A novel S-nitrosothiol (RIG200) causes prolonged relaxation in dorsal hand veins with damaged endothelium

BACKGROUND: Reduced nitric oxide bioavailability caused by endothelial dysfunction or damage is a contributory factor in the initiation and progression of a number of cardiovascular diseases. Delivery of exogenous nitric oxide is an attractive therapeutic option, but current agents lack selectivity for areas of endothelial damage. We tested the hypothesis that a novel nitric oxide donor drug, N-(S-nitroso-N-acetylpenicillamine)-2-amino-2-deoxy-1,3,4,6-tetra-O-acet yl-P-glucopyranose [RIG200], which has selective effects in endothelium-denuded isolated arteries in vitro, would exert similar effects in dorsal hand veins with experimentally damaged endothelium in vivo. METHODS: Venodilator responses to sodium nitroprusside and RIG200 were compared in two groups of healthy volunteers (age range, 18 to 63 years; n = 7 for each group) in norepinephrine 70% maximum effective concentration (EC70) preconstricted hand veins with use of the Aellig technique. In this doubleblind study, subjects were randomly assigned to receive either sodium nitroprusside or RIG200 (infusions of 0.06 and 6 nmol/min into the hand vein) before and 2 days after 15 minutes of local venous irription with distilled water. Endothelial function was assessed in all subjects on both visits with use of the endothelium-dependent vasodilator acetylcholine (1 nmol/min). RESULTS: Irrigation of hand veins with distilled water abolished endothelium-dependent dilatation in response to acetylcholine in both study groups (n = 14) but did not affect the amplitude or duration of responses to the conventional nitric oxide donor sodium nitroprusside (P = .87; n = 7). However, responses to RIG200 were significantly prolonged during the washout phase (30 minutes) in veins after water irrigation (P = .02; n = 7). CONCLUSION: These studies confirm that RIG200 has prolonged effects in veins with damaged endothelium, a characteristic that might be exploited therapeutically to target nitric oxide delivery to damaged blood vessels.     

Temporal events in the intravenous challenge model for experimental Candida albicans infections in female mice

We characterized the intravenous (i.v.) challenge model for disseminated Candida albicans infection in female BALB/c and DBA/2 mice. Clearance of fungi from the bloodstream and appearance of fungi in tissues were measured at intervals after challenge with various doses of C. albicans. The wild-type isolate SC5314 and derived strains CAF2-1 and CAI-4 transformed with CIp10 were of equal virulence in the model. Variability in mouse survival times, kidney fungal burdens and cachexia was lowest when challenge inocula were within the range 10(4)-10(5) CFU g(-1) body weight in BALB/c mice, but brain fungal burdens and outcomes in DBA/2 mice were variable for all inocula tested. Critical times in the development of infections in optimally challenged BALB/c mice were at 5-10 h (bloodstream fully cleared of fungi), 24 h (start of exponential fungal growth in kidneys) and 48 h (50% of blood cultures become positive). Differential involvement of right and left kidneys occurred almost exclusively in mice challenged with <2 x 10(4) CFU g(-1). We conclude that the i.v. challenge model in female BALB/c mice is now sufficiently well characterized to permit more refined experimentation in future virulence studies with C. albicans mutants.     

Real Time-PCR HBV-DNA Analysis: Significance and First Experience in Armed Forces

Background

HBV DNA quantitation is used extensively world wide for the diagnosis and monitoring of treatment of Hepatitis B virus (HBV) infection. However, it has still to be popular in India. The aim of this study was to quantitate HBV – DNA by Real time – PCR method in Hepatitis B and in immuno-compromised patients, to compare the results with HBeAg detection and to monitor the response to therapy of chronic Hepatitis B patients to antivirals.

