Study of morbidity of personnel with potential exposure to vinclozolin.

OBJECTIVES--To examine internal exposure and targeted health outcomes of employees exposed to 3-(3,5-dichlorophenyl)-5-methyl-5-vinyl-1,3-oxazolidine-2,4-dione; chemical abstracts service (CAS) number: 50471-44-8 (vinclozolin). METHODS--A cross sectional study of 67 men exposed to vinclozolin for one to 13 years during synthesis and formulation operations and 52 controls. Biomonitoring was based on determination of urinary metabolites that contained a 3,5-dichloroaniline (3,5-DCA) moiety. Targeted health endpoints were the same as in previous subchronic and chronic animal studies--namely, reversible changes in the concentrations of hormones of the adrenocorticotrophic and gonadotrophic feedback systems, signs of liver injury, haemolytic anaemia, cataract formation (uniquely in rats), and hormonally induced hyperplasia and tumours at high doses. The clinical investigation consisted of a medical and occupational history questionnaire, physical examination, laboratory determinations (including testosterone, LH, and FSH measurements), ultrasonography of the liver and prostate, a detailed eye examination, and routine spirometry. RESULTS--The mean 3,5-DCA concentration for two thirds of the study group exceeded an equivalent of the vinclozolin acceptable daily intake (ADI) used for consumer regulatory purposes. Even the highest concentrations were, however, at least 10 times below the no observable adverse effect level (NOAEL) based on animal studies. Analysis of physical examination and laboratory data provided no evidence of hormonal responses induced by vinclozolin. Furthermore, no evidence of liver injury, prostate changes, cataract formation, or haemolytic anaemia was found. CONCLUSION--There was no evidence of any health effects induced by vinclozolin among employees with potential long term exposure. In particular, no antiandrogenic effects were found.     

Early pathological changes in progressive multifocal leukoencephalopathy: a report of two asymptomatic cases occurring prior to the AIDS epidemic

Serial sections of formalin-fixed, paraffinembedded blocks from two asymptomatic, non-AIDS cases of progressive multifocal leukoencephalopathy (PML) were stained with a double-label immunocytochemical method for detection of glial fibrillary acidic protein and JC virus (JCV) capsid proteins and with luxol fast blue/hematoxylin-eosin. In case 1 small, rounded lesions of about 1-mm diameter were seen within a restricted area in the posterior part of the superior frontal gyrus of both cerebral hemispheres, suggesting an early manifestation of the disease. Fully developed demyelinated lesions of the classical type with JCV-infected oligodendrocytes appeared in the white matter and along its border with the cortex. Lesswell-developed lesions, believed to be precursors to the fully developed ones, were seen in the gray and white matter. Of special interest were areas which contained small collections of enlarged, glial fibrillary acidic protein (GFAP)-positive astrocytes without capsid antigen and which seemed to lack destruction of myelin as judged from the appearance of matching serial sections stained for myelin. Large lesions in the brain of case 2 showed the well-known features of advanced PML. The close relation between some astrocytes and oligodendrocytes with viral antigen raises the possibility of early intercellular passage of virus. Vacuolation, seen within or near lesions in both cases, has previously been noted in the CNS infected by HIV, but not in PML. It is suggested that PML, a disease of both oligodendrocytes and astrocytes, may actually begin in astroglial cells which, under the influence of a restricted JCV infection, become reactive, express GFAP and pass on virus to the more highly susceptible oligodendrocytes with which they are in contact.Supported in part by a grant N.S.07596 from the National Institute of Neurological Disorders and Stroke. The work was carried out in the Laboratory of Experimental Neurophathology, NINDS, and in the Department of Pathology II, Karolinska Institute, Stockholm     

Bacterial hydrogen peroxide contributes to cerebral hyperemia during early stages of experimental pneumococcal meningitis.

Alterations of blood flow contribute to major clinical complications in invasive infections such as sepsis and bacterial meningitis. As a unique feature streptococci -- in particular, Streptococcus pneumoniae, the most frequent pathogen in bacterial meningitis -- release hydrogen peroxide (H(2)O(2)) because of the absence of functional catalase. In a 6 h rat model of experimental meningitis, we studied the impact of bacterial H(2)O(2) production on regional cerebral blood flow (rCBF) and intracranial pressure (ICP). Compared to wild-type D39 pneumococci, the increase of rCBF was diminished in meningitis induced by the H(2)O(2) defective SpxB(-) mutant (maximum increase, 135% +/- 17% versus 217% +/- 23% of the individual baseline; P<0.01) or after treatment of D39-induced meningitis with H(2)O(2)-degrading catalase or with tetraethylammonium (TEA), a blocker of calcium-sensitive potassium channels, which mediate H(2)O(2)-induced vasodilation. Catalase did not significantly reduce the remaining rCBF increase caused by SpxB(-), supporting the predominant role of bacterial H(2)O(2). We conclude that in addition to host-sided mediators, bacterial-derived H(2)O(2) acts as a potent vasodilator, which accounts for a certain proportion of the early cerebral hyperperfusion in pneumococcal meningitis.     

