The Anti-HIV potency of cyclotriazadisulfonamide analogs is directly correlated with their ability to down-modulate the CD4 receptor

9-Benzyl-3-methylene-1,5-di-p-toluenesulfonyl-1,5,9-triazacyclododecane (CADA) has been identified as a novel antiviral lead compound with significant anti-human immunodeficiency virus and anti-human herpesvirus 7 activity. Surprisingly, this compound selectively decreased the expression of the CD4 glycoprotein, the primary receptor needed for the entry of both viruses. Herein, we describe the CD4 down-modulating and antiviral potencies of more than 25 CADA derivatives. Flow cytometric evaluation of cellular CD4 receptor expression in T cells demonstrated the specific CD4 down-modulating capacity of the CADA derivatives, with IC(50) values similar to those obtained in the antiviral assays. The close correlation observed between the CD4 down-regulating and anti-HIV potencies of the CADA derivatives further points to CD4 receptor down-modulation as the primary mode of antiviral action for this group of compounds.     

Suicide attempts in the United States: the role of physical illness

The study aimed to determine the relationship between physical illness, mental disorder, and the likelihood of suicide attempt among adults aged 15-54 in the United States. Data were drawn from the National Comorbidity Survey (N=8,098), a national probability sample of adults in the United States. Multivariate logistic regression analyses were used to determine the relationship between self-reported physical illness and the likelihood of suicide attempt. Lung disease (OR=1.8 (1.1, 2.7)), ulcer (OR=2.1 (1.3, 3.4)), and AIDS (OR=44.1 (10.5, 185.6)) were each associated with a significantly increased likelihood of suicide attempt, independent of the effects of mental disorders. Consistent with previous studies, the number of physical illnesses was linearly related to an increased odds of suicide attempt (OR=1.3 (1.2, 1.5)). Possible mechanisms for these associations are discussed. These findings call for the inclusion of a range of physical health problems, especially chronic illnesses, in future research on suicide attempts in the population.     

Molecular and antibiofilm approaches to prosthetic joint infection

The majority of patients with prosthetic joint replacement (arthroplasty) experience dramatic relief of pain and restoration of satisfactory joint function. In the United States, more than.5 million people have a primary arthroplasty each year. Less than 10% of prosthesis recipients have complications develop during their lifetime, commonly as a result of aseptic biomechanical failure, followed by prosthetic joint infection. The pathogenesis of prosthetic joint infection is related to bacteria in biofilms, in which they are protected from antimicrobial killing and host responses rendering these infections difficult to eradicate. Current microbiology laboratory methods for diagnosis of prosthetic joint infection depend on isolation of a pathogen by culture. However, these methods have neither ideal sensitivity nor ideal specificity. Therefore, culture-independent molecular methods have been used to improve the diagnosis of prosthetic joint infection. In the research setting, detection of 16S ribosomal deoxyribonucleic acid by polymerase chain reaction has been used in the molecular diagnosis of prosthetic joint infection. Various antibiofilm strategies directed at disruption of adherent bacteria are the focus of intense research to improve the detection of biofilm organisms and their eradication. In this article, molecular and antibiofilm approaches to prosthetic joint infection are reviewed.     

Detection and molecular characterisation of noroviruses and sapoviruses in asymptomatic swine and cattle in Slovenian farms

Acute infectious caliciviral gastroenteritis is a common illness in people all over the world. Two genera of the Caliciviridae family, Norovirus and Sapovirus, which usually cause disease in humans, can also be found in animals where they do not always cause clinical signs of gastroenteritis.To investigate the presence of norovirus (NoV) and sapovirus (SaV) strains in asymptomatic swine and cattle, a total of 525 faecal (406 pigs and 119 cattle) specimens were collected during 2004 and 2005 from 8 pig and 4 cattle farms geographically dispersed across Slovenia. RT-PCRs and sequencing were carried out using primers targeting RdRp and capsid regions of both NoVs and SaVs. NoV positivity was detected in both bovine (2/108 [1.9%]) and porcine (5/406 [1.2%]) faecal specimens while SaV positivity was present only in porcine (29/406 [7.1%]) specimens. All porcine NoV strains (n = 5) detected were attributed to a single farm, while the porcine SaV strains (n = 29) detected came from 5 different farms. Phylogenetic analysis of nucleotide sequences of partial RdRp fragments placed two of the bovine NoV strains in genogroup GIII. Of the 5 porcine NoV strains, 4 clustered with GII.11, while 1 strain showed the presence of GII.18. The majority [24/29, 82.7%] of the porcine SaV strains clustered in GIII within two separate lineages, while 5 strains clustered into recently identified genetic clusters GVII (3 strains), GVIII (1 strain) and unknown (1 strain), respectively.Although NoV and SaV strains in asymptomatic swine and cattle were detected at low levels, they were still phylogenetically placed in a common pattern within both genera showing great genetic variability. There were no detected human-like strains in this study.     

