellari Ioanna , Anagnostopoulos Achilles
Published: December 2003

Retroperitoneal haemorrhage due to metastatic disease is a rare event not previously reported in lymphomas. We describe a 36-year-old woman diagnosed with diffuse large B cell lymphoma (DLBCL) of bone marrow, liver and spleen presenting in the leukaemic phase. The patient attained complete remission after ‘ALL-like’ chemotherapy (cyclophosphamide, vincristine, adriamycin, dexamethasone); 22 months later, she developed an isolated central nervous system (CNS) relapse which was successfully managed with a combination of chemotherapy and CNS irradiation. Six months later, she was rehospitalized because of abdominal pain; an MRI revealed a large haemorrhagic mass in the left adrenal. Surgical removal of the lesion confirmed an adrenal relapse of the primary DLBCL.
Cardiovascular Risk of Young Growth-Hormone-Deficient Adolescents
Authors: Lanes Roberto , Paoli Mariela , Carrillo Eduardo , Villaroel Omar , Palacios Anselmo
Published: December 2003

Objective: To determine whether postprandial lipids, coagulation factors and homocysteine levels are abnormal in young growth hormone (GH)-deficient (GHD) adolescents. Methods: Fifteen GHD adolescents on GH replacement were studied. Ten untreated GHD adolescents and 15 healthy subjects served as controls. Fasting lipids, lipoprotein(a), fibrinogen, plasminogen activator inhibitor-1, homocysteine, folate and vitamin B12 levels were measured. Cholesterol and triglycerides were measured 4 h after a high fat meal. Results: Fasting and postprandial triglycerides and homocysteine levels of untreated GHD patients were increased compared to those of GH-treated GHD subjects and healthy controls; fibrinogen concentrations were elevated in both treated and untreated adolescents. Conclusions: GHD adolescents present an abnormal fasting and postprandial lipid profile. In addition, the increased fibrinogen and homocysteine levels are suggestive of the accumulation of cardiovascular risk factors early on in life.
In utero Allotransplantation of Fetal Hepatocytes in Primates
Authors: Mahieu-Caputo Dominique , Loux Nathalie , Simon Lionel , Allain Jean-Etienne , Beaudoin Sylvie , Bargy Frédéric , Andreoletti Marion , Weber Anne
Published: December 2003

Objective: Because intrauterine transplantation of fetal hepatocytes could become an effective approach for treating severe genetic disorders of the liver, the objective of this study was to demonstrate the feasibility of in utero allotransplantation of fetal hepatocytes in a nonhuman primate model using direct intraparenchymal administration of donor cells. Methods: Fetal primary hepatocytes were isolated from 3 fetal primates (Macaca mulatta) at 89–120 days of gestation, and cryopreserved. When a recipient was available, the cells were thawed and transduced by a β-galactosidase-expressing retrovirus (3 cases) or labelled with a fluorescent dye (4 cases). Hepatocytes were infused directly into the fetal liver under surgical visual control. Engraftment was assessed by surgical liver biopsies taken 8–60 days following transplantation. Results: Six recipients survived until liver biopsy, and 1 died during the surgical procedure. There was no evidence of engraftment in the 3 fetuses that received genetically marked hepatocytes. All 3 monkeys who received 20–25 × 106 hepatocytes from an 89-day-old donor labelled with fluorescent dye had positive liver biopsies 8–11 days following intrauterine transplantation. Conclusions: In utero allotransplantation of fetal hepatocytes is feasible in the nonhuman primate, and direct intraparenchymal administration enables short-term detection of persisting donor hepatocytes.
Prognose von Frühgeborenen mit einem Geburtsgewicht <1501 g
Authors: Urlesberger B. , Müller W.
Published: December 2003

Die Prognose von Frühgeborenen <1501 g ist eng an das Gestationsalter gebunden. Die Mortalität liegt zwischen 10 und 16%, wobei diese vor allem bei einem Gestationsalter ≤26 Schwangerschaftswochen hoch ist. In Bezug auf die neurologische Langzeitprognose ist die Zerebralparese mit einer Inzidenz von etwa 8% in dieser Patientengruppe die häufigste Ursache für Behinderungen. Ähnlich wie bei der Mortalität gibt es grosse Unterschiede in der Inzidenz, welche sich invers proportional zum Gestationsalter verhält. Eine klinisch verifizierte Chorioamnionitis erhöht das Risiko der Entwicklung einer Zerebralparese um bis das Vierfache.
Renoprotective Effects of Losartan in Renal Transplant Recipients
Authors: Iñigo Pablo , Campistol Josep M. , Saracho Ramón , Del Castillo Domingo , Anaya Fernando , Esforzado Nuria , Navarro Maria D. , Oppenheimer Federico
Published: December 2003