Pharmacokinetic characterization in xenografted mice of a series of first-generation mimics for HLA-DR antibody, Lym-1, as carrier molecules to image and treat lymphoma.

Despite their large size, antibodies (Abs) are suitable carriers to deliver systemic radiotherapy, often molecular image-based, for lymphoma and leukemia. Lym-1 Ab has proven to be an effective radioisotope carrier, even in small amounts, for targeting human leukocyte antigen DR (HLA-DR), a surface membrane protein overexpressed on B-cell lymphoma. Pairs of molecules (referred to as ligands), shown by computational and experimental methods to bind to each of 2 sites within the Lym-1 epitopic region, have been linked to generate small (<2 kDa) molecules (referred to as selective high-affinity ligands [SHALs]) to mimic the targeting properties of Lym-1 Ab. METHODS: A lysine-polyethylene glycol (PEG) backbone was used to synthetically link 2 of the following ligands: deoxycholate, 5-leuenkephalin, triiodothyronine, thyronine, dabsyl-L-valine, and N-benzoyl-L-arginyl-4-amino-benzoic acid to generate a series of 13 bidentate SHALs with a biotin or 1,4,7,10-tetraazacyclododecane-N,N',N',N'-tetraacetic acid (DOTA) chelate attached to the linker. These SHALs have been assessed for their selectivity in binding to HLA-DR10-expressing cells and for their pharmacokinetics and tissue biodistribution in mice. Biotinylated versions of these SHALs discriminated cell lines positive for HLA-DR10 expression with near-nanomolar affinity. The DOTA versions of 4 SHALs were labeled with (111)In for pharmacokinetic studies in mice with HLA-DR10-expressing malignant Raji xenografts. RESULTS: The bidentate, biotinylated, and DOTA-SHALs were synthesized in high-purity, multimilligram amounts. Mean radiochemical and product yields and purities were 90%, 75%, and 90% at mean specific activities of 3.9 MBq/microg (105 microCi/microg) for the (111)In-labeled SHALs. As expected, rapid blood clearance and tumor targeting were observed. The pharmacokinetics of the SHALs was influenced by the component ligands. Biliary clearance, kidney localization, and serum receptor binding contributed to less favorable tumor targeting. CONCLUSION: A series of SHALs was readily synthesized in multimilligram amounts and showed the expected selective binding in vitro. Better selection of the SHAL components should provide second-generation SHALs with improved properties to fulfill the substantial potential of these novel molecular carriers for targeting.     

Structure function interface with sequential shortening of basal and apical components of the myocardial band

Objective: To mechanically test the intact cardiac structure to determine the sequence of contraction within the myocardial mass to try to explain ejection and suction. Methods: In 24 pigs (30–85 kg), segment shortening at the site of sonomicrometer crystals was continuously recorded. The ECG evaluated rhythm, and Millar pressure transducers measured intraventricular pressure and dP/dt. Results: Study of segment shortening defined a sequence of contraction within the myocardial mass, starting at the free wall of the right ventricle and on the endocardial side of the antero-septal wall of the left. Crystal location defined underlying contractile trajectory; transverse in right ventricle followed by basal posterior left ventricle, and from the endocardial anterior wall to the posterior apical segment and finally to the epicardial side of the anterior wall. Mean shortening fraction averaged 18±3%, with endocardial exceeding epicardial shortening by 5±1%. Epicardial segment crystal displacement followed endocardial shortening by 82±23 ms in the anterior wall, and finished 92±33 ms after endocardial shortening stopped, time frame that matches the interval of fast drop of ventricular pressure and the start of suction. Conclusions: Crystal shortening fraction sequence followed the rope-like myocardial band model to contradict traditional thinking, with two starting points of excitation–contraction, the right anterior free wall of the right ventricle, and the endocardial side of the anterior wall. Active suction may be due to active shortening of the epicardial fibers of the anterior wall, because relaxation was not detected when both mitral and aortic valves were closed during the interval previously termed ‘isovolumetric relaxation’.     

Penile rehabilitation following treatment for prostate cancer: an analysis of the current state of the art

Despite recent advances in surgical technique using laparoscopic and robotic approaches for the management of early organ-confined prostate cancer, most contemporary reports demonstrate significant rates of erectile dysfunction comparable to standard open approaches. Controversy remains related to many of the pre-and postoperative management strategies, including agents to enhance nerve recovery, erectogenic drugs, antioxidants, vasoactive injectables, vacuum erection devices and nerve grafting procedures. Additionally, the optimal timing of these interventions and their duration, dose, frequency and outcome thresholds remain ill-defined. In our paper, we provide a comprehensive literature review involving both the basic and clinical data surrounding rehabilitative approaches.     

The hospitalized young adult: new directions for psychiatric treatment.

For effective treatment of young adult psychiatric patients, recognition of the complex interaction of developmental processes and psychopathology is necessary. An inpatient young adult service is described that uses academic engagement to mitigate the threat of hospitalization to identity, maintain age-appropriate activities, and facilitate the transition from hospital to educational settings. Application of the program to other milieus is discussed.