Exclusion of Usher syndrome gene from much of chromosome 4

Usher syndrome is an autosomal recessive disease characterized by dual sensory impairments; affected individuals are born with a sensorineural hearing loss and ultimately lose their sight as retinitis pigmentosa develops. Conventional protein markers previously tested in a Louisiana Acadian kindred suggested tentative linkage to vitamin D-binding protein on chromosome 4. DNA linkage studies do not confirm this linkage relationship and exclude much of chromosome 4 as the site of the Usher syndrome gene in these families.     

Wounding aggression during the formation and maintenance of captive,multimale chimpanzee groups

Although the multimale community is the natural social organization of chimpanzees, both wild and captive adult males have killed other adult males and infants in intercommunity conflicts and intragroup aggression. Despite the potential for serious aggression, the formation of captive, multimale social groups is desirable for the efficient, long-term, humane housing of chimpanzees in socially and physically enriched environments and for the education of zoo visitors. The University of Texas Science Park (UTSP) has maintained multimale groups of chimpanzees for 14 years. In the UTSP outdoor corral housing, multimale/multifemale social groups of unrelated adult and adolescent chimpanzees (42 F, 46 M) were formed by a series of 397 individual introductions. Wounding aggression was minimal during introductions of females to males or other females and upon male-male introductions of formerly single-caged adolescent and young adult males having had long-term prior visual familiarity. Serious wounding occurred during male-male introductions when there were major discrepancies in the age and social experience of the subjects or when adult, socially experienced males were reintroduced to former group mates following lengthy separations. Male wounding in the eight established long-term groups of 5–11 adults (2–7 males) averaged 1.4 episodes per male-year of residence; 14% of male wounding episodes required surgical therapy. Adult wounding was significantly associated with the presence of one or more group females with maximally tumescent genital swellings. No male-perpetrated infanticides occurred. Not all multimale groupings are successful, but the majority of formerly laboratory-housed chimpanzees may live and reproduce safely in multimale groups. Experience with all-male groups at UTSP suggests that bachelor groups are also practical for long-term housing. © 1995 Wiley-Liss, Inc.     

Genetic analysis of a cytomegalovirus-like agent isolated from human brain.

An unusual cytomegalovirus (CMV, strain Colburn) isolated from brain biopsy of a boy with clinical encephalopathy was studied for genetic relatedness to human and simian CMV. Cross-examination of the purified viral DNA by DNA-DNA reassociation kinetics analyses showed more than 90% homology between Colburn virus and simian CMV (strain GR2757) and a lack of detectable homology between Colburn virus and human CMV (strains AD-169 and TW-87). Restriction endonuclease analysis of Colburn DNA showed some similarity of the DNA fragment pattern with that of simian CMV DNA, although the DNA fragment patterns were not identical, and showed no similarity to that of human CMV DNA. The molecular size and density of viral DNA were close to those of simian CMV DNA. The antigenic study, as performed by complement fixation and neutralization tests, showed strong cross-reactivity of Colburn virus to simian GR2757 virus. One-way cross-reaction of Colburn virus to several human CMV isolates (AD-169, Davis, and Town) was detected by complement fixation; this one-way cross-reaction was not obvious in a plaque neutralization test. It was concluded that Colburn is a simian CMV-related virus.     

Transfer RNA control of the activation of isomeric tRNATrp's.

Previous studies of the homologous aminoacylations of Escherichia coli and yeast tRNATrp's terminating in 2'- and 3'-deoxyadenosine established that E. coli tryptophanyl-tRNA synthetase activates its cognate tRNA preferentially on the 2' position, while the corresponding yeast enzyme utilizes the 3' position on its homologous substrate tRNA. As this seemed to be the only change in positional specificity during evolution, the heterologous activations were investigated in an effort to determine the basis for this change. Remarkably, E. coli tRNATrp terminating in 3'-deoxyadenosine was found to be the preferred substrate for both the E. coli and yeast activating enzymes, while the same tryptophanyl-tRNA synthetase preparations both activated the isomeric yeast tRNATrp's preferentially on the 3' position. Thus, the preferred position of activation was found to be specified by the tRNA rather than the activating enzyme and, additionally, to be due to some process not reflected in initial velocity measurements. The variable utilization of individual modified aminoacyl-tRNA's as substrates in an enzyme-catalyzed deacylation process appears to provide the most likely explanation for the experimental observations.     