Background/Aims: Chronic allograft nephropathy is the main cause of late graft loss and nonimmunological factors, including hypertension and proteinuria, the principal etiological factors. In this context, blockage of the renin-angiotensin system could be helpful. The aim of the present study was to review the renoprotective efficacy of losartan in a large group of renal transplant patients undergoing long-term follow-up. Methods: A retrospective analysis of 276 renal transplant patients treated with losartan was performed. The indication for losartan was arterial hypertension in 163 patients, proteinuria in 37 patients and hypertension plus proteinuria in the remaining 76 patients. Clinical and biochemical parameters before starting losartan treatment (–6 months, –3 months and at baseline) and 3, 6, 9, 12, 18 and 24 months after the introduction of losartan were analyzed. Results: Arterial hypertension significantly decreased after the introduction of losartan (p = 0.000). Serum creatinine was significantly decreased by losartan therapy, and changes in the serum creatinine slope (1/sCr) before and after losartan were statistically significant. Proteinuria markedly decreased after the introduction of losartan. Clinical and biochemical tolerance of losartan was excellent in most patients and only 9 out of the 276 patients (3%) treated with losartan discontinued the drug because of an adverse event. During follow-up, only 3 patients required substitutive treatment with dialysis due to progressive deterioration of renal function in the context of chronic allograft nephropathy. Conclusion: Losartan demonstrated high efficacy as a renoprotective agent in renal transplant patients and could be useful in the treatment and prevention of chronic allograft nephropathy.
Determinants of Arterial Distensibility in Patients with Renal Failure
Authors: Beerenhout Charles M. , Konings Constantijn J.A.M. , Dammers Ruben , Rensma Pieter L. , Hoeks Arnold P.G. , Gladziwa Ulrich , Nieman Fred H.M. , van der Sande Frank M. , Leunissen Karel M.L. , Kooman Jeroen P.
Published: December 2003

Background: An increased stiffness of the arterial system is an adverse risk factor for the outcome in patients with renal disease. Few studies have focused on the determinants of an increased arterial stiffness in patients with renal failure. As the percentage of patients with renal failure secondary to vascular disease and/or diabetes mellitus is rapidly growing, and the underlying disease per se may also influence the arterial wall properties, it may also be of interest to study the arterial wall properties in relation to the etiology of kidney disease. Methods: The distensibility coefficient (DC) of the common carotid artery was used as a marker of arterial stiffness. One hundred and seventeen patients were studied: 47 patients (aged 63 ± 10 years) with renal failure secondary to vascular disease and/or diabetes mellitus and 70 patients (aged 57 ± 13 years) with other diagnoses. The origin of the renal failure was retrieved from the patients’ charts. Results: Age, mean arterial pressure, and serum calcium level were each independent predictors of arterial stiffness (DC). The DC was significantly lower in the patients with vascular renal disease or diabetes mellitus [11.0 ± 5.5 (1/MPa)] as compared with patients with renal/urological diseases [15.4 ± 7.5 (1/MPa)]. Nevertheless, after correction for potentially confounding variables, the relation between cause of renal disease and DC lost significance in the overall group, but remained significant (p < 0.05) in the younger age groups (≤61 years; median age of the patient group). Conclusions: Age, mean arterial pressure, and serum calcium level were independent predictors of arterial stiffness in our patients with renal failure. Only in younger dialysis patients, the origin of renal failure was an independent predictor of arterial wall stiffness.
Regulation of Renal Tubular Bile Acid Transport in the Early Phase of an Obstructive Cholestasis in the Rat
Authors: Schlattjan Jan Henrik , Winter Christian , Greven Joachim
Published: December 2003

Background/Aims: In obstructive liver diseases, urinary excretion of bile acids is markedly enhanced. The mechanism of this effect is not entirely clear. The aim of the present study was to assess the glomerular and tubular factors involved in the renal handling of bile acids during the early phase of an obstructive cholestasis induced by a 24-hour bile duct ligation in rats. Methods: In addition to conventional clearance experiments, taurocholate transport was studied on proximal tubular cells freshly isolated from rat kidneys. The expression of the taurocholate transport protein was determined in these cells by immunoblotting. Results: Glomerular filtration rate and arterial blood pressure were not significantly affected by the cholestasis induced. The 3H-taurocholate and 3H-cholate clearances significantly increased whereas the fractional tubular reabsorption rates of these bile acids significantly fell. Probenecid did not affect the 3H-taurocholate and 3H-cholate clearances. By employing S0960, a specific inhibitor of the sodium-dependent bile salt transporter ASBT, it could be shown that this transporter mediates 3H-taurocholate uptake into the proximal tubular cells. The bile duct ligation caused a significant decrease of the Vmax value of the taurocholate transporter indicating a downregulation of this transporter in cholestasis. The downregulation occurred without a change of the ASBT protein content of the proximal tubular cells. Conclusion: The results demonstrate that there is a functional adaptive downregulation of renal tubular bile acid transport enhancing renal clearance of bile acids during the early phase of an obstructive cholestasis.
Isolation of chromosomal regions controlling intersex development in a marsupial
Authors: Santucciu C. , Grützner F. , Carvalho-Silva D.R. , Graves J.A.M.
Published: December 2003

A marsupial (Sminthopsis douglasi) with bilateral intersexuality had a hemiscrotum on the right side and a hemi-pouch with nipples on the left. A normal female karyotype (2n = 14, XX) was present in cells from the right (male) side, while cells from the left (female) side initially had a female karyotype plus two dot-like chromosomes (2n = 14, XX + 2B). It is proposed that the dots represented a region deleted from the X chromosome that contains the “pouch-mammary/scrotum” (PMS) switch gene whose dosage determines development of a pouch and teats (two doses) or a scrotum (one dose). Mis-segregation early in embryonic development produced a lineage with one normal X and one deleted X (male side), and a lineage with a normal and deleted X, plus two copies of the deleted region (female side). The origin of the supernumerary elements was therefore investigated in the expectation that they may contain the long-sought pouch-mammary/scrotum switch gene. Several elements were microdissected, and amplified DNA was used for in situ hybridization, producing signals in five different chromosome regions including the X. This could represent a region of the X that contains, as well as PMS, repetitive DNA that is present also at other chromosomal sites.
Protein transduction as a strategy for evaluating important factors in mammalian sex determination and differentiation
Authors: Li Y. , Yue L. , Taketo T. , Lau Y.-F.C.
Published: December 2003

