COVID-19 mortality in the UK Biobank cohort: revisiting and evaluating risk factors

European Journal of Epidemiology - Most studies of severe/fatal COVID-19 risk have used routine/hospitalisation data without detailed pre-morbid characterisation. Using the community-based UK...     

Identification of group B streptococcal Sip protein, which elicits cross-protective immunity

A protein of group B streptococci (GBS), named Sip for surface immunogenic protein, which is distinct from previously described surface proteins, was identified after immunological screening of a genomic library. Immunoblots using a Sip-specific monoclonal antibody indicated that a protein band with an approximate molecular mass of 53 kDa which did not vary in size was present in every GBS strain tested. Representatives of all nine GBS serotypes were included in the panel of strains. Cloning and sequencing of the sip gene revealed an open reading frame of 1,305 nucleotides coding for a polypeptide of 434 amino acid residues, with a calculated pI of 6. 84 and molecular mass of 45.5 kDa. Comparison of the nucleotide sequences from six different strains confirmed with 98% identity that the sip gene is highly conserved among GBS isolates. N-terminal amino acid sequencing also indicated the presence of a 25-amino-acid signal peptide which is cleaved in the mature protein. More importantly, immunization with the recombinant Sip protein efficiently protected CD-1 mice against deadly challenges with six GBS strains of serotypes Ia/c, Ib, II/R, III, V, and VI. The data presented in this study suggest that this highly conserved protein induces cross-protective immunity against GBS infections and emphasize its potential as a universal vaccine candidate.     

Mental health and substance abuse services in the era of health care reform

In the face of the cost crisis in the U.S. health care delivery system and in the era of reform, mental health and substance abuse services are in jeopardy. As the Clinton health reform plan is being debated during the months ahead, however, advocates for mental health and substance abuse care can play an important role in preserving benefits. To do so, they must press on with research into the effectiveness and cost-effectiveness of all aspects of mental health and substance abuse treatment; they must focus energies on working with managed care companies to ensure the provision of only necessary care at the appropriate level and intensity; and they must strive toward understanding the reforms being proposed and the implications for mental health and substance abuse services. Successful integration of the full array of mental health and substance abuse services into a generic benefits package remains a realistic goal, but the challenge is formidable.     

Dosimetric verification of a commercial inverse treatment planning system

A commercial three-dimensional (3D) inverse treatment planning system, Corvus (Nomos Corporation, Sewickley, PA), was recently made available. This paper reports our preliminary results and experience with commissioning this system for clinical implementation. This system uses a simulated annealing inverse planning algorithm to calculate intensity-modulated fields. The intensity-modulated fields are divided into beam profiles that can be delivered by means of a sequence of leaf settings by a multileaf collimator (MLC). The treatments are delivered using a computer-controlled MLC. To test the dose calculation algorithm used by the Corvus software, the dose distributions for single rectangularly shaped fields were compared with water phantom scan data. The dose distributions predicted to be delivered by multiple fields were measured using an ion chamber that could be positioned in a rotatable cylindrical water phantom. Integrated charge collected by the ion chamber was used to check the absolute dose of single- and multifield intensity modulated treatments at various spatial points. The measured and predicted doses were found to agree to within 4% at all measurement points. Another set of measurements used a cubic polystyrene phantom with radiographic film to record the radiation dose distribution. The films were calibrated and scanned to yield two-dimensional isodose distributions. Finally, a beam imaging system (BIS) was used to measure the intensity-modulated x-ray beam patterns in the beam's-eye view. The BIS-measured images were then compared with a theoretical calculation based on the MLC leaf sequence files to verify that the treatment would be executed accurately and without machine faults. Excellent correlation (correlation coefficients > or = 0.96) was found for all cases. Treatment plans generated using intensity-modulated beams appear to be suitable for treatment of irregularly shaped tumours adjacent to critical structures. The results indicated that the system has potential for clinical radiation treatment planning and delivery and may in the future reduce treatment complexity.     

Functional expression of a cDNA encoding a human ecto-ATPase.