Methods

Ninety one serum samples of Hepatitis group of patients (all HBsAg positive), 41 samples from immuno-compromised patients (all HBsAg negative) and 49 patients of Chronic Hepatitis B group (all HBsAg positive) were the subjects of this first ever study in Armed Forces. Twenty serum samples from healthy volunteers and non-hepatitis B patients served as negative controls. The amplification detection was carried out in a Rotor-Gene 2000-sequence detector

Results

Amongst Hepatitis B group, 33% (30/91) of the samples were positive for HBV-DNA and 26% (24/91) of samples were positive for HBeAg. In the immuno-compromised group of patients 14.6% (6/11) of samples were positive for HIV-DNA and 9.7% (4/41) were positive for HBeAg. Of the Chronic Hepatitis B patients on treatment, all (100%) were positive by HBV-DNA, whereas 29/49 (59.2%) were positive by HBeAg before treatment. After treatment with antivirals, 06/49 (12.2%) were positive by both tests and 11/49 (22.5%) were positive only by HBV-DNA. 32/49 (65.3%) patients became negative serologically after therapy.

Conclusion

HBeAg status did not necessarily reflect HBV-DNA level in the serum, as 10/91 (11%) in the Hepatitis B group, 2/41 (4.9%) in the immuno compromised group and 20/49 (40.8%) patients in the Chronic Hepatitis B group were positive for HBV-DNA but negative for HBeAg. HBV-DNA was not found to be positive amongst any of the negative controls. Real time – PCR is a sensitive and reproducible assay for HBV-DNA quantitation and may be started in Armed Forces referral centers in the near future.Key Words: Real time – PCR, Chronic Hepatitis B, HBV – DNA, Antivirals     

Traffic related pollution and heart rate variability in a panel of elderly subjects

BACKGROUND: Particulate air pollution has been associated with increased cardiovascular deaths and hospital admissions. To help understand the mechanisms, the types of particles most involved, and the types of persons most susceptible, the association between exposure to summertime air pollution and heart rate variability (HRV) was examined in a panel study of 28 elderly subjects. METHODS: Subjects were seen once a week for up to 12 weeks and HRV (SDNN, r-MSSD, PNN50, low frequency/high frequency ratio (LFHFR)) was measured for approximately 30 minutes at each session using a defined protocol. Temperature, day of the week, and hour of the day were controlled, and dummy variables for each subject were controlled for subject specific risk factors. RESULTS: PM2.5 was associated with r-MSSD (-10.1% change for an interquartile range (IQR) increase in exposure (95% CI -2.8 to -16.9)) and PNN50, but stronger associations were seen with black carbon, an indicator of traffic particles, which was also associated with SDNN (-4.6% per IQR (95% CI -2.0 to -7.2)) and LFHFR. Secondary particles were more weakly associated with r-MSSD, as was ozone. No associations were seen with SO2 or NO2. CO had similar patterns of association to black carbon, which disappeared after controlling for black carbon. Black carbon had a substantially higher effect on SDNN in subjects who had had a previous myocardial infarction (-12.7%, 95% CI -5.7 to -19.25). CONCLUSIONS: Particles, especially from traffic, are associated with disturbances of autonomic control of the heart.     

PATIENT SATISFACTION IN PROSTHETIC REHABILITATION PROGRAMME

Patient satisfaction is an important outcome measure independent of other outcomes. Its measurement is important to assess the effectiveness of a programme and to gain insight into the patients'' perception of the programme. In this study conducted in a large rehabilitation centre it was found that majority of patients express satisfaction with care inspite of perceived discomfort. Various demographic factors, severity or duration of the disability or the level of rehabilitation do not influence patient satisfaction. Patients express more concern with aspects such as delay in issue of the prosthesis, or hotel component of the hospital services. Patients did not appear too concerned about the level of information provided. Patient satisfaction is an individual reaction to the overall care process and is influenced by the initial expectation level of the patient. Emotional response of the patient appears to be more important determinant of patient satisfaction than the cognitive evaluation. Periodical assessment of patient satisfaction should be an important component of any programme evaluation exercise.KEY WORDS: Amputation, Patient satisfaction, Programme evaluation, Prosthesis, Quality of care, Rehabilitation     

