Amidines are potent inhibitors of nitric oxide synthases: preferential inhibition of the inducible isoform.

We evaluated the ability of simple alkyl amidines to inhibit the activity of the inducible isoform of nitric oxide (NO) synthase in vitro. In immunostimulated J774 macrophages, 2-iminopiperidine (EC50 = 10 microM) and butyramidine (EC50 = 60 microM) were more potent than NG-methyl-L-arginine (EC50 = 70 microM) in inhibiting nitrite formation. The five amidines tested for their ability to inhibit the conversion of L-arginine to L-citrulline by bovine endothelial cell homogenates (a source of the constitutive, endothelial NO synthase isoform) were less effective than NG-nitro-L-arginine or NG-methyl-L-arginine. The rank-order of the potencies of the amidines against the endothelial NO synthase was, in general, similar to the rank-order of the pressor effects of these agents in anesthetized rats. Thus, certain amidines are potent inhibitors of NO synthase, and are more selective towards the inducible NO synthase than the commonly used L-arginine based NO synthase inhibitors.

Erysipeloid infection in a sheep farmer with coexisting orf.

Erysipeloid is a rarely reported zoonotic infection caused by Erysipelothrix rhusiopathiae. We report a case of coexisting erysipeloid and orf infections in a sheep farmer, an association not previously recorded to our knowledge.

The validity and reproducibility of clinical assessment of nutritional status in the elderly.

Malnutrition is an important predictor of morbidity and mortality. In the non-elderly, a subjective global assessment (SGA) has been developed. It has a high inter-rater agreement, correlates with other measures of nutritional status, and predicts subsequent morbidity. The purpose of this study was to determine the validity and reproducibility of the SGA in a group of patients older than 70 y of age. Consecutive patients from four geriatric/rehabilitation units were considered for the study. Each patient underwent independent nutritional assessments by a geriatrician and senior medical resident. At the completion of the assessment, skinfold caliper measurements were obtained and the patient reclassified according to the results, which were then compared with objective measures of nutritional status. Six-month follow-up was obtained on all patients. The agreement between the two clinicians was 0.48 +/- 0.17 (unweighted kappa), which represents moderate agreement and is less than the reported agreement in nonelderly subjects. Skin calipers improved the agreement between clinicians but did not improve the correlation with other nutritional markers or prediction of morbidity and mortality. There was a correlation between a patient's severely malnourished state and mortality. In addition, patients with a body mass index (BMI) of <75% or >150% age/sex standardized norms had an increased mortality. The SGA is a reproducible and valid tool for determining nutritional status in the elderly. The reproducibility is less than in the nonelderly, which may relate to changes in body composition or ability to obtain an accurate nutritional history.

Physiological control of warming and cooling during simulated shuttling and basking in lizards.

Differences in warming and cooling rates in basking lizards have long been thought to be brought about by adjustments in heart rate and blood flow. We examined the physiological control of warming and cooling in Iguana iguana, Sceloporus undulatus, and three species of Cordylus by measuring time constants, heart rate, and superficial capillary blood flow. Previously, techniques have not been available to measure time constants in shuttling animals. Using a combination of rapid measurements of temperature and blood flow and numerically intensive parameter-fitting methods, we measured dominant and subdominant time constants in lizards subjected to periods of both simulated basking and simulated shuttling. Cutaneous blood flow and heart rate were measured using laser Doppler flowmeters. Of the three, only the larger I. iguana measurably altered rates of warming and cooling during basking. During shuttling, none of the species effectively controlled warming and cooling. During both basking and shuttling, blood flow and heart rate tended to change in predicted directions. Superficial blood flow correlated with surface temperature while heart rate correlated more closely with core temperature. Changes in superficial blood flow and heart rate varied relatively independently in I. iguana. The techniques used here provide a better understanding of the ability of these species to control thermoregulation.

Thermal time constant estimation in warming and cooling ectotherms.

(1) Measurement of physiological control of warming and cooling in reptiles requires calculating the thermal time constant (tau) of the animal. (2) Previously reported methods of estimating tau are sensitive to multiple problems including measurement error in operative environmental temperature and equilibrium body temperature, drift of environmental temperatures, requirements for extremely simple thermal environments, and ill conditioning of the estimation techniques themselves. (3) We propose a physiologically based heat transfer model which is less sensitive to common experimental errors, more numerically robust, and can provide physiologically meaningful estimates of time constants. (4) The method presented here allows time constants to be measured for animals subjected to the traditional step change experiment as well as to shorter periods of warming and cooling such as during shuttling.

Runway malaria in a British serviceman.

'Runway malaria' is a clinical entity first described in 1990 and refers to a patient who has contracted malaria, in whom the only possible exposure has been when the aircraft in which they were travelling has landed transiently in a malarious zone. We describe such a case in a British Serviceman travelling from the South Atlantic to Germany, who acquired malaria in West Africa.

