Role of the MPTP in conditioning the heart - translatability and mechanism.

Mitochondria have long been known to be the gatekeepers of cell fate. This is particularly so in the response to acute ischaemia-reperfusion injury (IRI). Following an acute episode of sustained myocardial ischaemia, the opening of the mitochondrial permeability transition pore (MPTP) in the first few minutes of reperfusion, mediates cell death. Preventing MPTP opening at the onset of reperfusion using either pharmacological inhibitors [such as cyclosporin A (CsA) ] or genetic ablation has been reported to reduce myocardial infarct (MI) size in animal models of acute IRI. Interestingly, the endogenous cardioprotective intervention of ischaemic conditioning, in which the heart is protected against MI by applying cycles of brief ischaemia and reperfusion to either the heart itself or a remote organ or tissue, appears to be mediated through the inhibition of MPTP opening at reperfusion. Small proof-of-concept clinical studies have demonstrated the translatability of this therapeutic approach to target MPTP opening using CsA in clinical settings of acute myocardial IRI. However, given that CsA is a not a specific MPTP inhibitor, more novel and specific inhibitors of the MPTP need to be discovered - the molecular identification of the MPTP should facilitate this. In this paper, we review the role of the MPTP as a target for cardioprotection, the potential mechanisms underlying MPTP inhibition in the setting of ischaemic conditioning, and the translatability of MPTP inhibition as a therapeutic approach in the clinical setting.

DJ-1 protects against cell death following acute cardiac ischemia-reperfusion injury.

Novel therapeutic targets are required to protect the heart against cell death from acute ischemia-reperfusion injury (IRI). Mutations in the DJ-1 (PARK7) gene in dopaminergic neurons induce mitochondrial dysfunction and a genetic form of Parkinson's disease. Genetic ablation of DJ-1 renders the brain more susceptible to cell death following ischemia-reperfusion in a model of stroke. Although DJ-1 is present in the heart, its role there is currently unclear. We sought to investigate whether mitochondrial DJ-1 may protect the heart against cell death from acute IRI by preventing mitochondrial dysfunction. Overexpression of DJ-1 in HL-1 cardiac cells conferred the following beneficial effects: reduced cell death following simulated IRI (30.4±4.7% with DJ-1 versus 52.9±4.7% in control; n=5, P<0.05); delayed mitochondrial permeability transition pore (MPTP) opening (a critical mediator of cell death) (260±33 s with DJ-1 versus 121±12 s in control; n=6, P<0.05); and induction of mitochondrial elongation (81.3±2.5% with DJ-1 versus 62.0±2.8% in control; n=6 cells, P<0.05). These beneficial effects of DJ-1 were absent in cells expressing the non-functional DJ-1(L166P) and DJ-1(Cys106A) mutants. Adult mice devoid of DJ-1 (KO) were found to be more susceptible to cell death from in vivo IRI with larger myocardial infarct sizes (50.9±3.5% DJ-1 KO versus 41.1±2.5% in DJ-1 WT; n≥7, P<0.05) and resistant to cardioprotection by ischemic preconditioning. DJ-1 KO hearts showed increased mitochondrial fragmentation on electron microscopy, although there were no differences in calcium-induced MPTP opening, mitochondrial respiratory function or myocardial ATP levels. We demonstrate that loss of DJ-1 protects the heart from acute IRI cell death by preventing mitochondrial dysfunction. We propose that DJ-1 may represent a novel therapeutic target for cardioprotection.

"Pack year" smoking histories: what about patients who use loose tobacco?

Life time smoking of ready made cigarettes can be readily quantified as "pack years" smoked, but methods for measuring loose tobacco use are less well established. In this study the frequency of loose tobacco use by 247 hospital in-patients was determined; 64% were current or ex-smokers, 41.3% of whom (25.9% of participants) had smoked loose tobacco. A formula was developed for converting loose tobacco use to pack years smoked, based on the weight of tobacco in ready made cigarettes; 12.5 g or half an ounce of loose tobacco was approximately equivalent to one packet of 20 cigarettes. Using a questionnaire it was found that hospital physicians of all grades were able to convert smoking histories of ready made cigarettes, but not loose tobacco, into number of "pack years" smoked.

Surface texture of resin-modified glass ionomer cements: effects of finishing/polishing time.

This study compared the surface texture of resin-modified glass ionomer cements after immediate and delayed finishing with different finishing/polishing systems. Class V preparations were made on the buccal and lingual/palatal surfaces of 64 freshly extracted teeth. The cavities on each tooth were restored with Fuji II LC (GC) and Photac-Fil Quick (3M-ESPE) according to manufacturers' instructions. Immediately after light-polymerization, gross finishing was done with 8-fluted tungsten carbide burs. The teeth were then randomly divided into four groups of 16 teeth. Half of the teeth in each group were finished immediately, while the remaining half were finished after one-week storage in distilled water at 37 degrees C. The following finishing/polishing systems were employed: (a) Robot Carbides; (b) Super-Snap system; (c) OneGloss and (d) CompoSite Polishers. The mean surface roughness (microm; n=8) in vertical (RaV) and horizontal (RaH) axis was measured using a profilometer. Data was subjected to ANOVA/Scheffe's tests and Independent Samples t-test at significance level 0.05. Ra values were generally lower in both vertical and horizontal axis with delayed finishing/polishing. Although significant differences in RaV and RaH values were observed among several systems with immediate finishing/polishing, only one (Fuji II LC: RaH - Super-Snap < Robot Carbides) was observed with delayed finishing.

