Patterns in metabolite profile are associated with risk of more aggressive prostate cancer: A prospective study of 3,057 matched case–control sets from EPIC

Metabolomics may reveal novel insights into the etiology of prostate cancer, for which few risk factors are established. We investigated the association between patterns in baseline plasma metabolite profile and subsequent prostate cancer risk, using data from 3,057 matched case–control sets from the European Prospective Investigation into Cancer and Nutrition (EPIC). We measured 119 metabolite concentrations in plasma samples, collected on average 9.4 years before diagnosis, by mass spectrometry (AbsoluteIDQ p180 Kit, Biocrates Life Sciences AG). Metabolite patterns were identified using treelet transform, a statistical method for identification of groups of correlated metabolites. Associations of metabolite patterns with prostate cancer risk (OR_1SD) were estimated by conditional logistic regression. Supplementary analyses were conducted for metabolite patterns derived using principal component analysis and for individual metabolites. Men with metabolite profiles characterized by higher concentrations of either phosphatidylcholines or hydroxysphingomyelins (OR_1SD = 0.77, 95% confidence interval 0.66–0.89), acylcarnitines C18:1 and C18:2, glutamate, ornithine and taurine (OR_1SD = 0.72, 0.57–0.90), or lysophosphatidylcholines (OR_1SD = 0.81, 0.69–0.95) had lower risk of advanced stage prostate cancer at diagnosis, with no evidence of heterogeneity by follow-up time. Similar associations were observed for the two former patterns with aggressive disease risk (the more aggressive subset of advanced stage), while the latter pattern was inversely related to risk of prostate cancer death (OR_1SD = 0.77, 0.61–0.96). No associations were observed for prostate cancer overall or less aggressive tumor subtypes. In conclusion, metabolite patterns may be related to lower risk of more aggressive prostate tumors and prostate cancer death, and might be relevant to etiology of advanced stage prostate cancer.     

Closed versus open mitral commissurotomy in pure noncalcific mitral stenosis: hemodynamic studies before and after operation

Controversy persists regarding whether the efficacy of closed instrumental mitral commissurotomy compares well enough with that of open commissurotomy to warrant its continued use. The purpose of this study was to compare the results of operation as determined by catheterization studies in 63 patients with pure, severe, and noncalcified mitral stenosis. The patients were randomly assigned to one of two groups: thirty-two patients were operated on by the closed technique (group I) and 31 by the open technique (group II). All patients underwent left-sided and right-sided catheterization before and 4 months after operation. Preoperatively the two groups were statistically similar with regard to major clinical data and hemodynamic findings. There were no deaths at operation or systemic embolism in the two groups. The prevalence of surgically induced mitral regurgitation was similar in the two groups (12.4% versus 12.9%). Pulmonary arterial pressure and arteriolar and total pulmonary vascular resistance decreased significantly in the two groups. Pulmonary capillary wedge pressure decreased from 23.3 +/- 8.5 to 15.8 +/- 7 mm Hg in group I (p less than 0.001) and from 23.7 +/- 6 to 14 +/- 5.8 mm Hg in group II (p less than 0.001). Cardiac index increased from 2.86 +/- 0.84 to 3.14 +/- 0.78 L/min/m2 in group I, but this increase did not reach statistical significance. In group II cardiac index increased from 2.89 +/- 0.6 to 3.6 +/- 0.6 L/min/m2 (p less than 0.005). The mean and end-diastolic transmitral pressure gradients decreased significantly in the two groups, but the decrease was statistically greater in the open mitral commissurotomy group (p less than 0.001). Mitral valve area increased from 0.82 +/- 0.18 to 1.4 +/- 0.40 cm2 in group I (p less than 0.01) and from 0.84 +/- 0.15 to 2.14 +/- 0.53 cm2 in group II (p less than 0.001). The mean increase in mitral valve area was 0.61 cm2 in group I and 1.34 cm2 in group II (p less than 0.001). At exercise, in patients with resting pulmonary capillary wedge pressures of 18 mm Hg or less, cardiac index increased by 36% in group I (23 patients) and 48% in group II (24 patients), because of a smaller mitral valve area in group I (1.61 +/- 0.39 cm2) than in group II (2.45 +/- 0.65 cm2). Thus open commissurotomy improved hemodynamic values to a greater extent than closed commissurotomy at both rest and exercise.(ABSTRACT TRUNCATED AT 400 WORDS)     

