Computational chemical analysis of unconjugated bilirubin anions and insights into pKa values clarification

The pKa, the negative logarithm of the acid dissociation equilibrium constant, of the carboxylic acid groups of unconjugated bilirubin in water is a discussed issue because there are quite different experimental values reported. Using quantum mechanical calculations we have studied the conformational behavior of unconjugated bilirubin species (in gas phase and in solution modeled implicitly and explicitly) to provide evidence that may clarify pKa values because of its pathophysiological relevance. Our results show that rotation of carboxylate group, which is not restricted, settles it in a suitable place to establish stronger interactions that stabilizes the monoanion and the dianion to be properly solvated, demonstrating that the rationalization used to justify the high pKa values of unconjugated bilirubin is inappropriate. Furthermore, low unconjugated bilirubin (UCB) pKa values were estimated from a linear regression analysis.Fil: Vega Hissi, Esteban Gabriel. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Estrada, Mario Rinaldo. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; ArgentinaFil: Lavecchia, Martín José. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Centro de Química Inorgánica; ArgentinaFil: Pis Diez, Reinaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Centro de Química Inorgánica; Argentin

Sexual behavior research on a Cohort of gay men, 1984–1990: Can we predict how men will respond to interventions?

In 1984, over 1000 gay and bisexual men volunteered to participate in both the Chicago Multicenter AIDS Cohort Study (MACS) and a companion psychosocial study, the Coping and Change Study (CCS). Participants in the semiannual Chicago MACS/CCS evaluations comprise the largest cohort of high-risk men under continuous medical, behavioral, and psychosocial observation. Chicago MACS/CCS researchers prospectively chart the sexual behavior change patterns of the cohort and relate those behavioral changes to psychosocial correlates and actual HIV infection risk. This report summarizes the behavioral natural history of the Chicago MACS/CCS cohort from 1984 to 1990, focusing on receptive anal sex practices and use patterns for alcohol and the most frequently used recreational drugs. As these are prospective observational and not controlled intervention studies, psychosocial correlates of sexual behavior change by members of the cohort are suggestive of factors influencing behavior change rather than indicative of causal relationships. However, the voluntary availability to participants in the Chicago MACS/CCS of HIV-1 antibody test results beginning in late 1985 provided the opportunity to examine whether demographic, psychosocial, or behavioral factors were indicators of sexual behavior change following disclosure and counseling about HIV-1 serostatus. Recommendations for promotion and maintenance of safer sexual behavior for the long run, and limitations in the generalizability of these findings to the much more diverse populations of men who have sex with other men conclude this article.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44099/1/10508_2005_Article_BF01541496.pd

Amici Curiae Brief of the International Municipal Lawyers Association and Legal Scholars in Support of Defendants-Appellees in Portland Pipe Line Corporation, et al. v. City of South Portland, et al.

This brief to the Maine Supreme Judicial Court was filed in support of the City of South Portland by the Amici Curiae, including the International Municipal Lawyers Association and legal scholars, to provide the Court with a background on the role of local governments in land use planning, and to explain why the City of South Portland’s Clear Skies Ordinance falls easily within the City’s authority and was not preempted by state legislation.After studying the potential for bulk loading of crude oil within its boundaries, the City of South Portland concluded that the infrastructure requirements and environmental impacts of the activity posed a threat to public health and welfare and were incompatible with the community’s vision of itself for the future. The City therefore decided to enact the Clear Skies Ordinance, which prohibits the storing and handling of petroleum or petroleum products for the bulk loading of crude oil onto any marine tank vessel in specified zoning districts. Litigation followed, with plaintiffs arguing that the City lacked authority to enact the Ordinance and that, even if it had such authority in the first instance, that authority had been preempted by other state law. Defendants prevailed on summary judgment in the U.S. District Court for the District of Maine, and during the course of an appeal to the United States Court of Appeals for the First Circuit, the Circuit certified several questions to the Maine Supreme Judicial Court. This brief was filed in support of the City with regard to those certified questions.The brief begins by discussing how central the role of local governments is in making land use decisions, emphasizing the highly localized impacts of land use decisions for public health and welfare. It then describes the zoning mechanisms by which local governments exercise their land use power, and discusses why the zoning power is so important for protecting public health and environmental quality, and responding to the changing needs of communities.Next, the brief explains the legal underpinnings of the City of South Portland’s home rule authority. The Constitution of the State of Maine contains a broad grant of home rule authority that is further strengthened by a statutorily imposed rebuttable presumption of validity for exercises of that authority. Local exercises of zoning authority are consistent within this home rule grant, and the brief discusses why the Clear Skies Ordinance falls squarely within the local zoning power. Finally, the brief explains why the Ordinance has not been expressly or impliedly preempted by state law. For all of those reasons, the brief concludes that the City’s enactment of the Ordinance was valid in the first instance and should not be overturned

A prospective study of alcohol consumption and HIV acquisition among injection drug users

