Mitigative effects of epigallocatechin gallate in terms of diminishing apoptosis and oxidative stress generated by the combination of lead and amyloid peptides in human neuronal cells.

Environmental exposure to lead (Pb) is reported to associate with the development of Alzheimer's disease, where the formation of ß-amyloid peptides (APs) of (1-40), (1-42), and (25-35) is considered as the major risk factor. In this context, we aimed at investigating the effect of epigallocatechin gallate (EGCG), a major flavonoid polyphenol available in green tea, in mitigating the individual and combined toxicity generated by Pb and ß-APs in terms of oxidative stress and apoptosis in human neuronal cells. SH-SY5Y cells were exposed to Pb and ß-APs of (1-40) and (25-35) individually and in different combinations in the presence and absence of EGCG. The results indicated that EGCG mitigated both Pb- and ß-AP-induced oxidative stress in scavenging reactive oxygen species and apoptosis by improving the expression levels of Bax and bcl2 and inhibiting annexin V and caspase-3. Thus, our study shows that EGCG protects SH-SY5Y cells against the cytotoxicity induced by Pb and ß-APs by decreasing oxidative stress and inhibiting apoptosis.

The development of a nurse-led preoperative anaesthesia screening tool by Delphi consensus.

BACKGROUND: Low- and middle-income countries have a critical shortage of specialist anaesthetists. Most patients arriving for surgery are of low perioperative risk. Without immediate access to preoperative specialist care, an appropriate interim strategy may be to ensure that only high-risk patients are seen preoperatively by a specialist. Matching human resources to the burden of disease with a nurse-administered pre-operative screening tool to identify high-risk patients who might benefit from specialist review prior to the day of surgery may be an effective strategy. OBJECTIVE: To develop a nurse-administered preoperative anaesthesia screening tool to identify patients who would most likely benefit from a specialist review before the day of surgery, and those patients who could safely be seen by the anaesthetist on the day of surgery. This would ensure adequate time for optimisation of high-risk patients preoperatively and limit avoidable day-of-surgery cancellations. METHODS: A systematic review was conducted to identify preoperative screening questions for use in a three-round Delphi consensus process. A panel of 16 experienced full-time clinical anaesthetists representing all university-affiliated anaesthesia departments in South Africa participated to define a nurses' screening tool for preoperative assessment. RESULTS: Ninety-eight studies were identified, which generated 79 questions. An additional 14 items identified by the facilitators were added to create a list of 93 questions for the first round. The final screening tool consisted of 81 questions, of which 37 were deemed critical to identify patients who should be seen by a specialist prior to the day of surgery. CONCLUSION: A structured nurse-administered preoperative screening tool is proposed to identify high-risk patients who are likely to benefit from a timely preoperative specialist anaesthetist review to avoid cancellation on the day of surgery.

Acute kidney injury after major non-cardiac surgery: Incidence and risk factors.

BACKGROUND: Acute kidney injury (AKI) is a major post-surgical complication that contributes to morbidity and mortality. AKI is welldocumented after cardiac surgery. However, less is known regarding the incidence and risk factors following major non-cardiac surgery.Globally the incidence of AKI post major surgery has been evaluated; however, there are no data available for South Africa (SA). OBJECTIVES: To ascertain the incidence of AKI after major non-cardiac surgery at a tertiary academic SA hospital. Secondary outcomes wereto identify perioperative risk factors that are associated with an elevated risk to develop AKI in the postoperative period. METHODS: The study was conducted at Tygerberg Hospital, a single tertiary centre in Cape Town, SA. Perioperative records of adults whounderwent major non-cardiac surgery were retrospectively collected. Variables pertaining to potential risk factors for AKI were captured,and serum creatinine levels were recorded up to 7 days postoperatively and compared with baseline measurements to determine whetherAKI had developed. Descriptive statistics along with logistic regression analysis were used to interpret results. RESULTS: The overall incidence of AKI was 11.2% (95% confidence interval (CI) 9.8 - 12.6). Based on surgical discipline, trauma surgery(19%), followed by abdominal (18.5%) and vascular surgery (17%) had the highest incidence. Independent AKI risk factors wereidentified after multivariate analysis. These were: chronic obstructive pulmonary disease (odds ratio (OR) 2.19; 95% CI 1.09 - 4.37;p=0.005), trauma surgery (OR 3.00; 95% CI 1.59 - 5.64; p=0.001), abdominal surgery (OR 2.14; 95% CI 1.33 - 3.45; p=0.002), vascularsurgery (OR 2.42; 95% CI 1.31 - 4.45; p=0.004), urology procedures (OR 2.45; 95% CI 1.31 - 4.45; p=0.005), red blood cell transfusion(OR 1.81; 95% CI 1.21 - 2.70; p=0.004), emergency surgery (OR 1.74; 95% CI 1.15 - 2.65; p=0.009) and inotrope use (OR 2.77; 95% CI1.80 - 4.26; p<0.001). CONCLUSION: The results of our study are in keeping with international literature regarding the incidence of AKI after major non-cardiacsurgery. The risk factor profile, however, is in several regards different from what has been found elsewhere.

