Angiomyofibroblastoma of the vulva

A 30-year-old female presented with unilateral labial enlargement. The clinical impression was that of a benign cyst. The microscopic features were that of angiomyofibroblastoma showing hyper and hypocellular areas containing spindle and plump stromal cells admixed with blood vessels. This tumour is benign with extremely low rate of recurrence. Surgery is the only treatment as in this case.     

Prior Incarceration and Barriers to Receipt of Services among Entrants to Alternative to Incarceration Programs: A Gender-Based Disparity

The high levels of health and psychosocial needs among correctional populations strongly shape the well-being of the urban communities from which a large number of criminal justice-involved individuals come or to which they return. The benefits of providing services to correction-involved individuals and linking them to providers such as with alternative to incarceration (ATI) programs may be limited if they encounter difficulties accessing such services. This study identified the types of barriers that have prevented entrants into ATI programs from receiving health and psychosocial services. We then tested the association between number of prior incarcerations and number of barriers by gender. From a random sample of adults (N = 322; 83 women and 239 men) entering ATI programs in New York City, data were collected via structured interviews that elicited self-reported sociodemographics, substance use, prior incarcerations, and barriers that had actually prevented a participant from visiting or returning to a service provider. Participants reported an average of 3.0 barriers that have prevented them from receiving health and psychosocial services. The most prevalent barriers predominantly concerned service providers’ inability to accommodate constraints on participants’ time availability or flexibility, transportation, and money. Compared to women, men had a significantly different association that was in the adverse direction—i.e., more prior incarcerations was associated with more barriers—between prior incarcerations and encountering service barriers. Findings indicate that ATI program entrants experience many barriers that have prevented them from receiving health and/or psychosocial services. Furthermore, men with more extensive incarceration histories particularly are disadvantaged. ATI programs can improve the public health of urban communities if such programs are prepared and resourced to facilitate the receipt of services among program participants, especially men who have more extensive incarceration histories.     

Role of bile acids and neutral sterols in familial cancer syndromes of the colon

Cholesterol is quantitatively the most significant sterol in mammalian tissues. The major metabolic pathway of this sterol leads to the formation of bile acids. The structural similarities between carcinogenic aromatic hydrocarbons and bile acids aroused the suspicion that bile acids might play a role in carcinogenesis. In familial polyposis, a condition with a strong genetic predisposition to colonic cancer, a failure to degrade fecal cholesterol and bile acids to secondary products has been postulated as a marker of the phenotypic expression of this condition. In contrast, epidemiologic studies in populations at high risk for colonic cancer, and consuming diets rich in animal fat, protein, and refined carbohydrates, show a positive correlation with high fecal concentrations of bile acids and their metabolites. The suggestion that secondary bile acids might act in concert with colonic carcinogens in promoting neoplastic transformation is supported by observations from experimental studies. Among the secondary bile acids, lithocholic acid is unique in that it has been shown to be comutagenic, promote cell transformation, and induce DNA strand breakage,in vitro. It has also been shown to bind covalently to tissue proteins in human liver and in livers of carcinogen-treated rats.     

Peptidoglycan Cross-Linking in Glycopeptide-Resistant Actinomycetales

Synthesis of peptidoglycan precursors ending in d-lactate (d-Lac) is thought to be responsible for glycopeptide resistance in members of the order Actinomycetales that produce these drugs and in related soil bacteria. More recently, the peptidoglycan of several members of the order Actinomycetales was shown to be cross-linked by l,d-transpeptidases that use tetrapeptide acyl donors devoid of the target of glycopeptides. To evaluate the contribution of these resistance mechanisms, we have determined the peptidoglycan structure of Streptomyces coelicolor A(3)2, which harbors a vanHAX gene cluster for the production of precursors ending in d-Lac, and Nonomuraea sp. strain ATCC 39727, which is devoid of vanHAX and produces the glycopeptide {"type":"entrez-nucleotide","attrs":{"text":"A40296","term_id":"2296392","term_text":"A40296"}}A40296. Vancomycin retained residual activity against S. coelicolor A(3)2 despite efficient incorporation of d-Lac into cytoplasmic precursors. This was due to a d,d-transpeptidase-catalyzed reaction that generated a stem pentapeptide recognized by glycopeptides by the exchange of d-Lac for d-Ala and Gly. The contribution of l,d-transpeptidases to resistance was limited by the supply of tetrapeptide acyl donors, which are essential for the formation of peptidoglycan cross-links by these enzymes. In the absence of a cytoplasmic metallo-d,d-carboxypeptidase, the tetrapeptide substrate was generated by hydrolysis of the C-terminal d-Lac residue of the stem pentadepsipeptide in the periplasm in competition with the exchange reaction catalyzed by d,d-transpeptidases. In Nonomuraea sp. strain ATCC 39727, the contribution of l,d-transpeptidases to glycopeptide resistance was limited by the incomplete conversion of pentapeptides into tetrapeptides despite the production of a cytoplasmic metallo-d,d-carboxypeptidase. Since the level of drug production exceeds the level of resistance, we propose that l,d-transpeptidases merely act as a tolerance mechanism in this bacterium.     

Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy

Autosomal-dominant Stargardt-like macular dystrophy [Stargardt3 (STGD3)] results from single allelic mutations in the elongation of very-long–chain fatty acids-like 4 (ELOVL4), whereas recessive mutations lead to skin and brain dysfunction. ELOVL4 protein localizes to the endoplasmic reticulum, where it mediates the condensation reaction catalyzing the formation of very-long–chain (VLC) (C-28 to C-40) fatty acids, saturated and polyunsaturated (PUFA). The defective gene product is truncated at the C terminus, leading to mislocalization and aggregation in other organelles. We hypothesized that the STGD3 truncated mutant may generate mislocalized, and therefore toxic, keto intermediates of fatty acid elongation, thereby contributing to the disease process. Using cell-based and cell-free microsome assays, we found that the truncated protein lacked innate condensation activity. Coexpression of different forms of wild-type and mutant ELOVL4 revealed a large dominant-negative effect of mutant protein on ELOVL4 localization and enzymatic activity, resulting in reduced VLC-PUFA synthesis. The reduction in VLC-PUFA levels in STGD3 and age-related macular degeneration may be a contributing factor to their retinal pathology.     

Toxic effects of antileishmanial reverse-phase evaporation liposomes containing dicetyl phosphate in monkeys

Liposomes containing or lacking encapsulated pen-tavalent antimony (Sb), a widely used antileishmanial agent, were administered to cynomolgous monkeys to investigate possible toxicity. The liposomes consisted of either reverse-phase evaporation vesicles (REV) composed of dipalmitoyl phosphatidylcholine, choles- terol (CHOL), and dicetyl phosphate (DCP) or mul- tilamellar vesicles (MLV) composed of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol, with or without CHOL. Toxicity was observed in monkeys receiving REV containing or lacking Sb as evidenced by thrombocytopenia, splenomegaly, and hemorrhage. The severity of the symptoms was potentiated by two factors, the presence of Sb in REV and the frequency of REV administration. In contrast, no significant adverse reactions were observed in animals treated with MLV containing or lacking Sb. Since the main difference between REV and MLV was the presence of DCP in REV, this observation suggested that toxicity was due, at least partly, to DCP. An alternative theoretical mechanism for the toxic reaction was also investigated, namely, thrombocytopenia caused by complement activation induced by naturally occurring autoantibodies to liposomal components. All monkeys in the present study had high levels of autoantibodies to lipids that were detected by complement-dependent lysis of test liposomes. The levels of these antibodies decreased after injection of MLV or REV, indicating that both REV and MLV reacted with preexisting autoantibodies to lipids in monkey serum that were able to cause complement activation. Al- though complement-activating autoantibodies to lipids were present with both REV and MLV, in view of the observation that toxicity occurred exclusively with REV, our results suggest that REV induced the toxicity.     