Infection intensity and sampling locality affect Batrachochytrium dendrobatidis distribution among body regions on green-eyed tree frogs Litoria genimaculata

Batrachochytrium dendrobatidis (Bd) causes chytridiomycosis, which has caused devastating amphibian population declines. Little is known about the biology of Bd on hosts, and techniques for diagnosing it on living and preserved animals are still evolving. We investigated the spatial distribution of Bd on the integument of naturally infected Australian hylid frogs Litoria genimaculata at 4 rain forest localities in northern Queensland, Australia. We collected 555 samples by swabbing 111 individuals on 5 regions of the body (back, abdomen, legs, forefeet and hindfeet). Numbers of zoospore equivalents on each body region were quantified using a real-time TaqMan PCR assay. The intensity of infection differed significantly among body regions and this pattern of differences differed among sampling localities. The lightest infections were usually centered on the abdomen, while heavier infections were concentrated on the legs and feet. The back was always either lightly infected or uninfected. Many frogs with light infections had positive PCR results only for the abdomen or the legs. We compared swabs taken from the legs and abdomen and found that they provided similar sensitivity to detect infections, but using both regions together led to greater sensitivity than either region alone. Because swabbing may transfer zoospores from infected to uninfected regions within individuals, we suggest that the best procedure for all species is to employ separate swabs for each body region. If that cannot be done, swabbing patterns that minimize potential harm should be determined for each species, and possibly each class of individuals (e.g. males, females, juveniles) within species, by examining the distribution of infection among body parts in naturally infected individuals.     

CD46-induced immunomodulatory CD4+ T cells express the adhesion molecule and chemokine receptor pattern of intestinal T cells

Tissue homing of activated T cells is typically mediated through their specific integrin and chemokine receptor repertoire. Activation of human primary CD4(+) T cells in the presence of CD46 cross-linking induces the development of a distinct immunomodulatory T cell population characterized by high IL-10/granzyme B production. How these regulatory T cells (Tregs) migrate/home to specific tissue sites is not understood. In this study, we determined the adhesion protein and chemokine receptor expression pattern on human CD3/CD46-activated peripheral blood CD4(+) T cells. CD3/CD46-activated, but not CD3/CD28-activated, T cells up-regulate the integrin alpha(4)beta(7). The interaction of alpha(4)beta(7) with its ligand mucosal addressin cell adhesion molecule 1 (MAdCAM-1) mediates homing or retention of T cells to the intestine. CD3/CD46-activated Tregs adhere to/roll on MAdCAM-1-expressing HeLa cells, similar to T cells isolated from the human lamina propria (LP). This interaction is inhibited by silencing MAdCAM-1 expression in HeLa cells or by the addition of blocking Abs to beta(7). CD46 activation of T cells also induced the expression of the surface-bound cytokine LIGHT and the chemokine receptor CCR9, both marker constitutively expressed by gut LP-resident T cells. In addition, we found that approximately 10% of the CD4(+) T lymphocytes isolated from the LP of patients undergoing bariatric surgery contain T cells that spontaneously secrete a cytokine pattern consistent with that from CD46-activated T cells. These data suggest that CD46-induced Tregs might play a role in intestinal immune homeostasis where they could dampen unwanted effector T cell responses through local IL-10/granzyme B production.     

Endothelial cell migration on RGD-peptide-containing PEG hydrogels in the presence of sphingosine 1-phosphate