Screening for acute HIV infection in South Africa: finding acute and chronic disease.

BACKGROUND: The yield of screening for acute HIV infection among general medical patients in resource-scarce settings remains unclear. Our objective was to evaluate the strategy of using pooled HIV plasma RNA to diagnose acute HIV infection in patients with negative or discordant rapid HIV antibody tests in Durban, South Africa. METHODS: We prospectively enrolled patients with negative or discordant rapid HIV antibody tests from a routine HIV screening programme in an out-patient department in Durban with an HIV prevalence of 48%. Study participants underwent venipuncture for pooled qualitative HIV RNA, and, if this was positive, quantitative RNA, enzyme immunoassay and Western blot (WB). Patients with negative or indeterminate WB and positive quantitative HIV RNA were considered acutely infected. Those with chronic infection (positive RNA and WB) despite negative or discordant rapid HIV tests were considered to have had false negative rapid antibody tests. RESULTS: Nine hundred and ninety-four participants were enrolled with either negative (n=976) or discordant (n=18) rapid test results. Eleven [1.1%; 95% confidence interval (CI) 0.6-2.0%] had acute HIV infection, and an additional 20 (2.0%; 95% CI 1.3-3.1%) had chronic HIV infection (false negative rapid test). CONCLUSIONS: One per cent of out-patients with negative or discordant rapid HIV tests in Durban, South Africa had acute HIV infection readily detectable through pooled serum HIV RNA screening. Pooled RNA testing also identified an additional 2% of patients with chronic HIV infection. HIV RNA screening has the potential to identify both acute and chronic HIV infections that are otherwise missed by standard HIV testing algorithms.

Stress ulcer prophylaxis use in critical care units at public hospitals in Johannesburg, South Africa.

Background: Stress ulcer prophylaxis (SUP) is part of the management of critically ill patients in intensive care units (ICUs). However, inappropriate use of these drugs has important clinical implications such as ventilator-associated pneumonia and Clostridium difficile-associated gastrointestinal tract infections. The overuse of proton pump inhibitors (PPIs) as SUP is a rapidly growing problem globally. Objectives: To describe the use of SUP in three selected ICUs in Johannesburg, South Africa (SA). Methods: A retrospective, descriptive, contextual study design was used. Data were collected from ICU records of adult patients admitted into these units during the study period (1 August 2013 - 31 October 2013). Results: A total of 174 patients were included in the study. Of these, 156 were on SUP and only 38.5% (n=60/156) were appropriately treated with SUP according to the American Society of Health-System Pharmacists guidelines. There was an inappropriate use of SUP in over 50% of those who were treated. The most frequently prescribed SUP was histamine-2 receptor antagonist (H2RA) (51.3%; n=80/156), followed by PPIs (30.8%; n=48/156), sucralfate (17.3%; n=27/156), and a combination of PPI and H2RA (0.6%; n=1/156). Conclusion: The study demonstrated overuse of SUP. The most commonly used drug for SUP was H2RA and not PPIs. This study demonstrates that the problem of SUP overuse internationally also exists locally. The development of local guidelines may help to improve the practice of SUP in SA. Contributions of the study: This study showed overuse of SUP and should encourage doctors to critically evaluate why they prescribe SUP and whether it is really indicated. This should help in the adoption of practices towards appropriate use of SUP.