Protein transduction is a powerful tool to deliver biologically active protein into mammalian cells and whole animals. Transduced proteins are folded properly and can mediate their respective functions in their hosts. To examine the feasibility of applying this strategy to study the molecular events of gonadogenesis, we have studied the kinetics of protein transduction and stability of transduced protein in in vitro mouse gonad culture systems using two reporter proteins, TAT-β-gal and β-gal fusion proteins with and without the TAT protein transduction domain (PTD) respectively. Our results indicate that the TAT-PTD was critical and essential for protein transduction to cultured fetal gonads. The TAT-β-gal reporter entered the cells of the gonads and mesonephros efficiently for both sexes at E11.5 to E15.5 stages examined. The delivered protein persisted in the gonads for an extended period after an initial one-hour transduction. The distribution of the reporter was relatively even in gonads and mesonephros at E11.5 stage for both sexes and at later stages in female. The transduced protein was distributed heterogeneously in male gonads after seminiferous tubule differentiation in which the amount of reporter protein was higher outside than inside the tubules. Nevertheless, we surmise that such protein delivery technique should be useful in studies designed to evaluate the sex determining or differentiating functions of various new protein factors identified by advanced differential screening strategies.
Diet and General Health: Dietary Counselling
Authors: Sanders Thomas A.B.
Published: December 2003

Dietary guidelines are designed to maintain an adequate intake of nutrients and to protect against diet-related disease, particularly cardiovascular disease and obesity. Current population dietary guidelines advocate a reduction in total fat intake, particularly saturated fat intake, to 25–35% of the energy intake and an increased intake of carbohydrate to more than 55% of the dietary energy intake, which should mainly be derived from starch. There is a positive relationship between total sugar intake and the incidence of dental caries where dental hygiene is poor and exposure to fluoride is low. However, this relationship is stronger for frequency of consumption of sugary foods. The frequent consumption of acidic food and beverages should be also avoided as this can result in erosion of the tooth enamel. Risk of caries can be minimised by good oral hygiene, appropriate exposure to fluoride and by restricting the intake sugar containing snacks between meals to no more than four occasions per day. A need for randomized controlled trials to assess the effectiveness of dietary modification on oral health in adults is identified.
Short-Term versus Long-Term Longitudinal Changes in Processing Speed
Authors: Zimprich Daniel , Hofer Scott M. , Aartsen Marja J.
Published: December 2003

Background: Previous longitudinal studies of cognitive aging have focused on long-term performance changes. A recent surge of research has demonstrated that there are reliable interindividual differences in short-term cognitive performance changes. Objective: The present study links these two pathways of cognitive aging research by examining the association between short-term (learning, practice) versus long-term (development) changes in processing speed. Methods: Data from 963 elderly participants come from the Longitudinal Aging Study Amsterdam (LASA). Results: Nested latent growth curve analyses show that the amount of learning or practice in processing speed at first measurement occasion is positively related (r = 0.72) to individual differences in development of processing speed across 6 years. Conclusions: Short-term learning or practice gains in processing speed are positively associated with long-term developmental changes in processing speed in the elderly.
Gastrointestinal Stromal Tumors: Biology and Treatment
Authors: Duffaud Florence , Blay Jean-Yves
Published: December 2003

Scientific knowledge on gastrointestinal stromal tumors (GIST) has dramatically progressed over the last 10 years. During this period, this distinct disease entity was identified under various acronyms (GIST remaining the most commonly used), the molecular basis of disease transformation (i.e. activating c-kit mutations) was identified in sporadic and familial cases, and finally GIST was identified as the sarcoma subtype most resistant to chemotherapy in both retrospective and prospective studies. Until 2000, surgery was the only reported efficient treatment modality in this disease, both in the localized and metastatic phase. In 2000, the first GIST patient received Glivec, and in the last 3 years, more than 2,000 patients were included in prospective trials evaluating this compound in advanced phases. Disease control is initially achieved in 80–90% of patients, with only 10–15% of patients dying in the first year following the occurrence of metastases, while the median overall survival was less than 12 months with previous treatment options. However, there still remain several questions regarding long-term outcome, tolerance, cure, dose of Glivec, and alternative treatment upon relapse of GIST in patients receiving Glivec. Additional follow-up is necessary. Glivec treatment of GIST is the first example of an efficient targeted treatment in a solid tumor.
Forced Expression of Cytidine Deaminase Confers Sensitivity to Capecitabine
Authors: Morita Tatsuo , Matsuzaki Atsushi , Kurokawa Shinsuke , Tokue Akihiko
Published: December 2003