Identification of subcellular organelles involved in Ba2+- and Cd2+-induced adrenomedullary secretion

To determine which subcellular organelles of bovine adrenal medulla are mainly involved in catecholamine secretion evoked by Ba²⁺ or Cd²⁺, glands were stimulated with these trace metals and subsequently subcellular fractions were assayed for Ba or Cd. Media of varying pH were used since low H+ concentrations are thought to promote Ba²⁺ and Cd²⁺ penetration into adrenal medulla. Of all the adrenomedullary fractions isolated, only the microsomes contained significantly more Cd when exposure to Cd²⁺ was accomplished at the high pH, and only mitochondrial Ba was enhanced after exposure to Ba²⁺ at the high pH. Furthermore, a significant correlation was found between adrenal catecholamine release and residual microsomal Cd. Similary, adrenal catecholamine release by Ba²⁺ was proportional to the Ba content of mitochondria. Since Cd and Ba levels in tissue fractions were determined only after a 15-min washout of the adrenals with trace metal-free Locke's solution, residual Cd and Ba in microsomes and mitochondria, respectively, probably represent metallic cations removed from the cytoplasm during termination of the secretory response. It is therefore proposed that microsomal structures remove Cd²⁺ from the cytoplasm to limit Cd²⁺-induced adrenal catecholamine release and that mitochondria remove Ba²⁺ from adrenomedullary cytoplasm to terminate Ba²⁺-induced catecholamine release.     

Surface treatment: a potential approach for enhancement of solid-state photostability

The potentials of a simple surface treatment technique aiming at modifying solid-state properties with emphasis on photostability were investigated using methyldopa (MD), a photosensitive drug substance. MD was treated with a preselected solvent by stirring a drug suspension in the solvent in a predetermined solid/solvent ratio under controlled conditions. At the end of the solvent treatment period, MD powder was separated, dried and screened. Changes in the solid-state properties of surface-treated MD were monitored using flowability measurements, scanning electron microscopy, thermal analysis and dissolution rate. Further, photostability testing, according to the ICH guidelines, was conducted using compressed disks of MD treated with solvents in the absence and presence of antioxidants, namely ascorbic acid, butylated hydroxytoluene (BHT) and cysteine HCl. The color change (DeltaE) was determined according to the CIELAB system. Surface treatment of MD drug substance with ethanol, methanol and isopropanol resulted in a marked improvement in flowability which was associated with morphological crystalline changes. Treatment of MD with methanol provided free flowing spherical agglomerates. Disks of solvent-treated MD showed improved photostability which was further potentiated by the inclusion of antioxidants, although only traces of the antioxidant were retained in the treated powder. Tablets containing MD surface treated with methanol containing a mixture of 2% ascorbic acid and 0.2% BHT were prepared by direct compression using a simple formula. The tablets conformed to official requirements.     

Effect of pentoxifylline on hepatic injury caused in the rat by the administration of carbon tetrachloride or acetaminophen

The effect of pentoxifylline (PTX) on acute liver injury caused by CCl4 or acetaminophen was studied in the rat. PTX was given twice daily (18, 36 or 72 mg/kg), intraperitoneally (ip) for 5 days prior to CCl4 or acetaminophen. In addition, the effect of PTX administered simultaneously with CCl4 or acetaminophen was evaluated. Rats were killed 72 h or 48 h after CCl4 or acetaminophen administration, respectively. The administration of PTX at 72 mg/kg, conferred significant protection against the hepatotoxic actions of CCl4, reducing serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels to 31%, 59.2% and 63%, respectively. Histological examination showed a decrease in centrilobular necrotic areas in rats pretreated with PTX. Histochemical investigation revealed a decrease in glycogen and protein contents caused by CCl4 and these were prevented by PTX pretreatment. When administered with CCl4, PTX did not reduce CCl4-induced hepatic injury. In contrast, hepatic injury induced by acetaminophen was prevented by prior or co-treatment with PTX. Accordingly, with 72 mg/kg of PTX, the elevation of AST, ALT and ALP levels was lower by 45%, 80.6%, 54.3% for the former and by 32.4%, 77.2%, 52.4% for the latter, respectively. Stained sections were subjected to morphometric evaluation using computerized image analyzer. Quantitative analysis of the acetaminophen area of damage showed a reduction by 34.8, 65.5 and 89.2% by 18, 36 or 72 mg/kg for PTX, respectively. Rats treated with PTX revealed more or less normal hepatocyte architecture as well as marked improvement in protein and glycogen content. The study demonstrates that prior but not co-toxicant administration of PTX in a model of CCl4-induced liver injury results in less liver damage. In contrast, PTX is equally protective, when given either as a pretreatment or with acetaminophen exposure.