Structural white matter abnormalities in patients with idiopathic dystonia

We investigated whether structural white matter abnormalities, in the form of disruption of axonal coherence and integrity as measured with diffusion tensor imaging (DTI), constitute an underlying pathological mechanism of idiopathic dystonia (ID), independent of genotype status. We studied seven subjects with ID: all had cervical dystonia as their main symptom (one patient also had spasmodic dysphonia and two patients had concurrent generalized dystonia, both DYT1‐negative). We compared DTI MR images of patients with 10 controls, evaluating differences in mean diffusivity (MD) and fractional anisotropy (FA). ID was associated with increased FA values in the thalamus and adjacent white matter, and in the white matter underlying the middle frontal gyrus. ID was also associated with increase in MD in adjacent white matter to the pallidum and putamen bilaterally, left caudate, and in subcortical hemispheric regions, including the postcentral gyrus. Abnormal FA and MD in patients with ID indicate that abnormal axonal coherence and integrity contribute to the pathophysiology of dystonia. These findings suggest that ID is not only a functional disorder, but also associated with structural brain changes. Impaired connectivity and disrupted flow of information may contribute to the impairment of motor planning and regulation in dystonia. © 2006 Movement Disorder Society     

Craniosynostosis,ectopia lentis,and congenital heart defects: Further delineation of an autosomal dominant syndrome with incomplete penetrance

The association of craniosynostosis with ectopia lentis is extremely rare. This was recently reported in monozygotic twin sisters, supporting a genetic etiology for this syndromic association. We report on female first cousins once removed who were born with unilateral coronal synostosis. One cousin also had peripheral pulmonic branch stenosis at birth and was later found to have ectopia lentis and severe myopia. The other cousin had an atrial septal defect, mitral valve prolapse, and only mild myopia. Their intelligence is normal. The inheritance is likely autosomal dominant with variable expression and incomplete penetrance and further defines this syndrome to include congenital heart defects. These findings will have important implications for genetic counseling. © 2001 Wiley‐Liss, Inc.     

Health-seeking behavior and the meaning of medications in Balochistan, Pakistan

A wide variety of health care options--home-based, indigenous, and cosmopolitan--exists in northern Balochistan, Pakistan. This paper examines health-seeking behavior in the area of mother and child health for villagers in this pluralistic medical setting. The analysis of a specific series of illness episodes shows that the majority of cases obtain treatment from different medical systems for a single episode. Interest in medications takes precedence over practitioners, and the meaning the villagers attach to such substances is explored. Long-established patterns of behavior relating to indigenous medicine continue to occur when cosmopolitan medicine is utilized. Information presented here helps to explain problems in utilization of cosmopolitan pharmaceuticals and delineates areas for future health programme activity.     

Comparison of DNA fingerprinting by PFGE and PCR-RFLP of the coagulase gene to distinguish MRSA isolates

Staphylococcus aureus isolates were collected from epidemiologically unrelated clinical sources in Japan between 1991 and 1993. A total of 40 isolates, five each of eight coagulase types, were analysed by polymerase chain reaction (PCR) of the coagulase gene, PCR-restriction fragment length polymorphism (RFLP) after AluI digestion, and pulsedfield gel electrophoresis (PFGE) of chromosomal DNA after SmaI digestion. The efficiency of discrimination among the isolates increased in the order of PCR < PCR-RFLP < PFGE, yielding five, 13 and 31 different types, respectively. To assess the clinical use of these methods, 42 additional methicillin-resistant S. aureus (MRSA) isolates collected from 27 inpatients in a hospital were analysed. PFGE and PCR-RFLP were able to discriminate 11 and four types, respectively. PFGE analysis detected cross-infection between four postoperative patients in an intensive-care unit, and in six neonates in intensive care. We conclude that of the three methods tested, PFGE analysis currently allows the most effective discrimination of MRSA strains.     