Genetic polymorphisms in vasoactive genes and preeclampsia: a meta-analysis

There are controversies in reports on the association of polymorphisms in endothelial nitric oxide synthase, angiotensinogen, angiotensin receptor type 1 and angiotensin-converting enzyme genes with an increased risk of developing preeclampsia. We performed a systematic search of published case-control studies through the PubMed database up to January 2006, and report the results of a meta-analysis of polymorphisms investigated in more than five studies: Glu298Asp in eNOS gene (9 analyses involving 1055 patients and 1788 controls), Met235Thr in AGT gene (13 analyses involving 1128 patients and 2278 controls), and intron 16 insertion-deletion polymorphism in ACE gene (10 analyses involving 1121 patients and 1361 controls). Statistically significant associations with preeclampsia were identified for the Met235Thr/AGT polymorphism: OR 1.65 (95% CI 1.19, 2.29) if the polymorphism is considered under the dominant genetic model, and OR 1.54 (95% CI 1.12, 2.11) under the recessive model. For insertion-deletion/ACE polymorphism, statistical significance was demonstrated when the polymorphism was considered under the recessive model: OR 1.51 (95% CI 1.17, 1.94). No single polymorphism was identified as having a major effect.     

Short-term effects of a new bicarbonate/lactate-buffered and conventional peritoneal dialysis fluid on peritoneal and systemic inflammation in CAPD patients: a randomized controlled study.

OBJECTIVES: This study was designed to compare the local peritoneal and systemic inflammatory effects of a conventional lactate-based (Lac) peritoneal dialysis (PD) solution and a new biocompatible bicarbonate/lactate-based (Bic/Lac) solution having low concentration of glucose degradation products. METHODS: 26 stable, prevalent PD patients were enrolled in this prospective study. They sequentially underwent 3 months of therapy with the Lac solution and 3 months with the Bic/Lac solution in a randomized order. Flow cytometry was used to measure the expression of inflammatory molecules on peritoneal cells in overnight effluent collected at the end of each study period. RESULTS: 21 patients successfully completed the study. Mean fluorescence intensity of human leukocyte antigen (HLA)-DR and CD14 expression by macrophages were not different between Lac and Bic/Lac. The peritoneal appearance rate of cancer antigen 125 (kU/minute) was 68 +/- 37 with Lac and 133 +/- 66 with Bic/Lac (p < 0.001), and of interleukin (IL)-6 (ng/minute), 0.28 +/- 0.2 with Lac and 0.18 +/- 0.16 with Bic/Lac (p = 0.014). HLA-DR macrophage expression and IL-6 peritoneal appearance rates did not correlate. Serum concentrations with Lac and Bic/Lac were, for IL-6, 3.49 +/- 2.28 and 3.72 +/- 2.46 ng/L (p = 0.17), and for high-sensitivity C-reactive protein, 2.31 +/- 2.98 and 2.71 +/- 3.31 mg/L (p = 0.32) respectively. The concentration of effluent macrophages (x10(6)/L) with Lac was 1.6 +/- 1.6 and with Bic/Lac 2.6 +/- 3.3 (p = 0.07). CONCLUSIONS: We conclude that, although there was a significant reduction in peritoneal IL-6 in patients using Bic/Lac solution, systemic levels of inflammatory markers did not differ between the two solutions and no changes were present in macrophage surface activation markers, suggesting perhaps a less important role of peritoneal macrophages in the intraperitoneal chronic inflammatory process. The number of effluent macrophages tended to be higher in patients using the Bic/Lac solution, possibly contributing to improved intraperitoneal defense.     