1 The metabolism of extracellular nucleotides plays an important role in nucleotide signalling mediated by P2 receptors. The nucleotide sequence encoding a putative human ecto-ATPase named CD39L1 was reported recently. However, the biological activity of this protein has not been established. 2 Based on the sequence of CD39L1 we isolated from mRNA from human ECV-304 cells a sequence encoding a 495 amino acid protein that is identical to CD39L1, with the exception that this sequence contains a 23 amino acid stretch in the putative extracellular loop that is missing in CD39L1. Partial sequence of a genomic DNA clone indicates that the CD39L1 gene corresponds to an alternative spliced form of the human ecto-ATPase. 3 Stable expression of isolated sequence in NIH-3T3 mouse fibroblasts conferred a marked nucleotide hydrolytic activity consistent with the activity of an ecto-ATPase. 4 The human ecto-ATPase hydrolyzed all naturally occurring nucleoside triphosphates in a Ca(2+)- or Mg(2+)-dependent manner. Nucleoside diphosphates were hydrolyzed at a rate approximately 5% of that of the corresponding triphosphates. The apparent Km and Vmax values were: 394+/-62 microM and 107+/-7 nmol Pi min-1 10(6) cells-1 for the hydrolysis of ATP, and 102+/-33 microM and 4+/-0.4 nmol Pi min-1 10(6) cells-1 for the hydrolysis of ADP, respectively. 5 In conclusion, we report here the cloning and functional expression of a human ecto-ATPase. The study of the biochemical properties and the regulatory mechanisms of ecto-ATPases of defined sequence will be valuable in the definition of their role in nucleotide signalling.     

Hepatic toxicity and persistence of ser/thr protein phosphatase inhibition by microcystin in the little skate Raja erinacea

Microcystin-induced ser/thr protein phosphatase (PP) inhibition and toxicity were examined in the little skate (Raja erinacea), an evolutionarily primitive marine vertebrate. As in mammals, PP inhibition and toxicity were exclusively hepatocellular, but were much more persistent in the skate. A dose of 63 microg/kg given iv to adult male skates resulted in the near complete inhibition of hepatic PP activity at 24 h. PP activity was still 95% inhibited 7 days after dosing in skates given 125 microg/kg microcystin. Mortality occurred at doses of 500 microg/kg or more. Hepatic lesions were only seen in animals with fully inhibited PP activity in liver. The histological changes seen at 125 microg/kg were mild periportal inflammatory changes increasing in severity together with hepatocyte necrosis at higher doses of microcystin. Microcystin persisted and could be detected in plasma up to 7 days after dosing. This finding shows that, in the skate, as in mammals, the liver is the only organ capable of uptake of microcystin, since there was no significant inhibition of PP activity in the rectal gland and small decreases in PP activity of the kidney that were not time or dose dependent. In vitro microcystin caused dose-dependent inhibition of PP activity in isolated skate hepatocytes, while it was without effect in cultured rectal glands. Uptake of microcystin and the accompanying inhibition of PP activity in skate hepatocytes was prevented by the addition of a series of organic dyes and bile acids. The spectrum of inhibitors of microcystin uptake in skate is similar to that seen in the rat, indicating common features of the carrier(s) in these diverse species.     

Mechanism of mercurial inhibition of sodium-coupled alanine uptake in liver plasma membrane vesicles from Raja erinacea

In mammalian hepatocytes the L-alanine carrier contains a sulfhydryl group that is essential for its activity and is inhibited by mercurials. In hepatocytes of the evolutionarily primitive little skate (Raja erinacea), HgCl2 inhibits Na(+)-dependent alanine uptake and Na+/K(+)-ATPase and increase K+ permeability. To distinguish between direct effects of HgCl2 on the Na(+)-alanine cotransporter and indirect effects on membrane permeability, [3H]alanine transport was studied in plasma membrane vesicles. [3H]Alanine uptake was stimulated by an "out-to-in" Na+ but not K+ gradient and was saturable confirming the presence of Na(+)-alanine cotransport in liver plasma membranes from this species. Preincubation of the vesicles with HgCl2 for 5 min reduced initial rates of Na(+)-dependent but not Na(+)-independent alanine uptake in a dose-dependent manner (10-200 microM). In the presence of equal concentrations of NaCl or KCl inside and outside of the vesicles, 75 microM HgCl2 directly inhibited sodium-dependent alanine-[3H]alanine exchange, demonstrating that HgCl2 directly affected the alanine cotransporter. Inhibition of Na(+)-dependent alanine uptake by 30 microM HgCl2 was reversed by dithiothreitol (1 mM). HgCl2 (10-30 microM) also increased initial rates of 22Na uptake (at 5 sec), whereas 22Na uptake rates were decreased at HgCl2 concentrations greater than 50 microM. Higher concentrations of HgCl2 (100-200 microM) produced nonspecific effects on vesicle integrity. These studies indicate that HgCl2 inhibits Na(+)-dependent alanine uptake in skate hepatocytes by three different concentration-dependent mechanisms: direct interaction with the transporters, dissipation of the driving force (Na+ gradient), and loss of membrane integrity. Inactivation of the Na(+)-coupled alanine carrier by mercury in hepatocytes of this evolutionarily primitive vertebrate, as in mammals, suggests that the sulfhydryl groups on this transport protein are highly conserved.     