Unrecognised postoperative residual curarisation in developing countries remains a common problem.

BACKGROUND: Postoperative residual curarisation (PORC) is a potentially life-threatening complication of non-depolarising muscle relaxant use in anaesthesia. Quantitative neuromuscular monitoring has the potential to reduce the risk of PORC, but many anaesthetists rely on clinical assessment of neuromuscular function alone. OBJECTIVES: To investigate the occurrence of PORC in the recovery room at an academic hospital in Gauteng, South Africa. Additionally, this prospective, cross-sectional study aimed to determine the extent of intraoperative neuromuscular monitoring and to assess clinical factors that may influence the risk of PORC. METHODS: Patient characteristics and clinical information, including whether neuromuscular monitoring had been conducted, were recorded. Patients were evaluated by clinical assessment and determination of a quantitative train-of-four ratio (TOFR). PORC assessment methods were compared and clinical characteristics were analysed for association with TOFR status. RESULTS: The incidence of PORC (TOFR <0.9) in the study group was 45.5%; however, 78% passed the clinical assessment. The specificity of clinical assessment to detect residual paralysis was 24%. Notably, only 3 patients (6%) were monitored intraoperatively for neuromuscular function. Advanced age (p=0.011, r=-0.34) and female gender (p=0.001) were shown to be associated with a TOFR <0.7. CONCLUSIONS: PORC is more common in practice than currently recognised. This deduction is supported by the low rate of intraoperative neuromuscular monitoring conducted and the high pass rate on clinical assessment. Routine use of quantitative monitoring of neuromuscular function should be encouraged to minimise the risk of this serious yet preventable condition.

Microwave-Assisted Synthesis of Quasi-Pyramidal CuInS2 -ZnS Nanocrystals for Enhanced Near-Infrared Targeted Fluorescent Imaging of Subcutaneous Melanoma.

Near-infrared (NIR) fluorescent CuInS2 -ZnS nanocrystals (CIZS NCs) are synthesized via an ultra-fast, non-injection microwave (MW)-assisted nanoalloying process at 230 ºC within 5 min using 1-dodecanethiol (DDT) as both the sulfur source and solvent under solvothermal (ST) condition. The structural and surface analyses reveal that DDT-functionalized CIZS NCs exhibit quasi-pyramids of tetragonal-phase with well-defined facets. The DDT-functionalized CIZS NCs present a photoluminescence quantum yield (PLQY) of 76% and a long-lived fluorescence lifetime of ≈0.6 µs in organic-phase. Subsequently, DDT-functionalized CIZS NCs are phase-transferred via ligand-exchange using 11-mercaptoundecanoic acid (MUA) into water-soluble MUA-CIZS NCs that exhibit a substantial PLQY of 55%. In addition, the NIR-fluorescent MUA-functionalized CIZS NCs in conjugation with folic acid (FA), as a tumor-targeting ligand, demonstrates enhanced tumor-targeted imaging ability. The FA-MUA-CIZS NC conjugates exhibit a cell viability of ≈75% even at the highest concentration of 1 mg mL-1 and a labeling efficiency of 95.4%. The in vivo imaging results corroborate that FA-MUA-CIZS NCs conjugates are actively targeted to folate receptor-positive B16F10 tumor-bearing C57BL/6 mice in 2 h. The histopathological and hematological studies confirm no significant changes in tissue architecture and blood biochemical parameters. The confocal microscopy studies reveal deep penetration and uniform distribution of FA-MUA-CIZS NCs conjugates in subcutaneous melanoma.

The Critical Care Society of Southern Africa Consensus Statement on ICU Triage and Rationing (ConICTri).