Diagnostic Parameters to Differentiate Benign From Malignant Ovarian Masses With Contrast‐Enhanced Transvaginal Sonography

Objective. The aim of this study was to evaluate diagnostic parameters to differentiate between benign versus malignant ovarian masses using contrast‐enhanced transvaginal sonography (TVS). Methods. Thirty‐three consecutive patients with 36 morphologically abnormal ovarian masses (solid or cystic with papillary excrescences, focally thickened walls, or irregular solid areas) smaller than 10 cm received a microbubble contrast agent intravenously while undergoing pulse inversion harmonic TVS. The following parameters were assessed: presence of contrast enhancement, time to peak enhancement, peak contrast enhancement, half wash‐out time, and area under the enhancement curve (AUC). Tumor histologic analysis was used to distinguish benign from malignant ovarian tumors. Results. Twenty‐six benign masses and 10 malignancies were studied. Of all examined criteria, an AUC of greater than 787 seconds^?1 was the most accurate diagnostic criterion for ovarian cancer, with 100.0% sensitivity and 96.2% specificity. Additionally, peak contrast enhancement of greater than 17.2 dB (90.0% sensitivity and 98.3% specificity) and half wash‐out time of greater than 41.0 seconds (100.0% sensitivity and 92.3% specificity) proved to be useful. Conclusions. Our data suggest that the AUC, peak enhancement, and half wash‐out time had the greatest diagnostic accuracy for contrast‐enhanced TVS in differentiation between benign and malignant ovarian masses.     

Molecular mechanisms of insulin resistance and associated diseases

Insulin resistance is a state in which higher than normal concentrations of insulin are required for normal response. The most common underlying cause is central obesity, although primary insulin resistance in normal-weight individuals is also possible. Excess abdominal adipose tissue has been shown to release increased amounts of free fatty acids which directly affect insulin signalling, diminish glucose uptake in muscle, drive exaggerated triglyceride synthesis and induce gluconeogenesis in the liver. Other factors presumed to play the role in insulin resistance are tumour necrosis factor alpha, adiponectin, leptin, IL-6 and some other adipokines. Hyperinsulinaemia which accompanies insulin resistance may be implicated in the development of many pathological states, such as hypertension and hyperandrogenaemia. Insulin resistance underlies metabolic syndrome and is further associated with polycystic ovary syndrome and lipodystrophies. When beta-cells fail to secrete the excess insulin needed, diabetes mellitus type 2 emerges, which is, besides coronary heart disease, the main complication of insulin resistance and associated diseases.     

Microcalorimetry: a novel method for detection of microbial contamination in platelet products

BACKGROUND: Measuring heat from replicating microorganisms in culture may be a rapid, accurate, and simple screening method for platelets (PLTs). Microcalorimetry for detection of microorganisms in in vitro contaminated PLT products was evaluated. STUDY DESIGN AND METHODS: Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus sanguinis, Escherichia coli, Propionibacterium acnes, and Candida albicans were inoculated in single-donor apheresis PLTs to achieve target concentrations of 10(5), 10(3), 10, or 1 colony-forming units (CFU) per mL of PLTs. Contaminated PLTs in growth medium were incubated at 37 degrees C for 5 days in a calorimeter. Positivity was defined as heat flow of at least 10 microW above the lowest value of the power-time curve. RESULTS: With microcalorimetry, inocula of 10 CFUs per mL PLTs could be detected with the following detection times: S. epidermidis (31.65 hr), S. aureus (24.24 hr), S. sanguinis (7.82 hr), E. coli (7.53 hr), P. acnes (73.57 hr), and C. albicans (43.77 hr). The detection time was less than 4 hr at 10(5) CFUs per mL PLTs for S. aureus, S. sanguinis, and E. coli. Noncontaminated PLTs remained negative. The total heat ranged from 2.8 (S. sanguinis) to 8.3 J (E. coli).The shape of the power-time curve was species-specific and independent from the initial concentration of microorganisms. CONCLUSION: The detection limit of microcalorimetry was 1 to 10 CFUs per mL PLTs. Microcalorimetry is a promising novel method for detection of contaminated PLTs. Applying this method to all PLT products could reduce the frequency of transfusion-related sepsis and prolong the shelf life of PLTs.