Objective: Cytidine deaminase (CDD) is involved in the metabolism of new pyrimidine analogues, capecitabine (N4-pentyloxycarbonyl-5′-deoxy-5-fluorocytidine) and gemcitabine (2′,2′-difluorodeoxycytidine). The purpose of the present study was to directly examine the role of CDD in tumor cells themselves in mediating the sensitivity to capecitabine compared with gemcitabine. Methods: The human bladder cancer cell line T24 was transfected with human CDD2 cDNA by the lipofectin method. Results: Transfection of CDD2 cDNA did not change the levels of thymidine phosphorylase, dihydropyrimidine dehydrogenase and thymidylate synthase (TS) but increased the CDD activity significantly (p < 0.01). Forced expression of CDD made T24 sensitive to 5′-deoxy-5-fluorocytidine (5′DFCR) in vitro and capecitabine in vivo, but resistant to gemcitabine both in vitro and in vivo. Tetrahydrouridine, a specific CDD inhibitor, abrogated the changes in the in vitro sensitivity to 5′DFCR and gemcitabine by transfection of CDD2 cDNA. Transfection of CDD2 cDNA resulted in a significant increase in cellular 5-fluorouracil level (p < 0.01) and inhibition of TS activity (p < 0.01) after treatment with 5′DFCR in vitro. Conclusions: The present study clearly showed direct evidence for the contribution of CDD in tumor cells themselves to the sensitivities to capecitabine and gemcitabine.
Regulation of Cell Death in the Lymphoid System by Bcl-2 Family Proteins
Authors: Ivanovska Iva , Galonek Heidi L. , Hildeman David A. , Hardwick J. Marie
Published: December 2003

Programmed cell death is an ordered process that is essential for the normal development and homeostasis of an organism. Dysregulation of this programmed pathway, resulting in either excess cell numbers or unscheduled cell death, underlies a number of disease states. Bcl-2 family proteins play a key role in regulating cell death and survival, and a number of studies have demonstrated their role as important regulators of cell fate in the lymphoid system. Mice that are genetically deficient or overexpress various Bcl-2 family proteins have provided important clues regarding their roles in lymphocyte development, progression of lymphoid tumors and analogous human disorders. In addition, lymphotropic viruses may trigger cell proliferation and inhibit cell death with the help of their own Bcl-2 homologues. Comparing the shared and distinct functions of viral and cellular Bcl-2-related proteins yields new insight into their fundamental mechanisms.
Apoptosis of Neutrophils
Authors: Maianski N.A. , Maianski A.N. , Kuijpers T.W. , Roos D.
Published: December 2003

Regulation of the neutrophil life span by apoptosis provides a fine balance between their function as effector cells of host defense and a safe turnover of these potentially harmful cells. Alterations of neutrophil apoptosis are associated with a number of diseases. As do other cell types, neutrophils possess components of both extrinsic and intrinsic apoptotic routes. The intrinsic pathway of apoptosis seems to be of major importance in neutrophils since they are programmed for a rapid spontaneous cell death. However, in neutrophils this mechanism of apoptosis has special features, probably due to peculiarities of neutrophil mitochondria, which are believed to be a core regulator of intrinsic cell death. A better understanding of mechanisms underlying neutrophil cell death would help to understand neutrophil physiology and contribute to the search of new approaches for handling of pathology related to disturbances in neutrophil apoptosis and also increase our knowledge of inflammation in general.
Role of Apoptotic Processes in Platelet Biogenesis
Authors: Kaluzhny Yulia , Ravid Katya
Published: December 2003

Platelets are anucleate cells that fragment from mature megakaryocytes and play an essential role in thrombosis and hemostasis. Platelets are among the first cell types to be recruited to an injured blood vessel, assisting in endothelial repair. Platelet hyperactivation contributes to the development of atherosclerosis, myocardial infarction, and ischemia of peripheral limbs. A fall in platelet counts, due to a variety of conditions, including disseminated intravascular coagulation, chemotherapy or genetic disorders, may lead, in most severe cases, to death from hemorrhage. This review focuses on the late stages of megakaryocyte differentiation and platelet fragmentation, including associated cytoskeletal changes, and on the importance of apoptotic events for these processes. Studies point to a unique biological system in which programmed cell death may be linked with biogenesis of new cells.
Importance of Adipocytokines in Obesity-Related Diseases
Authors: Matsuzawa Yuji , Shimomura Iichiro , Kihara Shinji , Funahashi Tohru
Published: December 2003

To elucidate the biological characteristics of adipose tissue, we analyzed the gene expression profile of visceral and subcutaneous fat. Unexpectedly, adipose tissue, especially visceral fat, expressed a variety of genes for secretory proteins. About 30% of the genes expressed in visceral adipose tissue encoded secretory proteins and most were biologically active molecules, which we called adipocytokines. We found plasminogen activator inhibitor type 1 and heparin binding EGF-like growth factor. Production of these atherogenic adipocytokines was shown to increase with the accumulation of visceral fat, which may be one of the mechanisms of vascular disease in visceral obesity. We found a unique and novel collagen-like protein, adiponectin, encoded by the most abundantly expressed gene in adipose tissue, termed apM1 (adipose most abundant gene transcript-1). Plasma levels of adiponectin ranged from 0.3 to approximately 3 mg/dl but were decreased in patients with visceral obesity, type 2 diabetes and coronary artery disease (CAD). Screening for mutations in the adiponectin gene revealed that patients carrying a missense mutation showed markedly decreased plasma levels of adiponectin and had CAD. These data suggest that hypoadiponectinemia may be considered an important risk factor for CAD. Cell biology studies revealed that adiponectin has a potent inhibitory effect on the expression of adhesion molecules in endothelial cells and an inhibitory effect on the expression in macrophages. In order to confirm these antidiabetic and antiatherogenic functions of adiponectin, we developed adiponectin knockout mice. Adiponectin knockout mice showed severe insulin resistance and impaired glucose metabolism when fed a high-fat, high-sucrose diet. Knockout mice also developed intimal thickening in response to endothelial injury.
Normal Acquisition and Loss of Bone Mass
Authors: Abrams Steven A.
Published: December 2003