Background: In South Africa (SA), intensive care is faced with the challenge of resource scarcity as well as an increasing demand for intensive care unit (ICU) services. ICU services are expensive, and practitioners in low- to middle-income countries experience daily the consequences of limited resources. Critically limited resources necessitate that rationing and triage (prioritisation) decisions are frequently necessary in SA, particularly in the publicly funded health sector. Purpose: The purpose of this consensus statement is to examine key questions that arise when considering the status of ICU resources in SA, and more specifically ICU admission, rationing and triage decisions. The accompanying guideline in this issue is intended to guide frontline triage policy and ensure the best utilisation of intensive care in SA, while maintaining a fair distribution of available resources. Fair and efficient triage is important to ensure the ongoing provision of high-quality care to adult patients referred for intensive care. Recommendations: In response to 14 key questions developed using a modified Delphi technique, 29 recommendations were formulated and graded using an adapted GRADE score. The 14 key questions addressed the status of the provision of ICU services in SA, the degree of resource restriction, the efficiency of resource management, the need for triage, and how triage could be most justly implemented. Important recommendations included the need to formally recognise and accurately quantify the provision of ICU services in SA by national audit; actively seek additional resources from governmental bodies; consider methods to maximise the efficiency of ICU care; evaluate lower level of care alternatives; develop a triage guideline to assist policy-makers and frontline practitioners to implement triage decisions in an efficient and fair way; measure and audit the consequence of triage; and promote research to improve the accuracy and consistency of triage decisions. The consensus document and guideline should be reviewed and revised appropriately within 5 years. Conclusion: In recognition of the absolute need to limit patient access to ICU because of the lack of sufficient intensive care resources in public hospitals, recommendations and a guideline have been developed to guide policy-making and assist frontline triage decision-making in SA. These documents are not a complete plan for quality practice but rather the beginning of a long-term initiative to engage clinicians, the public and administrators in appropriate triage decision-making, and promote systems that will ultimately maximise the efficient and fair use of available ICU resources.

The Critical Care Society of Southern Africa Consensus Guideline on ICU Triage and Rationing (ConICTri).

Background: In South Africa (SA), administrators and intensive care practitioners are faced with the challenge of resource scarcity as well as an increasing demand for intensive care unit (ICU) services. ICU services are expensive, and practitioners in low- to middle-income countries experience the consequences of limited resources daily. Critically limited resources necessitate that rationing and triage (prioritisation) decisions are routinely necessary in SA, particularly in the publicly funded health sector. Purpose: The purpose of this guideline is to utilise the relevant recommendations of the associated consensus meeting document and other internationally accepted principles to develop a guideline to inform frontline triage policy and ensure the best utilisation of adult intensive care in SA, while maintaining the fair distribution of available resources. Recommendations: An overall conceptual framework for the triage process was developed. The components of the framework were developed on the basis that patients should be admitted preferentially when the likely incremental medical benefit derived from ICU admission justifies admission. An estimate of likely resource use should also form part of the triage decision, with those patients requiring relatively less resources to achieve substantial benefit receiving priority for admission. Thus, the triage system should maximise the benefits obtained from ICU resources available for the community. Where possible, practical examples of what the consensus group agreed would be considered appropriate practice under specified South African circumstances were provided, to assist clinicians with practical decision-making. It must be stressed that this guideline is not intended to be prescriptive for individual hospital or regional practice, and hospitals and regions are encouraged to develop specified local guidelines with locally relevant examples. The guideline should be reviewed and revised if appropriate within 5 years. Conclusion: In recognition of the absolute need to limit patient access to ICU because of the lack of sufficient intensive care resources in public hospitals, this guideline has been developed to guide policy-making and assist frontline triage decision-making in SA. This document is not a complete plan for quality practice, but rather a template to support frontline clinicians, guide administrators and inform the public regarding appropriate triage decision-making.

The Critical Care Society of Southern Africa Consensus Statement on ICU Triage and Rationing (ConICTri).