Sphingosine 1-phosphate (S1P) is a potent chemokinetic agent for endothelial cells that is released by activated platelets. We previously developed Arg-Gly-Asp (RGD)-containing polyethylene glycol biomaterials for the controlled delivery of S1P to promote endothelialization. Here, we studied the effects of cell adhesion strength on S1P-stimulated endothelial cell migration in the presence of arterial levels of fluid shear stress, since an upward shift in optimal cell adhesion strengths may be beneficial for promoting long-term cell adhesion to materials. Two RGD peptides with different integrin-binding specificities were added to the polyethylene glycol hydrogels. A linear RGD bound primarily to β₃ integrins, whereas a cyclic RGD bound through both β₁ and β₃ integrins. We observed increased focal adhesion formation and better long-term adhesion in flow with endothelial cells on linear RGD peptide, versus cyclic RGD, even though initial adhesion strengths were higher for cells on cyclic RGD. Addition of 100 nM S1P increased cell speed and random motility coefficients on both RGD peptides, with the largest increases found on cyclic RGD. For both peptides, much of the increase in cell migration speed was found for smaller cells (<1522 μm² projected area), although the large increases on cyclic RGD were also due to medium-sized cells (2288-3519 μm²). Overall, a compromise between high cell migration rates and long-term adhesion will be important in the design of materials that endothelialize after implantation.     

Novel mimics of sialyl Lewis X: design, synthesis and biological activity of a series of 2- and 3-malonate substituted galactoconjugates.

A series of potent inhibitors of P-selectin as potential anti-inflammatory agents is reported. These compounds are derivatives of galactocerebrosides bearing a malonate side chain in positions 2 and 3 of the galactose moiety. Based on the binding mode of sialyl Lewis X, the two acidic groups of the malonate are designed to form ionic interactions with two important lysines in the active site of P-selectin, Lys113 and Lys111. On the other hand, the 4- and 6-hydroxy groups on the galactose ring are arranged to chelate the calcium ion in the P-selectin active site. The synthesis and the biological activity of this series of compounds are described. Lead compounds having a greater potency than sialyl Lewis X are identified.     

Lifestyle modifications to prevent and control hypertension. 1. Methods and an overview of the Canadian recommendations. Canadian Hypertension Society,Canadian Coalition for High Blood Pressure Prevention and Control,Laboratory Centre for Disease Control at Health Canada,Heart and Stroke Foundation of Canada

OBJECTIVE: To provide updated, evidence-based recommendations for health care professionals on lifestyle changes to prevent and control hypertension in otherwise healthy adults (except pregnant women). OPTIONS: For people at risk for hypertension, there are a number of lifestyle options that may avert the condition--maintaining a healthy body weight, moderating consumption of alcohol, exercising, reducing sodium intake, altering intake of calcium, magnesium and potassium, and reducing stress. Following these options will maintain or reduce the risk of hypertension. For people who already have hypertension, the options for controlling the condition are lifestyle modification, antihypertensive medications or a combination of these options; with no treatment, these people remain at risk for the complications of hypertension. OUTCOMES: The health outcomes considered were changes in blood pressure and in morbidity and mortality rates. Because of insufficient evidence, no economic outcomes were considered. EVIDENCE: A MEDLINE search was conducted for the period January 1996 to September 1996 for each of the interventions studied. Reference lists were scanned, experts were polled, and the personal files of the authors were used to identify other studies. All relevant articles were reviewed, classified according to study design and graded according to level of evidence. VALUES: A high value was placed on the avoidance of cardiovascular morbidity and premature death caused by untreated hypertension. BENEFITS, HARMS AND COSTS: Lifestyle modification by means of weight loss (or maintenance of healthy body weight), regular exercise and low alcohol consumption will reduce the blood pressure of appropriately selected normotensive and hypertensive people. Sodium restriction and stress management will reduce the blood pressure of appropriately selected hypertensive patients. The side effects of these therapies are few, and the indirect benefits are well known. There are certainly costs associated with lifestyle modification, but they were not measured in the studies reviewed. Supplementing the diet with potassium, calcium and magnesium has not been associated with a clinically important reduction in blood pressure in people consuming a healthy diet. RECOMMENDATIONS: (1) It is recommended that health care professionals determine the body mass index (weight in kilograms/[height in metres]2) and alcohol consumption of all adult patients and assess sodium consumption and stress levels in all hypertensive patients. (2) To reduce blood pressure in the population at large, it is recommended that Canadians attain and maintain a healthy body mass index. For those who choose to drink alcohol intake should be limited to 2 or fewer standard drinks per day (maximum of 14/week for men and 9/week for women). Adults should exercise regularly. (3) To reduce blood pressure in hypertensive patients, individualized therapy is recommended. This therapy should emphasize weight loss for overweight patients, abstinence from or moderation in alcohol intake, regular exercise, restriction of sodium intake and, in appropriate circumstances, individualized cognitive behaviour modification to reduce the negative effects of stress. VALIDATION: The recommendations were reviewed by all of the sponsoring organizations and by participants in a satellite symposium of the fourth international Conference on Preventive Cardiology. They are similar to those of the World Hypertension League and the Joint National committee, with the exception of the recommendations on stress management, which are based on new information. They have not been clinically tested. SPONSORS: The Canadian Hypertension Society, the Canadian Coalition for High Blood Pressure Prevention and Control, the Laboratory Centre for Disease Control at health Canada, and the Heart and Stroke Foundation of Canada.     