Estimate the effect of alcohol consumption on HIV acquisition while appropriately accounting for confounding by time-varying risk factors

Modulation of Mrp1 (ABCc1) and Pgp (ABCb1) by Bilirubin at the Blood-CSF and Blood-Brain Barriers in the Gunn Rat

Accumulation of unconjugated bilirubin (UCB) in the brain causes bilirubin encephalopathy. Pgp (ABCb1) and Mrp1 (ABCc1), highly expressed in the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) respectively, may modulate the accumulation of UCB in brain. We examined the effect of prolonged exposure to elevated concentrations of UCB on expression of the two transporters in homozygous, jaundiced (jj) Gunn rats compared to heterozygous, not jaundiced (Jj) littermates at different developmental stages (2, 9, 17 and 60 days after birth). BBB Pgp protein expression was low in both jj and Jj pups at 9 days (about 16–27% of adult values), despite the up-regulation in jj animals (2 and 1.3 fold higher than age matched Jj animals at P9 and P17–P60, respectively); Mrp1 protein expression was barely detectable. Conversely, at the BCSFB Mrp1 protein expression was rather high (60–70% of the adult values) in both jj and Jj at P2, but was markedly (50%) down-regulated in jj pups starting at P9, particularly in the 4th ventricle choroid plexuses: Pgp was almost undetectable. The Mrp1 protein down regulation was accompanied by a modest up-regulation of mRNA, suggesting a translational rather than a transcriptional inhibition. In vitro exposure of choroid plexus epithelial cells obtained from normal rats to UCB, also resulted in a down-regulation of Mrp1 protein. These data suggest that down-regulation of Mrp1 protein at the BSCFB, resulting from a direct effect of UCB on epithelial cells, may impact the Mrp1-mediated neuroprotective functions of the blood-cerebrospinal fluid barrier and actually potentiate UCB neurotoxicity

COVID-19—Zoonosis or Emerging Infectious Disease?

The World Health Organization defines a zoonosis as any infection naturally transmissible from vertebrate animals to humans. The pandemic of Coronavirus disease (COVID-19) caused by SARS-CoV-2 has been classified as a zoonotic disease, however, no animal reservoir has yet been found, so this classification is premature. We propose that COVID-19 should instead be classified an “emerging infectious disease (EID) of probable animal origin.” To explore if COVID-19 infection fits our proposed re-categorization vs. the contemporary definitions of zoonoses, we reviewed current evidence of infection origin and transmission routes of SARS-CoV-2 virus and described this in the context of known zoonoses, EIDs and “spill-over” events. Although the initial one hundred COVID-19 patients were presumably exposed to the virus at a seafood Market in China, and despite the fact that 33 of 585 swab samples collected from surfaces and cages in the market tested positive for SARS-CoV-2, no virus was isolated directly from animals and no animal reservoir was detected. Elsewhere, SARS-CoV-2 has been detected in animals including domesticated cats, dogs, and ferrets, as well as captive-managed mink, lions, tigers, deer, and mice confirming zooanthroponosis. Other than circumstantial evidence of zoonotic cases in mink farms in the Netherlands, no cases of natural transmission from wild or domesticated animals have been confirmed. More than 40 million human COVID-19 infections reported appear to be exclusively through human-human transmission. SARS-CoV-2 virus and COVID-19 do not meet the WHO definition of zoonoses. We suggest SARS-CoV-2 should be re-classified as an EID of probable animal origin

Clinical practice: Protein-losing enteropathy in children

Protein-losing enteropathy (PLE) is a rare complication of a variety of intestinal disorders characterized by an excessive loss of proteins into the gastrointestinal tract due to impaired integrity of the mucosa. The clinical presentation of patients with PLE is highly variable, depending upon the underlying cause, but mainly consists of edema due to hypoproteinemia. While considering PLE, other causes of hypoproteinemia such as malnutrition, impaired synthesis, or protein loss through other organs like the kidney, liver, or skin, have to be excluded. The disorders causing PLE can be divided into those due to protein loss from intestinal lymphatics, like primary intestinal lymphangiectasia or congenital heart disease and those with protein loss due to an inflamed or abnormal mucosal surface. The diagnosis is confirmed by increased fecal concentrations of alpha-1-antitrypsin. After PLE is diagnosed, the underlying cause should be identified by stool cultures, serologic evaluation, cardiac screening, or radiographic imaging. Treatment of PLE consists of nutrition state maintenance by using a high protein diet with supplement of fat-soluble vitamins. In patients with lymphangiectasia, a low fat with medium chain triglycerides (MCT) diet should be prescribed. Besides dietary adjustments, appropriate treatment for the underlying etiology is necessary and supportive care to avoid complications of edema. PLE is a rare complication of various diseases, mostly gastrointestinal or cardiac conditions that result into loss of proteins in the gastrointestinal tract. Prognosis depends upon the severity and treatment options of the underlying disease