Role of FDA in establishing tolerable levels for dioxin and PCBs in aquatic organisms

When fishery products shipped in interstate commerce contain an environmental contaminant that presents a potential threat to public health, the Food and Drug Administration (FDA) undertakes appropriate regulatory steps to minimize exposure. These efforts range from seizure of the affected product to formal rule-making to establish a limit. The basic provision of the Food, Drug, and Cosmetic (FD&C) Act by which the agency deals with environmental contaminants in the food supply is section 402(a)(1), which deals with poisonous and deleterious substances. Poisonous and deleterious components are deemed to be "added," even if they are natural constituents of food, if any amount is present through the artifice of man. Furthermore, when the level of a naturally occurring toxin is increased in the food through handling and/or processing, the sum of all of the contaminant is deemed to be "added." Unavoidable environmental contaminants may be controlled and/or regulated under this section by the "may render injurious" standard, whereby the agency must demonstrate that there is a significant possibility that exposure to the contaminant could be injurious to human health. "Action levels" are administrative guidelines or instructions to the agency field units that define the extent of contamination at which the agency may regard food as adulterated. Except for polychlorinated biphenyls, for which there is a tolerance established by regulation, FDA has controlled contaminants in aquatic organisms by using action levels. Under section 406 of the FD&C act, the agency can also establish tolerances for unavoidably added poisonous or deleterious substances. This section allows the agency to consider the extent to which a contaminant is unavoidable in food while it limits exposure to the extent necessary to protect the public health. Section 406 requires that the tolerance be established by assessing several factors, including risk. One of these is the capability of processing technology to prevent, reduce, or otherwise control the level of the contaminant. Another factor is the necessity to avoid the needless removal of large amounts of valuable food from the market. Finally, the available analytical and sampling methods must be capable of measuring the contaminant so as to ensure the enforceability of the tolerance. Although the FDA has no statutory authority over intrastate fishing considerations, such as noncommercial fishing, it does provide advice to local or state authorities. It is the best scientific opinion the agency can give, but it is not enforceable per se. Advice is provided when requested by local and state officials where no guideline or tolerance is available, and is meant to deal with local and/or regional public health concerns.(ABSTRACT TRUNCATED AT 400 WORDS)     

Iatrogenic Thyrotoxicosis: Causal Circumstances, Pathophysiology, and Principles of Treatment—Review of the Literature

Thyrotoxicosis is the clinical syndrome that results when tissues are exposed to high levels of circulating thyroid hormones. In most instances thyrotoxicosis is due to hyperthyroidism, a term reserved for disorders characterized by overproduction of thyroid hormones by the thyroid gland. Nevertheless, thyrotoxicosis may also result from a variety of conditions other than thyroid hyperfunction. The present report focuses on the etiologies, pathophysiology, and treatment of iatrogenic thyrotoxicosis. Iatrogenic thyrotoxicosis may be caused by (1) subacute thyroiditis (a result of lymphocytic infiltration, cellular injury, trauma, irradiation) with release of preformed hormones into circulation; (2) excessive ingestion of thyroid hormones (“thyrotoxicosis factitia”); (3) iodine-induced hyperthyroidism (radiologic contrast agents, topical antiseptics, other medications). Among these causes of iatrogenic thyrotoxicosis, that induced by the iodine overload and cytotoxicity associated with amiodarone represents a significant challenge. Successful management of amiodarone-induced thyrotoxicosis requires close cooperation between endocrinologists and endocrine surgeons. Surgical treatment may have a leading yet often underestimated role in view of the potential life-threatening severity of this disease, whereas others kinds of iatrogenic thyrotoxicosis are usually treated conservatively.