The natural patterns of bone mass accumulation and loss with age represent the templates of individual life cycle periods that are distinguished by marked, physiologically and genetically identifiable, changes in bone mass. During the third trimester of pregnancy, maternal calcium absorption increases and the fetus accumulates about two-thirds of the total bone mass of the term infant. In early infancy, human milk calcium is derived primarily from maternal bone stores, which incur substantial bone losses that are quickly replenished during and after weaning. At puberty, a marked increase in bone mass occurs in conjunction with the initial physical and hormonal changes that characterize this stage. Calcium absorption and bone calcium deposition rates peak in females shortly before menarche. At that time, the bone calcium deposition rate is approximately five times that of adulthood. Skeletal bone mass reaches over 90% of its maximum by age 18 (earlier in females) but does not peak until age 25–30. At some point in mid-life, women experience perimenopause, the 3- to 5-year period prior to menopause during which estrogen levels begin to drop and there are marked increases in bone resorption and loss. Throughout adulthood, calcium absorption efficiency from the diet gradually declines.
Growth Hormone and Bone Health
Authors: Bex Marie , Bouillon Roger
Published: December 2003

Growth hormone (GH) and insulin-like growth factor-I have major effects on growth plate chondrocytes and all bone cells. Untreated childhood-onset GH deficiency (GHD) markedly impairs linear growth as well as three-dimensional bone size. Adult peak bone mass is therefore about 50% that of adults with normal height. This is mainly an effect on bone volume, whereas true bone mineral density (BMD; g/cm3) is virtually normal, as demonstrated in a large cohort of untreated Russian adults with childhood-onset GHD. The prevalence of fractures in these untreated childhood-onset GHD adults was, however, markedly and significantly increased in comparison with normal Russian adults. This clearly indicates that bone mass and bone size matter more than true bone density. Adequate treatment with GH can largely correct bone size and in several studies also bone mass, but it usually requires more than 5 years of continuous treatment. Adult-onset GHD decreases bone turnover and results in a mild deficit, generally between –0.5 and –1.0 z-score, in bone mineral content and BMD of the lumbar spine, radius and femoral neck. Cross-sectional surveys and the KIMS data suggest an increased incidence of fractures. GH replacement therapy increases bone turnover. The three controlled studies with follow-up periods of 18 and 24 months demonstrated a modest increase in BMD of the lumbar spine and femoral neck in male adults with adult-onset GHD, whereas no significant changes in BMD were observed in women. GHD, whether childhood- or adult-onset, impairs bone mass and strength. Appropriate substitution therapy can largely correct these deficiencies if given over a prolonged period. GH therapy for other bone disorders not associated with primary GHD needs further study but may well be beneficial because of its positive effects on the bone remodelling cycle.
Insulin-Like Growth Factor (IGF)-I, IGF Binding Protein (IGFBP)-3, Phosphoisoforms of IGFBP-1 and Postnatal Growth in Very-Low-Birth-Weight Infants
Authors: Kajantie Eero
Published: December 2003

Small preterm infants experience a unique postnatal period characterized by slow growth, inadequate nutrition and growth inhibiting treatments. Many have already been growth-restricted in utero. Studying this period is important when developing growth optimizing strategies for these infants and, in a broader context, as a model of extreme conditions that restrict growth. By following short-term growth of 48 very-low-birth-weight (VLBW; birth weight <1,500 g) infants for 9 postnatal weeks, we found that circulating insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-3 levels are low and reflect rigorously measured (knemometry and weight) concurrent growth velocity. Moreover, weight growth velocity is correlated with the ratio of lesser to highly phosphorylated IGFBP-1 but not with absolute IGFBP-1 concentrations. Thus, IGF-I, IGFBP-3 and the phosphorylation status of IGFBP-1 in circulation are likely to be involved in growth regulation during the postnatal period in VLBW infants.
Correlation of Meropenem Plasma Levels with Pharmacodynamic Requirements in Critically Ill Patients Receiving Continuous Veno-Venous Hemofiltration
Authors: Krueger Wolfgang A. , Neeser Gertraud , Schuster Harald , Schroeder Torsten H. , Hoffmann Edgar , Heininger Alexandra , Dieterich Hans-Juergen , Forst Helmuth , Unertl Klaus E.
Published: December 2003

Background: In patients with acute renal failure, the pharmacokinetics of meropenem depend on the operational characteristics of the renal replacement therapy. Dosage recommendations are based on the correlation of plasma levels with pharmacodynamic requirements. Methods: Eight critically ill patients with acute renal failure were treated by continuous veno-venous hemofiltration with a filtrate flow of 1,600 ml/h and received 500 mg of meropenem every 12 h. Plasma and hemofiltrate concentrations of meropenem at steady state were determined by HPLC. Results: Peak levels in plasma amounted to 39.5 ± 10.5 mg/l (mean ± SD) and trough levels were 2.4 ± 1.5 mg/l. The minimal inhibitory concentration (MIC) for susceptible bacteria (4 mg/l) was covered for 40% of the dosing interval or longer in all patients. The MIC for intermediately susceptible organisms (8 mg/l) was covered for 33% in 6 of the 8 patients. The elimination half-life was prolonged to 3.63 ± 0.77 h. The sieving coefficient of meropenem was 0.91 ± 0.10 and the recovery in hemofiltrate amounted to 30.9 ± 11.5% of the dose. Conclusions: A dosage of 500 mg twice daily provides appropriate serum levels for the treatment of infections caused by susceptible bacteria. A higher dosage is adequate for infections by intermediately susceptible bacteria or for renal replacement therapies with markedly higher filtrate flow rates.
Postantibiotic and Sub-MIC Effects of Benzylpenicillin against Streptococcus pneumoniae with Different Susceptibilities for Penicillin
Authors: Odenholt Inga , Gustafsson Ingegerd , Löwdin Elisabeth
Published: December 2003