Background. In South Africa (SA), intensive care is faced with the challenge of resource scarcity as well as an increasing demand for intensive care unit (ICU) services. ICU services are expensive, and practitioners in low- to middle-income countries experience daily the consequences of limited resources. Critically limited resources necessitate that rationing and triage (prioritisation) decisions are frequently necessary in SA, particularly in the publicly funded health sector. Purpose. The purpose of this consensus statement is to examine key questions that arise when considering the status of ICU resources in SA, and more specifically ICU admission, rationing and triage decisions. The accompanying guideline in this issue is intended to guide frontline triage policy and ensure the best utilisation of intensive care in SA, while maintaining a fair distribution of available resources. Fair and efficient triage is important to ensure the ongoing provision of high-quality care to adult patients referred for intensive care. Recommendations. In response to 14 key questions developed using a modified Delphi technique, 29 recommendations were formulated and graded using an adapted GRADE score. The 14 key questions addressed the status of the provision of ICU services in SA, the degree of resource restriction, the efficiency of resource management, the need for triage, and how triage could be most justly implemented. Important recommendations included the need to formally recognise and accurately quantify the provision of ICU services in SA by national audit; actively seek additional resources from governmental bodies; consider methods to maximise the efficiency of ICU care; evaluate lower level of care alternatives; develop a triage guideline to assist policy-makers and frontline practitioners to implement triage decisions in an efficient and fair way; measure and audit the consequence of triage; and promote research to improve the accuracy and consistency of triage decisions. The consensus document and guideline should be reviewed and revised appropriately within 5 years. Conclusion. In recognition of the absolute need to limit patient access to ICU because of the lack of sufficient intensive care resources in public hospitals, recommendations and a guideline have been developed to guide policy-making and assist frontline triage decision-making in SA. These documents are not a complete plan for quality practice but rather the beginning of a long-term initiative to engage clinicians, the public and administrators in appropriate triage decision-making, and promote systems that will ultimately maximise the efficient and fair use of available ICU resources.

The Critical Care Society of Southern Africa Consensus Guideline on ICU Triage and Rationing (ConICTri).

Background. In South Africa (SA), administrators and intensive care practitioners are faced with the challenge of resource scarcity as well as an increasing demand for intensive care unit (ICU) services. ICU services are expensive, and practitioners in low- to middle-income countries experience the consequences of limited resources daily. Critically limited resources necessitate that rationing and triage (prioritisation) decisions are routinely necessary in SA, particularly in the publicly funded health sector. Purpose. The purpose of this guideline is to utilise the relevant recommendations of the associated consensus meeting document and other internationally accepted principles to develop a guideline to inform frontline triage policy and ensure the best utilisation of adult intensive care in SA, while maintaining the fair distribution of available resources. Recommendations. An overall conceptual framework for the triage process was developed. The components of the framework were developed on the basis that patients should be admitted preferentially when the likely incremental medical benefit derived from ICU admission justifies admission. An estimate of likely resource use should also form part of the triage decision, with those patients requiring relatively less resources to achieve substantial benefit receiving priority for admission. Thus, the triage system should maximise the benefits obtained from ICU resources available for the community. Where possible, practical examples of what the consensus group agreed would be considered appropriate practice under specified South African circumstances were provided, to assist clinicians with practical decision-making. It must be stressed that this guideline is not intended to be prescriptive for individual hospital or regional practice, and hospitals and regions are encouraged to develop specified local guidelines with locally relevant examples. The guideline should be reviewed and revised if appropriate within 5 years. Conclusion. In recognition of the absolute need to limit patient access to ICU because of the lack of sufficient intensive care resources in public hospitals, this guideline has been developed to guide policy-making and assist frontline triage decision-making in SA. This document is not a complete plan for quality practice, but rather a template to support frontline clinicians, guide administrators and inform the public regarding appropriate triage decision-making.

A new way of teaching an old subject: Pharmacy Law and Ethics.

