Rare pre-core stop-codon mutant nt. 1897 predominates over wide-spread mutant nt. 1896 in an unusual course of chronic hepatitis B

Summary We present a patient with an unusual course of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B who had repeated reactivations of his disease progressing to cirrhosis with terminal liver failure. Each flare up presented like an acute hepatitis with very high titres of hepatitis B virus (HBV) and high inflammatory activity followed by rapid clearance of viraemia. The pre-core genome of HBV isolated from sera during 5 years of follow up was analysed. Direct sequencing of polymerase chain reaction (PCR) products derived from consecutive sera showed a rare pre-core stop-codon mutation at nucleotide (nt.) 1897 G→A with an accompanying mutation nt. 1857 C→T as well as a stop-codon mutation nt. 1896 G→A. By cloning and sequencing of PCR products the mutant strain with mutation nt. 1897 was shown to predominate over viral strains with a mutation nt. 1896 during the course of disease, although the stop-codon mutation nt. 1896 in general is observed more frequently. Both mutations allow viral replication by stabilizing the encapsidation signal ε. This allowed HBV replication at a very high level as observed during flare ups. The absence of HBeAg may be responsible for the massive cytotoxic T-cell response towards hepatocytes which might explain the rapid progression to liver cirrhosis although no, or very little, HBV replication was observed for long periods. However, there is no clear explanation as to why the nt. 1897 mutant strain overwhelmed the other virus strains.     

Substance P and NPY innervation of microvessels in the rabbit tenuissimus muscle

The distribution of substance P (SP)- and neuropeptide Y (NPY)-immunoreactive (IR) nerve fibers in the rabbit tenuissimus muscle was investigated by means of immunohistochemistry. Electron microscopy was used to study the ultrastructural appearance of nerve fibers and terminals. SP-IR nerve fibers were sparse in the main feeding vessels to the muscle and in the central artery and vein, but moderately dense in the motor nerve and in nerve bundles running in the vicinity of the vessels. Occasionally, fibers were seen in apposition to arterioles and venules in the muscle. NPY-IR nerves formed a dense network of a typically adrenergic appearance encircling the feeding artery, central artery, and arterioles of all sizes. NPY-IR nerves were not seen around venules or veins. In the motor nerve, NPY immunoreactivity could be seen after ligation. Electron microscopy showed nerve terminals containing both small vesicles and large dense core vesicles outside the media of arterioles and, more seldom, of venules. Also, unmyelinated fibers followed myelinated nerve bundles along arterioles. The fact that there are a great many SP- and NPY-immunoreactive fibers in the tenuissimus muscle, with a distribution that harmonizes with their pharmacological actions, supports the view that local release of these neuropeptides contributes significantly to microvascular regulation in skeletal muscle.     

Estimating the Degree of Emergency Department Overcrowding in Academic Medical Centers: Results of the National ED Overcrowding Study (NEDOCS)

OBJECTIVES: No single universal definition of emergency department (ED) overcrowding exists. The authors hypothesize that a previously developed site-sampling form for academic ED overcrowding is a valid model to quantify overcrowding in academic institutions and can be used to develop a validated short form that correlates with overcrowding. METHODS: A 23-question site-sampling form was designed based on input from academic physicians at eight medical schools representative of academic EDs nationwide. A total of 336 site-samplings at eight academic medical centers were conducted at 42 computer-generated random times over a three-week period by independent observers at each site. These sampling times ranged from very slow to severely overcrowded. The outcome variable was the degree of overcrowding as assessed by the charge nurse and ED physicians. The full model consisted of objective data that were obtained by counting the number of patients, determining patients' waiting times, and obtaining information from registration, triage, and ancillary services. Specific objective data were indexed to site-specific demographics. The outcome and objective data were compared using a multiple linear regression to determine predictive validity of the full model. A five-question reduced model was calculated using a backward stepdown procedure. Predictive validity and relationships between the outcome and objective data were assessed using a mixed-effects linear regression model, treating center as random effect. RESULTS: Overcrowding occurred 12% to 73% of the time (mean, 35%), with two hospitals being overcrowded more than 50% of the time. Comparison of objective and outcome data resulted in an R(2) of 0.49 (p < 0.001), indicating a good degree of predictive validity. A reduced five-question model predicted the full model with 88% accuracy. CONCLUSIONS: Overcrowding varied widely between academic centers during the study period. Results of a five-question reduced model are valid and accurate in predicting the degree of overcrowding in academic centers.     

Thymic T cell development and progenitor localization depend on CCR7

T cell differentiation in the adult thymus depends on sequential interactions between lymphoid progenitors and stromal cells found in distinct regions of the cortex and medulla. Therefore, migration of T cell progenitors through distinct stromal environments seems to be a crucial process regulating differentiation and homeostasis inside the thymus. Here we show that CCR7-deficient mice are distinguished by a disturbed thymic architecture, impaired T cell development, and decreased numbers of the thymocytes. Analysis of developing double negative (CD4-CD8-) pool of wild-type thymus reveals that CCR7 expression is restricted to a CD25intCD44+ subpopulation. Correspondingly, CCR7 deficiency results in an accumulation of this population in mutant thymus. Furthermore, immunohistology shows that in CCR7-deficient mice CD25+CD44+ cells accumulate at the cortico-medullary junction, suggesting that CCR7 signaling regulates the migration of early progenitors toward the outer thymic cortex, thereby continuing differentiation. Results obtained from mixed bone marrow chimeras support this view, since the development of CCR7-deficient thymocytes is also disturbed in a morphologically intact thymus. Thus, our findings establish an essential role for CCR7 in intrathymic migration and proper T cell development.     

The management of the obese diabetic patient

The prevalence of obesity and diabetes is increasing in the United States and worldwide. These diseases are predicted to explode to epidemic proportions, unless appropriate counteractive measures are taken. Several large studies (DCCT, UKPDS, Kumamoto) clearly showed that intensive glycemic control in the diabetic patient reduced microvascular complications and improved mortality. Despite this, the NHANES III showed that only 50% of diabetics have been able to achieve a HgbAic level that is less than 7%; this suggests the need for a re-evaluation of our approach to these patients. The management of the obese diabetic patient involves glycemic control and weight reduction. These goals are particularly difficult to achieve in the obese diabetic patient because progressive beta-cell dysfunction and increasing insulin resistance necessitates the administration of increasingly higher dosages of insulin, which, in turn, promotes weight gain. A vicious cycle may ensue. Lifestyle modifications with diet and exercise are an essential part of the management of the obese diabetic patient. These measures alone are often insufficient and concomitant pharmacologic therapy is usually required to achieve glycemic and weight control. Oral agents that improve glycemia, decrease insulin resistance, and limit weight gain are desirable. Because of the progressive nature of diabetes, glycemic control with monotherapy often deteriorates over time, which necessitates the addition of other pharmacologic agents, including insulin. When insulin therapy is required in the treatment of the obese diabetic patient, combinations with oral agents that have been shown to minimize the amount of exogenous insulin that is required, may minimize weight gain. In addition, the obese diabetic patient who is poorly controlled with maximum oral hypoglycemic therapy may benefit from weight-reducing agents, such as sibutramine or orlistat. The introduction of these agents at other points in the management of the obese diabetic patients have been successful. Finally, for the severely obese diabetic patient, bariatric surgery may be the only effective treatment. Gastric bypass has been unequivocally shown to produce significant weight loss and improve glycemic control on a long-term basis in the obese diabetic patient. It is recommended that physicians avail themselves of all of these strategies in the management of the obese patient who has type 2 diabetes.