Background: The purpose of the study was to examine whether penicillin-susceptible and nonsusceptible strains of Streptococcus pneumoniae exhibited different pharmacodynamic responses to benzylpenicillin. Methods: The postantibiotic effects (PAEs) and the postantibiotic sub-MIC effects (PA SMEs) were investigated by optical density against strains of S. pneumoniae with different susceptibilities to benzylpenicillin. To validate the data, the PAE and PA SME of one susceptible and one resistant strain were also tested with the viable count method. The post-MIC effects (PMEs) were studied in an in vitro kinetic model, simulating human pharmacokinetics with a half-life of 1 h and a time above MIC of approximately 20% of 24 h. Results: There were no differences with respect to the PAEs, PA SMEs and PMEs of benzylpenicillin for the various strains of S. pneumoniae, irrespective of their susceptibility to penicillin. For both some of the susceptible and resistant strains investigated, longer PA SMEs at 0.2 and 0.3 × MIC were noted, indicating that these parameters might be more dependent on the type of strain rather than on the susceptibility status. Conclusion: No differences in the pharmacodynamic response after similar drug exposure were seen for S. pneumoniae strains with different penicillin susceptibility.
The Farnesyl Protein Transferase Inhibitor Lonafarnib (SCH66336) Is an Inhibitor of Multidrug Resistance Proteins 1 and 2
Authors: Wang Er-jia , Johnson William W.
Published: December 2003

Clinical studies indicate that the farnesyl protein transferase inhibitor SCH66336 (lonafarnib), an anticancer agent developed to antagonize oncogenic Ras, is generally well tolerated. Lonafarnib has also demonstrated therapeutic synergy with coadministered taxanes, vincristine, cisplatin, cyclophosphamide, 5-fluorouracil (5-FU) and Gleevec. Lonafarnib has recently been shown, in addition, to be a potent inhibitor of the transmembrane efflux transporter P-glycoprotein (P-gp), which confers cellular resistance to the substrates vincristine, taxol and paclitaxel. Treatment with lonafarnib would therefore be predicted to be synergistic with these coadministered cancer therapeutics that are substrates of P-gp. However, cisplatin, 5-FU and cyclophosphamide are not P-gp substrates, yet cisplatin, 5-FU and possibly cyclophosphamide are purported substrates for multidrug resistance proteins (MRPs) 1 and 2 (known to cause chemotherapy resistance). Lonafarnib is shown here to inhibit the function of MRP1 and MRP2 with a potency similar to that of cyclosporin A and may therefore cause the observed synergy with cisplatin and other agents by inhibiting these MRPs. Coadministration of lonafarnib could thus reduce chemotherapy dosage and hence produce lower exposure to normal cells and less undesired toxicity.
20-MHz Ultrasound and Its Value in Imaging of Lacrimal Plugs
Authors: Tost Frank H.W. , Darman Jaques , Clemens Stefan
Published: December 2003

Background: High-frequency B scan ultrasonography is a proven method for the assessment of anterior segment diseases. Only few studies have used sonography to examine the lacrimal drainage system. We examined the proximal lacrimal drainage system by high-resolution 20-MHz ultrasound to verify the possibility to identify intracanalicular lacrimal plugs. Methods: Eight patients who had received 12 lacrimal plug implants were examined by high-resolution ultrasound. A 20-MHz sector scanner was used for detection and localization of 2 types of intracanalicular plugs (Herrick® lacrimal silicone plug, Smart™ acrylic polymer plug) and 1 punctum plug. Ultrasound examinations were performed 1–24 months after plug placement. Cross-sections of the lacrimal canaliculi were obtained. Results: The various intracanalicular implants were successfully viewed using the 20-MHz ultrasound sector scanner. Intracanalicular plugs were located at the appropriate position as intended. The silicone plugs could be seen as areas of higher reflectivity. In contrast, acrylic polymer plugs were seen as low-reflective inner structures. In a longitudinal echogram, the interface between the acrylic polymer plug and the lacrimal canaliculus produced a strong acoustic impedance. In patients with an intracanalicular acrylic polymer plug, the caliber of the plug could be ascertained and the diameter measured. Conclusion: High-resolution ultrasound with a 20-MHz sector scanner is helpful in detecting intracanalicular plugs and is a valuable tool to assess the migration of lacrimal plugs through lacrimal canaliculi. A 20-MHz sector scanner can be used to identify and locate lacrimal plugs in the proximal drainage system even if biomicroscopic signs or clinical data are absent.
PCR with the Aqueous Humor, Blood Leukocytes and Vitreous of Patients Affected by Cytomegalovirus Retinitis and Immune Recovery Uveitis
Authors: Siqueira Rubens Camargo , Cunha Aldo , Oréfice Fernando , Campos Wesley Ribeiro , Figueiredo Luiz Tadeu M.
Published: December 2003