BACKGROUND: Pharmacy educators are responsible for ensuring that students are equipped with the necessary regulatory knowledge required to deal with ethical challenges that arise in practice. Teaching methods have a strong impact on student learning, making it essential to determine how learning is influenced when changing pedagogy. OBJECTIVE: To describe students' experience and perceptions of the use of a case-based learning (CBL) activity as an adjunctive method to didactic teaching of pharmacy law and ethics. METHOD: A survey was conducted among 3rd-year pharmacy students enrolled for a Pharmacy Law and Ethics course at the University of KwaZulu-Natal, Durban, South Africa. The course content was delivered didactically, followed by a CBL activity for which the students were divided into groups and assigned various real-life case studies. RESULTS: Most of the 74 respondents (66%) agreed that the activity was enjoyable and metacognitively useful. A majority (77%) found the activity interactive, and 92% agreed that it enhanced their understanding of pharmacy law concepts. Eighty percent agreed that it facilitated their understanding of law and ethics concepts, and their application to real-life situations. CONCLUSION: The use of CBL was beneficial to both the individual student's learning experience and the overall class learning process. More importantly, the exercise improved their metacognitive awareness, and suggests the need to consider this method of teaching as part of the formal curriculum to better equip students to deal with ethical issues that will arise in practice.

A proposed management algorithm for late-onset efavirenz neurotoxicity.

A high proportion of HIV-positive patients in South Africa receive concomitant efavirenz (EFV) and isoniazid (INH) therapy. EFV is metabolised in the liver via CYP2B6, and genetic polymorphism of CYP2B6 is known to result in slowed metabolism of the drug. INH is also metabolised in the liver, causing inhibition of a pathway that plays an important role in slow EFV metabolisers. Concomitant INH use therefore affects plasma levels of EFV. EFV is well known to cause neuropsychiatric side-effects on initiation, and a recent adult case series described late-onset neurotoxicity in the form of subacute ataxia and encephalopathy in patients treated with EFV for a median of 2 years, in association with toxic plasma levels of the drug. We have seen an increase in cases of EFV toxicity presenting to our neurology referral unit. All cases have been in the context of recent initiation of concomitant INH. We therefore conducted a retrospective case record audit to describe these seven cases with the additional advantage of tertiary-level assessment. We outline the clinical features and investigation results, as well as outcomes after EFV was stopped. Our main objectives are to highlight the probable role of concomitant INH use in the development of this syndrome, and to suggest that only limited work-up may be warranted in suspected cases.

Sustainable, Rapid Synthesis of Bright-Luminescent CuInS2-ZnS Alloyed Nanocrystals: Multistage Nano-xenotoxicity Assessment and Intravital Fluorescence Bioimaging in Zebrafish-Embryos.

Near-infrared (NIR) luminescent CuInS2-ZnS alloyed nanocrystals (CIZS-NCs) for highly fluorescence bioimaging have received considerable interest in recent years. Owing, they became a desirable alternative to heavy-metal based-NCs and organic dyes with unique optical properties and low-toxicity for bioimaging and optoelectronic applications. In the present study, bright and robust CIZS-NCs have been synthesized within 5 min, as-high-as 230 °C without requiring any inert-gas atmosphere via microwave-solvothermal (MW-ST) method. Subsequently, the in vitro and in vivo nano-xenotoxicity and cellular uptake of the MUA-functionalized CIZS-NCs were investigated in L929, Vero, MCF7 cell lines and zebrafish-embryos. We observed minimal toxicity and acute teratogenic consequences upto 62.5 µg/ml of the CIZS-NCs in zebrafish-embryos. We also observed spontaneous uptake of the MUA-functionalized CIZS-NCs by 3 dpf older zebrafish-embryos that are evident through bright red fluorescence-emission at a low concentration of 7.8 µg/mL. Hence, we propose that the rapid, low-cost, large-scale "sustainable" MW-ST synthesis of CIZS-NCs, is an ideal bio-nanoprobe with good temporal and spatial resolution for rapid labeling, long-term in vivo tracking and intravital-fluorescence-bioimaging (IVBI).

Balloon valvuloplasty versus closed commissurotomy for pliable mitral stenosis: a prospective hemodynamic study.