Lifestyle modifications to prevent and control hypertension. 5. Recommendations on dietary salt. Canadian Hypertension Society,Canadian Coalition for High Blood Pressure Prevention and Control,Laboratory Centre for Disease Control at Health Canada,Heart and Stroke Foundation of Canada

OBJECTIVE: To provide updated, evidence-based recommendations concerning the effects of dietary salt intake on the prevention and control of hypertension in adults (except pregnant women). The guidelines are intended for use in clinical practice and public education campaigns. OPTIONS: Restriction of dietary salt intake may be an alternative to antihypertensive medications or may supplement such medications. Other options include other nonpharmacologic treatments for hypertension and no treatment. OUTCOMES: The health outcomes considered were changes in blood pressure and in morbidity and mortality rates. Because of insufficient evidence, no economic outcomes were considered. EVIDENCE: A MEDLINE search was conducted for the period 1966-1996 using the terms hypertension, blood pressure, vascular resistance, sodium chloride, sodium, diet, sodium or sodium chloride dietary, sodium restricted/reducing diet, clinical trials, controlled clinical trial, randomized controlled trial and random allocation. Both trials and review articles were obtained, and other relevant evidence was obtained from the reference lists of the articles identified, from the personal files of the authors and through contacts with experts. The articles were reviewed, classified according to study design and graded according to level of evidence. In addition, a systematic review of all published randomized controlled trials relating to dietary salt intake and hypertension was conducted. VALUES: A high value was placed on the avoidance of cardiovascular morbidity and premature death caused by untreated hypertension. BENEFITS, HARMS AND COSTS: For normotensive people, a marked change in sodium intake is required to achieve a modest reduction in blood pressure (there is a decrease of 1 mm Hg in systolic blood pressure for every 100 mmol decrease in daily sodium intake). For hypertensive patients, the effects of dietary salt restriction are most pronounced if age is greater than 44 years. A decrease of 6.3 mm Hg in systolic blood pressure and 2.2 mm Hg in diastolic blood pressure per 100 mmol decrease in daily sodium intake was observed in people of this age group. For hypertensive patients 44 years of age and younger, the decreases were 2.4 mm Hg for systolic blood pressure and negligible for diastolic blood pressure. A diet in which salt is moderately restricted appears not to be associated with health risks. RECOMMENDATIONS: (1) Restriction of salt intake for the normotensive population is not recommended at present, because of insufficient evidence demonstrating that this would lead to a reduced incidence of hypertension. (2) To avoid excessive intake of salt, people should be counselled to choose foods low in salt (e.g., fresh fruits and vegetables), to avoid foods high in salt (e.g., pre-prepared foods), to refrain from adding salt at the table and minimize the amount of salt used in cooking, and to increase awareness of the salt content of food choices in restaurants. (3) For hypertensive patients, particularly those over the age of 44 years, it is recommended that the intake of dietary sodium be moderately restricted, to a target range of 90-130 mmol per day (which corresponds to 3-7 g of salt per day). (4) The salt consumption of hypertensive patients should be determined by interview. VALIDATION: These recommendations were reviewed by all of the sponsoring organizations and by participants in a satellite symposium of the fourth International Conference on Preventive Cardiology. They have not been clinically tested. SPONSORS: The Canadian Hypertension Society, the Canadian Coalition for High Blood Pressure Prevention and Control, the Laboratory Centre for Disease Control at Health Canada, and the Heart and Stroke Foundation of Canada.