Purpose: To detect the cytomegalovirus (CMV) genome by PCR in the aqueous humor, blood leukocytes and vitreous of patients affected by retinitis and immune recovery uveitis (IRU). Methods: A PCR for CMV genome detection was carried out with the aqueous humor, vitreous and blood leukocytes of 54 patients with retinitis, including 25 HIV-infected patients presenting CMV retinitis in different stages (active lesion 6 cases, healed lesion 14 cases and IRU 5 cases), and 29 non-HIV-infected patients (retinitis unrelated to CMV) as negative controls. Results:  The CMV genome was detected in the vitreous, aqueous humor and blood leukocytes of 3 out of 6 HIV-infected patients, presenting active lesions in the retina. No CMV genome was detected in the vitreous, aqueous humor and blood leukocytes of the 5 HIV-infected patients presenting IRU. Conclusions:  CMV genome detection by PCR in aqueous humor could be used as a specific and highly predictive technique for confirmation of this infection in the retina. The absence of CMV, based on the results of PCR done in clinical samples of the 5 IRU cases, does not confirm the hypothesis of a viral replication in the vitreous body and aqueous humor of these patients.
Reversal of Reserpine-Induced Orofacial Dyskinesia and Cognitive Dysfunction by Quercetin
Authors: Naidu Pattipati S. , Singh Amanpreet , Kulkarni Shrinivas K.
Published: December 2003

Tardive dyskinesia (TD) is a serious neurological syndrome associated with long-term administration of neuroleptics to humans and experimental animals. The pathophysiology of this disabling and commonly irreversible movement disorder is still obscure. It may be caused by a loss of dopaminergic cells or may be due to free radicals as a product of high synaptic dopamine levels. Quercetin is a bioflavonoid with strong antioxidant properties. Repeated treatment with reserpine (1.0 mg/kg) on each other day for a period of 5 days (days 1, 3 and 5) significantly induced vacuous chewing movements (VCMs) and tongue protrusions (TPs) in rats. Chronic treatment with quercetin for a period of 4 weeks to reserpine-treated animals significantly and dose dependently (50 and 100 mg/kg) reduced the reserpine-induced VCMs and TPs. Reserpine-treated animals also showed poor retention of memory in elevated plus-maze task paradigm. Chronic quercetin administration significantly reversed reserpine-induced retention deficits. Biochemical analysis revealed that chronic reserpine treatment significantly induced lipid peroxidation and decreased the glutathione (GSH) levels in the brains of rats. Chronic reserpine-treated rats showed decreased levels of antioxidant defense enzymes, superoxide dismutase (SOD) and catalase. Chronic administration of quercetin dose dependently (50–100 mg/kg) and significantly reduced the lipid peroxidation and restored the decreased GSH levels by chronic reserpine treatment. It also significantly reversed the reserpine-induced decrease in brain SOD and catalase levels in rats. The results of the present study clearly indicated that quercetin has a protective role against reserpine-induced orofacial dyskinesia and memory impairment. Consequently, the use of quercetin as a therapeutic agent for the treatment of TD should be considered.
Cardioprotective Effects of (2S,3R,4S)-N’-Benzyl-N’’-Cyano-N-(3,4-Dihydro-2-Dimethoxymethyl-3-Hydroxy-2-Methyl-6-Nitro-2H-Benzopyran-4-yl)-Guanidine (KR-31372) in Rats and Dogs
Authors: Lee Byung Ho , Seo Ho Won , Yoo Sung-Eun
Published: December 2003

The cardioprotective effects of (2S,3R,4S)-N′-benzyl- N′′-cyano-N-(3,4-dihydro-2-dimethoxymethyl-3-hydro- xy-2-methyl-6-nitro-2H-benzopyran-4-yl)-guanidine (KR-31372) were evaluated against ischemic/reperfusion injury in isolated rat hearts in vitro and in anesthetized rats and dogs in vivo. In isolated perfused rat hearts subjected to a 30-min global ischemia/30-min reperfusion, KR-31372 (1–10 µM) significantly improved severe contracture (end-diastolic pressure and time to contracture), markedly reduced reperfusion lactate dehydrogenase release, and enhanced the recovery of reperfusion contractile function (left ventricular developed pressure and double product) in a concentration-dependent manner compared with the vehicle-treated group. In anesthetized rats subjected to a 45-min coronary occlusion and a 90-min reperfusion, intravenous KR-31372 dose-dependently reduced infarct size from 58.6% to 48.5, 48.1 and 39.6% at 0.3, 1.0 and 3.0 mg/kg, respectively (p < 0.05). In anesthetized beagle dogs that underwent a 1.5-hour occlusion followed by a 5-hour reperfusion, KR-31372 (2 mg/kg, i.v.) markedly reduced infarct size from 57.0% in controls to 28.0% (p < 0.05). The cardioprotective effects of KR-31372 on contractile function in globally ischemic rat hearts and on reperfusion injury in anesthetized rats were significantly reversed by pretreatment with selective adenosine triphosphate-sensitive potassium (KATP) channel blockers, sodium 5-hydroxydecanoate and glibenclamide. Taken together, these results indicate that KR-31372 possesses potent cardioprotective effects in rats and dogs and its effects may be mediated by activation of mitochondrial KATP channels.
Activities of Pt(II) and Ru(III) Triazole-Pyrimidine Complexes against Trypanosoma cruzi and T. brucei brucei
Authors: Magán Rosa , Marín Clotilde , Rosales Maria Jose , Barrera Mario Antonio , Salas Juan Manuel , Sánchez-Moreno Manuel
Published: December 2003