Closed surgical mitral valvotomy is the procedure of choice in most patients with symptomatic pliable mitral stenosis in developing countries. The procedure is efficacious and safe. Mitral valvotomy performed with a balloon has shown similar good results, with infrequent complications in selected subjects. Because there is a paucity of studies comparing the two techniques, this study was undertaken to compare the results of percutaneous balloon mitral valvuloplasty with those of closed commissurotomy as determined by catheterization studies. Forty-five patients with tight pliable mitral stenosis were randomly assigned to one of two groups: 23 patients had balloon valvuloplasty by the single catheter technique (group I) and 22 underwent closed surgical valvotomy (group II). The two groups were similar with regard to clinical and hemodynamic findings before intervention. Mitral valve area increased from 0.8 +/- 0.3 to 2.1 +/- 0.7 cm2 in group I (p less than 0.001) and from 0.7 +/- 0.2 to 1.3 +/- 0.3 cm2 in group II (p less than 0.001). Pulmonary artery pressure and pulmonary vascular resistance decreased in both groups, but these changes did not reach statistical significance in group II. Treadmill exercise time increased from 3.8 +/- 2.3 to 7.3 +/- 2.6 min in group I (p less than 0.001) and from 4 +/- 2.6 to 5.6 +/- 2.6 min in group II (p less than 0.001). There were no deaths. One patient in each group developed moderate (3+) mitral regurgitation. A small interatrial shunt (less than 1.5:1) was detected in three patients in group I immediately after the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

Arrhythmia in hypertrophic cardiomyopathy: exercise and 48 hour ambulatory electrocardiographic assessment with and without beta adrenergic blocking therapy.

Submaximal treadmill exercise electrocardiography and 48 hour ambulatory electrocardiographic monitoring were performed in 30 patients with hypertrophic cardiomyopathy both with and without beta adrenergic blocking therapy. During ambulatory electrocardiographic monitoring 1 patient (3 percent) had no arrhythmia, 14 patients (46 percent) had supraventricular tachycardia or paroxysmal atrial fibrillation, 13 (43 percent) had multiform or paired ventricular extrasystoles and 8 (26 percent) had ventricular tachycardia. The frequency of these ventricular arrhythmias was almost identical with and without beta adrenergic blocking drugs (mean dose in "propranolol equivalents" 280 mg daily). With beta blocking therapy fewer patients had supraventricular tachycardia; however, the difference was not significant. During exercise testing 18 patients (60 percent) had ventricular extrasystoles and 3 patients (10 percent) had paired ventricular extrasystoles and the frequency was almost identical with and without beta adrenergic blocking therapy. No routine echocardiographic or hemodynamic measurement predicted the serious ventricular arrhythmias. It is concluded that asymptomatic ventricular arrhythmia is a common occurrence in patients with hypertrophic cardiomyopathy and its frequency is not reduced with beta adrenergic blocking therapy. Because occult arrhythmia may be the cause of sudden death it is important to detect it in these patients so that an effort can be made to improve prognosis with specific antiarrhythmic treatment.

Effect of chlordecone on pH and temperature dependent substrate activation kinetics of rat brain synaptosomal ATPases.

Chlordecone, a polycyclic chlorinated insecticide known as Kepone, inhibited the activities of (Na+-K+)ATPase and Mg2+-ATPase in rat brain synaptosomes. Altered pH and specific activity curves for both enzymes demonstrated significant inhibition by chlordecone in buffered acidic, neutral and alkaline pH ranges. Noncompetitive inhibition with respect to activation by ATP in the case of (Na+-K+)ATPase was indicated by altered Vmax values with no significant change in Km values at any pH studied, except at pH 9.5. Mg2+-ATPase was inhibited uncompetitively as evidenced by altered Vmax and Km values. The activities of both ATPase were decreased in the presence of chlordecone at higher temperatures. Activation energy (delta E) values were found to be decreased significantly in the presence of chlordecone at 37 degrees. Arrhenius plots of both ATPases preincubated with chlordecone were found to be nonlinear. In the presence of chlordecone, Vmax was decreased without significant change in Km values for (Na+-K+)ATPase at all temperatures, suggesting a noncompetitive type of inhibition. In the case of Mg2+-ATPase, similar noncompetitive type inhibition was obtained at 27 degrees but not at 32 and 37 degrees. The kinetic data in general suggest that the chlordecone inhibited (Na+-K+)ATPase noncompetitively and Mg2+-ATPase uncompetitively at all pHs and temperatures studied. The present data suggest that inhibition of (Na+-K+)ATPase and Mg2+-ATPase, the two membrane-bound enzymes in synaptosomes, by chlordecone is temperature dependent and pH independent.