The requirement for hepatitis A vaccine in Gurkha soldiers.

This Hepatitis A seroprevalence study aimed to determine the cost effectiveness of Hepatitis A vaccination for Gurkha soldiers. One hundred and sixty Gurkha recruits had serum analysed for Hepatitis A IgG. One hundred and fifty nine (99.4%) were IgG positive. Continuing to vaccinate Gurkha soldiers against Hepatitis A will confer little benefit and is not cost effective.

Preinvasive lesions of the endometrium.

Endometrial glandular proliferations form a morphological and biologic continuum. The new definition of stromal invasion provides a means of identifying lesions with a relatively high probability of myometrial invasion and malignant behavior. With more standardized terminology and classification, the natural history of preinvasive lesions is better understood. Caution must be exercised because confusion is hard to avoid completely. It is now apparent that the presence of cytological atypia in a preinvasive lesion identifies a lesion at high risk to develop carcinoma. Glandular hyperplasia without cytological atypia identifies a patient likely to have an abnormal endocrine milieu, but it is not a significant preinvasive lesion and has little tendency to develop into one. The presence of cytological atypia provides the basis for selection of therapy.

Developing senior doctors as mentors: a form of continuing professional development. Report Of an initiative to develop a network of senior doctors as mentors: 1994-99.

BACKGROUND: Senior doctors report that mentoring skills are transferable to everyday medical practice and managing juniors. An analysis of views from consultants and general practitioners, who had trained together on a regional mentoring scheme, reveals significant potential for personal and professional development in such networks. CONTEXT: The Northern and Yorkshire Region Doctors' Development and Mentoring Network was set up in 1994. Since then there have been six programmes with 116 senior doctors participating. In 1997 there was an evaluation of the first four programmes. METHOD: Focus groups and postal questionnaire. RESULTS: There were responses from 71 senior doctors, giving a response rate of 86%, and responses from 78 professional stakeholders in 49 NHS organizations, a response rate of 54%. Results indicate that the programmes were highly valued by the participants, particularly with regard to: being part of a network of senior doctors; developing mentoring skills, and engaging in personal and professional development. The most difficult part of the programme was setting up mentoring networks for junior doctors, and reasons included: personal factors, such as levels of confidence in providing mentoring; cultural factors, such as juniors not wishing to be seen to need help, and organizational factors, such as lack of time allocated for mentoring. RECOMMENDATIONS AND ISSUES FOR FURTHER DEBATE: The positive benefits from the scheme raise questions about how to develop mentoring training for senior doctors. Issues include: developing mentors; who needs mentoring; mentoring and the organization; transferability of mentoring skills, and widening the network.

Silicone-grease-based immobilisation method for the preparation of enzyme electrodes.

An approach to the construction of amperometric biosensors based on the incorporation of an enzyme in silicone grease and using the grease to fill micropores on a graphite surface is described. The enzyme-grease electrode concept, illustrated with the enzyme tyrosinase, offers a very simple, rapid and inexpensive approach to the fabrication of enzyme electrodes. The tyrosinase electrode responds very rapidly to dynamic changes in the concentration of phenolic compounds. A response time (t95%) as low as 5 s has been determined. With flow injection, 120 samples per hour can be processed with a relative standard deviation of 2.4%. The electrode remains active for about 12 d. The detection limit for dopamine is 6 x 10(-6) M. This method of biosensor construction should be applicable to other enzyme-substrate systems.

An Industry Health Management Program.

An employee fitness program helped reduce some coronary risk factors, but this is only one measure of success. The author says that long-term changes in diet and exercise habits are the real challenge.

Studies of oral neutrophil levels in patients receiving G-CSF after autologous marrow transplantation.

Patients are at risk of mucositis and infections in the oral cavity during the neutropenic period after chemotherapy, which are significant causes of morbidity. In phase I/II studies with the haemopoietic growth factor granulocyte colony stimulating factor (G-CSF), a reduction in post-chemotherapy mucositis has been observed in addition to haematologic effects. To understand this phenomenon better in patients receiving G-CSF following high-dose chemotherapy with autologous bone marrow transplantation (ABMT), we studied the effects of G-CSF on levels of neutrophils recoverable from the oral cavity using a quantitative mouthrinse assay. In normal subjects, mouthrinses contained 472 +/- 329 x 10(3) neutrophils/mouthrinse. After chemotherapy followed by ABMT, mouthrinse neutrophil levels decreased to undetectable levels during the neutropenic period, but recovered 1-2 and 3-9 d before circulating neutrophil levels reached 0.1 and 1 x 10(9)/l respectively, whether or not patients received G-CSF. In patients who received G-CSF, the mean cumulative mucositis score was reduced from 35 +/- 9 to 21 +/- 12 (P < 0.05), and the maximum mean daily mucositis score was reduced from 2.8 +/- 0.5 to 1.7 +/- 0.9 (P < 0.01), compared to patients who did not receive G-CSF after ABMT. These studies provide in vivo evidence that neutrophils produced during G-CSF therapy are available to leave the circulation and enter tissues where their function is required for host defence. Since the usual temporal relationship between oral and peripheral blood neutrophil recovery was preserved during G-CSF administration after ABMT, these data support the hypothesis that the reduction in post-ABMT mucositis observed with G-CSF therapy may reflect a beneficial effect of G-CSF on the kinetics of oral mucosal neutrophil recovery in addition to the effect of G-CSF to accelerate peripheral blood neutrophil recovery.