We studied the biological activity of three newly synthesized metal complexes of triazole-pyrimidine derivatives that were previously observed to inhibit in vitro growth of epimastigotes of Trypanosoma cruzi and procyclic forms of Trypanosoma bruceibrucei. We analyzed the possible inhibitory effect of these compounds on the synthesis of DNA, RNA and protein, ultrastructure and excretion of metabolites by these parasites. RNA synthesis was inhibited by all three complexes assayed. These complexes also led to anomalies of the main organelles (e.g. nucleus, kinetoplast and mitochondria). In addition, these complexes may be capable of altering the excretion of metabolites by the parasites.
Chronic Methionine Load-Induced Hyperhomocysteinemia Enhances Rat Carotid Responsiveness for Angiotensin II
Authors: Bonaventura Daniella , Tirapelli Carlos R. , Haddad Renato , Höehr Nelci F. , Eberlin Marcos N. , de Oliveira Ana M.
Published: December 2003

The purpose of the present study was to investigate the effects of chronic methionine treatment on vascular smooth muscle contractility for angiotensin II (Ang II). Methionine at 0.1, 1 and 2 g/kg body weight was administered daily in the drinking water for 2, 4, 8 and 16 weeks. Rat carotid rings from control and treated animals were placed in an organ chamber containing Krebs solution. Concentration-response curves for Ang II and potassium chloride (KCl) were determined. Methionine-rich diet enhanced the plasmatic homocysteine concentration, and the magnitude of the contractile response to Ang II was increased in carotid rings from treated animals after 8 and 16 weeks. However, the treatment did not alter KCl-induced contraction. In another set of experiments, the rings were incubated with indomethacin and curves for Ang II were obtained. Exposure of the rings to indomethacin inhibited the enhancement in the contractile response to Ang II. The present findings show that chronic methionine treatment enhances homocysteine plasmatic concentration leading to an enhanced Ang-II-induced contraction, which appears to be related to the release of vasoconstrictor prostanoid(s).
Definition and Diagnosis of Dementia with Lewy Bodies
Authors: Ballard Clive G.
Published: December 2003

Significant advances have been made in neuropathologic identification procedures for dementia with Lewy bodies (DLB), but difficulties remain in clinical diagnosis. Consensus criteria state that the core features of DLB are fluctuating cognition with pronounced variation in attention and alertness, recurrent visual hallucinations and spontaneous motor features of parkinsonism. At least two of these features must be present for the diagnosis of probable DLB. Assessments of the validity of the consensus criteria against autopsy generally indicate high specificity but varying sensitivity. More detailed assessments of core diagnostic features or better operationalization, particularly of fluctuating cognition, may help improve the diagnostic guidelines. Greater utilization of some features described as supporting the diagnosis (such as auditory hallucinations) and the potential inclusion of additional symptoms (such as REM sleep behavioral disorder) also may be useful. In addition, the potential role of more detailed neuropsychology and neuroimaging in the diagnostic process needs to be evaluated, although it is important that changes to the diagnostic criteria are based on empirical evidence. Other key issues pertain to the classification of DLB patients with concurrent Alzheimer’s disease and the differentiation of DLB and Parkinson’s disease dementia based on less than a 1-year history of parkinsonism preceding the dementia.
Pharmacologic Treatment Expectations in the Management of Dementia with Lewy Bodies
Authors: Kaufer Daniel I.
Published: December 2003

Recently recognized as an entity separate from Alzheimer’s disease (AD) and Parkinson’s disease with dementia, dementia with Lewy bodies (DLB) is a frequent cause of dementia. It is characterized by progressive cognitive decline and attention deficits, but in contrast to AD, the cognitive changes typically fluctuate over time. Patients with DLB often experience Parkinson-like spontaneous motor features as well as recurrent visual hallucinations. Another frequent finding in DLB is rapid eye movement (REM) sleep disorder. Ideally, each of the major symptom domains associated with DLB (behavioral, motor, and cognitive) would be treated, but drug interactions in these patients are a serious concern. In addition, many patients with DLB are hypersensitive to neuroleptics, which can induce severe extrapyramidal and other symptoms – sometimes ending in death. Compared with conventional neuroleptics, the newer atypical antipsychotic agents may be associated with lower rates of extrapyramidal side effects. Cholinergic deficits in DLB are even more severe than in AD, whereas the extent of cerebral atrophy and neuronal damage may be less. These observations and emerging clinical data support the treatment of DLB with acetylcholinesterase inhibitors. Encouraging results have been obtained from studies of DLB patients treated with rivastigmine, donepezil, and galantamine, but large-scale, controlled trials are needed to confirm the efficacy and safety of acetylcholinesterase inhibitors in patients with DLB.
Giant Colonic Diverticula
Authors: Steenvoorde P. , Vogelaar F.J. , Oskam J. , Tollenaar R.A.E.M.
Published: December 2003

Background: A rare complication of diverticulosis of the colon is giant colonic diverticula (GCD). The condition was first described in English literature in 1953 [1, 2]. Methods: A Medline search was undertaken for English, French and German language articles on ’giant colonic diverticula’. Results: A total of 135 patients were identified, presenting with a total of 155 GCD [1–98]. With a complication rate of 28% and an operative mortality of 5%, GCD seems to have a high clinical significance. Radiological examination of choice seems to be plain abdominal X-ray and CT examination, barium enema carries the risk of perforation of the diverticulum, and should not be performed. Conclusions: There are different therapeutic options, in our opinion diverticulectomy alone is not the treatment of choice. Because of the possibility of recurrence and oncological reasons, colectomy seems to be the best treatment. The creation of a protecting colostomy depends on other operative findings.