HLA, complement C2, C4, properdin factor B and glyoxalase types in South Indian diabetics.

A series of diabetic patients from 3 centres in South India have been tested for HLA A, HLA B, BF, C2, C4A, C4B and GLO types. For insulin-dependent diabetes mellitus (IDDM) patients there was a significant increase in HLA B8, of BF F and decrease of C4 A6. No significant variation in HLA, BF, C2 or GLO frequencies was found in non-insulin-dependent diabetes mellitus (NIDDM) patients, but there was a significant decrease in C4B 1 and an increase in C4B 2. The HLA and BF association in South Indian IDDM patients is very different from that reported previously in North India.

Inhibition of calmodulin activated adenylate cyclase in rat brain by selected insecticides.

Effect of various insecticides on basal and calmodulin (CaM) activated adenylate cyclase activity was studied in solubilized rat brain nuclear and P2 fractions. Our earlier experiments indicated that plictran, chlordecone and other insecticides affect the calcium transport across cell membranes. The present experiments were designed with the assumption that these compounds might exert their neurotoxic action by interfering with CaM (a calcium receptor protein) regulated processes. We have used detergent solubilized adenylate cyclase for our studies, since membrane bound form is not sensitive to externally added CaM. CaM significantly elevated the adenylate cyclase activity in both the fractions and a maximum stimulation of 97% in nuclear fraction and 50% in P2 fraction was observed with 1 microgram of CaM. All the insecticides studied inhibited both basal and CaM activated adenylate cyclase activity in nuclear and P2 fractions to a different extent. A significant inhibition was observed at 0.05 microM and higher concentrations of plictran. Chlordecone and toxaphene inhibited both basal and CaM activated adenylate cyclase in a concentration dependent manner. Although dieldrin and aldrin inhibited basal adenylate cyclase in a concentration dependent manner, they did not exhibit a similar pattern on CaM activated adenylate cyclase. Of all the insecticides studies, chlordecone is more potent in inhibiting both basal and CaM activated adenylate cyclase which is in agreement with the greater neurotoxic action of this compound. These results indicate that all the insecticides studied are potent inhibitors of detergent solubilized adenylate cyclase, and might exert their neurotoxic differential action by interfering with CaM regulated events in central nervous system.

Sympathetic and platelet adrenergic activity and salt sensitivity: an experimental study.

The objective of the study was to evaluate the advanced hypothesis that genetically predisposed salt-sensitivity contributes to an increased adrenergic susceptibility and platelet activity and both these factors play a role in the pathogenesis of hypertension in a Dahl rat model. The results showed: i) Dahl salt-sensitive rats (DS) gradually develop a diastolic hypertension by the end of 3 months of age, in spite of the diet they are fed. Low-Na diet (0.5% NaCl) does not prevent hypertension but delays its development. High-Na diet (8%) exacerbates their hypertension. ii) After 2 months of Na-loading, DS rats expressed significantly increased sodium and water retention and increased plasma volume by 15%, compared with 2.8% in Dahl salt-resistant (DR) rats on high-Na diet. iii) The increased activity of the sympathetic nervous system (SNS) in DS rats paralleled the development of hypertension and was stimulated by Na-loading. It was assessed by their catecholamines status and heart rate changes. iv) Platelet activity of DS rats was increased as reflected in collagen-induced nonstimulated and adrenaline-stimulated aggregation, and an increased plasma T x B2/6-keto PGF1 alpha ratio. Na-loading further increased platelet activity. v) Both DR and DS rat platelets displayed alpha 2-adrenoceptors (A2) of low binding capacity (Bmax 25 and 35 fmol/mg protein, respectively) and low affinity (KD 5.6 nM for both groups), suggesting that platelet alpha 2 adrenoceptors in this strain of rats might not play a significant biological role in their increased platelet activity. The fact that platelet alpha 2-adrenoceptors do not define the stimulation of SNS in DS rat do not exclude their participation in development of salt-dependent hypertension, since a genetic defect(s) of these ubiquitous receptors (brain, kidney, blood vessels) could still contribute to the pathogenesis of the disease.