Vitamin D receptor genotype is not associated with bone mineral density in three ethnic/regional groups.

We report a cross-sectional study of 48 men, 56 premenopausal women, and 80 postmenopausal women who were of three ethnic/regional backgrounds: southern European (Greek, Italian), eastern European (Jewish, Polish, Hungarian), and western European (French, British). We determined bone mineral density (BMD) at four skeletal sites and assessed the vitamin D receptor (VDR) genotype by the Bsml restriction site polymorphism. Age and body mass index had significant effects on BMD by multiple regression analysis. In addition, ethnic/regional group had a significant effect on spinal BMD in premenopausal females (P = 0.014) and in males (P = 0.039). However, VDR genotype had no significant effect on BMD in any of the three study groups.

Thermal independence of muscle tissue metabolism in the leatherback turtle, Dermochelys coriacea.

Metabolic rates of animal tissues typically increase with increasing temperature and thermoregulatory control in an animal is a regional or whole body process. Here we report that metabolic rates of isolated leatherback turtle (Dermochelys coriacea) pectoralis muscle are independent of temperature from 5-38 degrees C (Q10 = 1). Conversely, metabolic rates of green turtle (Chelonia mydas) pectoralis muscle exhibit a typical vertebrate response and increase with increasing temperature (Q10 = 1.3-3.0). Leatherbacks traverse oceanic waters with dramatic temperature differences during their migrations from sub-polar to equatorial regions. The metabolic stability of leatherback muscle effectively uncouples resting muscle metabolism from thermal constraints typical of other vertebrate tissues. Unique muscle physiology of leatherbacks has important implications for understanding vertebrate muscle function, and is another strong argument for preservation of this endangered species.

Protection against peroxynitrite-induced fibroblast injury and arthritis development by inhibition of poly(ADP-ribose) synthase.

Peroxynitrite, a cytotoxic oxidant formed from nitric oxide (NO) and superoxide, induces DNA strand breakage, which activates the nuclear enzyme poly(ADP-ribose) synthase (PARS; EC 2.4.2.30). The cellular function of PARS was determined in fibroblast lines from PARS knockout animals (PARS-/-) and corresponding wild-type animals (PARS+/+), with the aid of the lipophilic PARS inhibitor 5-iodo-6-amino-1,2-benzopyrone (INH2BP). We investigated the role of PARS in peroxynitrite-induced fibroblast injury in vitro and also in the development of arthritis in vivo. Exposure of embryonic fibroblasts from the PARS+/+ animals to peroxynitrite caused DNA single-stand breakage and PARS activation and caused an acute suppression of mitochondrial respiration. INH2BP protected the PARS+/+ cells against the suppression of mitochondrial respiration in response to peroxynitrite (50-100 microM). Similarly to PARS inhibition with INH2BP, the PARS-/- cells were protected against peroxynitrite-induced injury. The protection against cellular injury by PARS-/- phenotype or INH2BP waned when cells were challenged with higher concentrations of the oxidant. Inhibition of PARS by INH2BP or by PARS-/- phenotype reduced inducible nitric-oxide synthase (iNOS; EC 1.14.13.39) mRNA levels and inhibited production of NO in immunostimulated cells. INH2BP had no peroxynitrite scavenging or hydroxyl radical scavenging effects, and it exerted no additional (nonspecific) effects in the PARS-/- cells. In collagen-induced arthritis, significant staining for nitrotyrosine, a marker of peroxynitrite formation, was found in the inflamed joints. Oral treatment with INH2BP (0.5 g/kg, daily), starting at the onset of arthritis (day 25), delayed the development of the clinical signs at days 26-35 and improved histological status in the knee and paw. Our data demonstrate that deletion of PARS by genetic manipulation or pharmacological inhibition of PARS protects against oxidant-induced cellular injury in vitro and exhibits anti-inflammatory effects in vivo.