C3d binding to the circumsporozoite protein carboxy-terminus deviates immunity against malaria

The immunogenicity of recombinant protein or anti-viral DNA vaccines can be significantly improved by the addition of tandem copies of the complement fragment C3d. We sought to determine if the efficacy of a circumsporozoite protein (CSP)-based DNA vaccine delivered to mouse skin by gene gun was improved by using this strategy. Instead, we found that C3d suppressed the protective immunity against Plasmodium berghei malaria infection and deviated immunity, most notably by suppressing the induction of antibodies specific for the CSP C-terminal flanking sequence and by suppressing the induction of CSP-specific IL-4-producing spleen cells. We further showed that C3d bound to the C-terminal flanking sequence of the CSP, which may explain the immune deviation observed in CS/C3d chimeric antigen. We have thus identified C3d-mediated epitope masking and shifting of both the humoral and cellular immune responses as a potential novel escape mechanism, which plasmodia may use to divert the induction of protective immunity.     

Serodiagnosis of tuberculosis and leprosy by enzyme immunoassay

Objective: To evaluate the use of serodiagnosis for tuberculosis and leprosy using mycobacterial antigen 38 kDa, with kits from Omega laboratories, to detect IgG by enzyme immunoassay (EIA).
Method: The study population consisted of 58 patients with evidence of tuberculous infection (culture of Mycobacterium tuberculosis complex or microscopic evidence), of whom 23 had pulmonary and 35 had extrapulmonary disease. There were six subjects who had recently been treated for tuberculosis, 11 patients on treatment for leprosy and 137 patients suspected of having tuberculosis on clinical or radiologic grounds (without laboratory evidence). A control group comprised 35 healthy individuals or patients suffering from diseases other than tuberculosis.
Results: The tests showed that there was a significant difference in antibody levels between the patients with active pulmonary disease, extrapulmonary tuberculosis and leprosy in comparison with the control group ( p <0.001). The sensitivities of the two tests together for proven pulmonary tuberculosis were 100% and 95.7% at 1.0–1.5 and >1.6 EIA cut-off points respectively, while the specificities were 88.5% and 100% at the same cut-off points. The sensitivities for extrapulmonary tuberculosis were 71.4% and only 51.4% at 1.0–1.5 and >1.6 EIA cut-off points. The test was positive in 30 (21.9%) of the 137 suspected patients, while 43 (31.4%) had an equivocal result and the remaining 64 (47.7%) suspects were definitely negative. There was again a significant difference in positivity rates between suspects and the control group.
Conclusions: Omega IgG test is useful in the serodiagnosis of active pulmonary tuberculosis and leprosy, but less sensitive in extrapulmonary disease, particularly in children. Equivocal results may only add to the evidence of tuberculosis in early or minimal disease.     

Interferon Gamma Alters the Phenotype of Rat Thymic Epithelial Cells in Culture and Increases Interleukin-6 Production

Rat thymic epithelial cells (TEC) in long-term culture were characterized by anticytokeratin monoclonal antibodies (mAbs) and electron microscopy. Phenotypic analysis performed by a large panel of mAbs showed that the highest percentage of these cells was of the subcapsular/medullary type. Recombinant rat interferon (IFN)-gamma up-regulated class-I and class-II MHC expression by TEC in culture as confirmed by immunohistochemistry and flow cytometry, but did not significantly alter other cell markers. TEC supernatants of IFN-gamma- treated cultures showed higher interleukin-6 (IL-6) activity, compared to the control, as determined by proliferation of the IL-6-sensitive B9-cell line. Increased IL-6 activity was probably not a consequence of increased TEC number in IFN-gammatreated cultures because IFN did not significantly stimulate TEC proliferation in vitro. In contrast, IL-6 significantly stimulated TEC proliferation, indicating that this cytokine is not only a regulatory molecule for T-cell proliferation, but could also be an autocrine growth factor for thymic epithelium.