Adrenomedullin (ADM) in the human forearm vascular bed: effect of neutral endopeptidase inhibition and comparison with proadrenomedullin NH2-terminal 20 peptide (PAMP)

AIMS: To compare the haemodynamic responses of proadrenomedullin N-terminal 20 peptide (PAMP) and adrenomedullin (ADM) in the forearm vascular bed of healthy male volunteers, and to investigate the role of neutral endopeptidase (NEP) in the metabolism of ADM. METHODS: On two separate occasions, ADM (1-30 pmol x min(-1)) and PAMP (100-3000 pmol x min(-1)) were infused into the brachial artery of eight male subjects, and forearm blood flow (FBF) assessed using venous occlusion plethysmography. In a second study, eight male subjects received the same doses of ADM, co-infused with either the NEP inhibitor thiorphan (30 nmol x min(-1)) or the control vasoconstrictor noradrenaline (120 pmol x min(-1)), on separate occasions. Both studies were conducted in a double-blind, randomized manner. RESULTS: ADM and PAMP produced a dose-dependent increase in FBF (P < or = 0.002). Based on the dose producing a 50% increase in FBF, ADM was approximately 60 times more potent than PAMP. Thiorphan and noradrenaline produced similar reductions in FBF of 14 +/- 4% (mean +/- s.e. mean) and 22 +/- 6%, respectively (P = 0.4). However, the area under the dose-response curve was significantly greater during co-infusion of ADM with thiorphan than with noradrenaline (P = 0.028), as was the maximum increase in FBF ratio (2.1 +/- 1.0 vs 1.2 +/- 0.2; P = 0.030). CONCLUSIONS: ADM and PAMP both produce a local dose-related vasodilatation in the human forearm, but PAMP is approximately 60 times less potent than ADM. In addition, NEP inhibition potentiates the haemodynamic effects of ADM. These findings suggest that PAMP may not play a role in the physiological regulation of blood flow. However, in pathophysiological conditions such as hypertension and heart failure, NEP inhibition may exert a beneficial effect by increasing the biological activity of ADM.     

Effect of feeding on the chemical control of breathing in the newborn infant

To examine the influence of feeding on the chemical control of breathing in neonates, we studied the ventilatory response to 3% CO2 in air in nine bottle fed (BOT) and eight breast fed (BR) term infants during feeding while the infants were alert. Control responses were obtained either before or after feeding, VE, respiratory frequency, tidal volume, inspiratory time, expiratory time, and sum of inspiratory and expiratory time, VT/Ti/Ttot, PACO2 and slope (S) of CO2 response (liter/min/kg/mmHg) were determined. During 3% CO2 while resting BR had a lower VE, VT, VT/Ti than BOT and S in BR was 40% of BOT (P less than 0.05). During feeding and CO2 when compared to resting and CO2 there was no difference in either BR or BOT in VT/Ti but Ti/Ttot decreased in both groups. During feeding, S in BOT was reduced from 0.049 +/- 0.012 (mean +/- S.E.) to 0.013 +/- 0.002 (74% reduction) and in BR from 0.020 +/- 0.002 to 0.009 +/- 0.002 (55%). Thus, behavioral activity (either BR or BOT) markedly depresses the ventilatory response to chemical stimuli (CO2). This modification is primarily related to changes in "effective" respiratory timing (Ti/Ttot) rather than mean inspiratory flow (VT/Vi).     

Quantitative noninvasive method to measure cerebral blood flow in newborn infants.

We measured cerebral blood flow (CBF) in 32 healthy neonates by venous occlusion plethysmography. Mean CBF was 63 ml/min/100 gm which compared favorably with invasive methods used in older children and adult subjects. We suggest that this is a useful method to quantify CBF in neonates. It may be valuable in assessing sequential changes occurring during asphyxia, intracranial hemorrhage, or during administration of various gas mixtures and drugs such as theophylline.