Surface texture of resin-modified glass ionomer cements: effects of finishing/polishing systems.

This study investigated the surface texture of two resin-modified glass ionomer cements (RMGICs) in the vertical and horizontal axis after treatment with different finishing/polishing systems. Class V preparations were made on the buccal and lingual/palatal surfaces of freshly extracted teeth. The cavities on each tooth were restored with Fuji II LC (GC) and Photac-Fil Quick (ESPE) according to manufacturers' instructions. Immediately after light-polymerization, gross finishing was done with 8-flute tungsten carbide burs. The teeth were then randomly divided into four groups and finished/polished with (a) Robot Carbides (RC); (b) Super-Snap system (SS); (c) OneGloss (OG) and (d) CompoSite Points (CS). The sample size for each material-finishing/polishing system combination was eight. The mean surface roughness (microm) in vertical (RaV) and horizontal (RaH) axis was measured using a profilometer. Data was subjected to ANOVA/Scheffe's tests and Independent Samples t-test at significance level 0.05. Mean RaV ranged from 0.59-1.31 and 0.83-1.52, while mean RaH ranged from 0.80-1.43 and 0.85-1.58 for Fuji II LC and Photac-Fil, respectively. Results of statistical analysis were as follows: Fuji II LC: RaV-RC, SS

Optimisation of electroporation for biochemical experiments in live cells.

To introduce into cells small molecules, which do not permeate the cell membrane naturally, electroporation is the fastest and most efficient technique. Although it is not completely benign, the speed at which a full population of cells can be permeated gives it a strong advantage over all other cell permeation techniques. Here we describe the potential damaging effects of electroporation and how to derive conditions which avoid these and assure its use for biochemical experiments in live cells.

Neuroleptic malignant syndrome in Malaysia: a university hospital experience.

The neuroleptic malignant syndrome (NMS) is a potentially fatal complication of antipsychotic therapy. A retrospective study of nine patients seen over six years at the University Hospital, Kuala Lumpur (UHKL), is described. The estimated annualised incidence was 1.2 per 1000 in-patients with psychosis. No ethnic difference was detected. Clinical features were similar to experiences elsewhere, with wide variability seen in the severity of illness. The neuroleptic drugs implicated were haloperidol, trifluoperazine, chlorpromazine, fluphenazine and clopenthixol. Treatment consisted of withdrawal of offending drugs and supportive measures. Specific therapy was given to five patients. There was one death. At follow-up no deterioration was detected. A different neuroleptic drug was successfully re-introduced in four patients. In view of the wide usage of major tranquillizers, a high degree of clinical awareness of this serious complication is necessary for early diagnosis to reduce morbidity and mortality.

Association of diabetic autonomic neuropathy with painless myocardial ischaemia induced by exercise.

Silent myocardial ischaemia is now well-recognised in patients with symptomatic coronary artery disease. Its pathogenesis remains speculative, though diminished sensitivity to pain is thought to be one of the mechanisms involved. Because cardiovascular autonomic dysfunction occurs frequently in diabetic patients, we postulate that it contributes towards painless myocardial ischaemia among them. Forty consecutive diabetic (type II) male patients and ten normal volunteers were studied. Using 5 previously-validated noninvasive tests for autonomic dysfunction, 14 of these diabetic men had definite autonomic neuropathy (at least 2 abnormal tests). All 50 subjects were then exercised on a motor-driven treadmill to either exhaustion or chest pains. Thirty-three diabetic subjects were tested positive, with significant (greater than 1 mm) ST segment depression over at least 2 contiguous leads. Of these, 18 were associated with typical angina but the other 15 stopped because of fatigue or exhaustion (ie painless). Thirteen subjects who had definite autonomic neuropathy (AN+) had positive exercise ECG tests-10 had painless ischaemia, and only 3 had angina. This contrasted with 15 patients who had painful ischaemia and 5 who had painless ischaemia among the group without (AN-)autonomic dysfunction (p = 0.0047, Fisher's exact test). There were no significant differences among the various groups for peak rate-pressure-product, all subjects attaining similar maximal oxygen consumption states during which ischaemic ST segment changes were noted (painful AN+: 21917 +/- 4753; painless AN+: 20117 +/- 6752; painful AN-: 16544 +/- 4063; painless AN-: 22220 +/- 4341, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Sexual morbidity after myocardial infarction.

Sixty five patients were interviewed on an average of 42 months after a myocardial infarction. Using a semi structured interview, they were systematically questioned on their usual sexual activity just before their infarction and at the time of follow up. All were married men with a mean age of 54.4 years and had resumed a normal active life. Forty six (70%) reported a decrease in frequency of sexual intercourse (mean 6.9 times/month before infarction and 0.8 times/month at time of interview, p less than 0.01). The majority had difficulty in discussing sex with their doctors because of impaired doctor-patient communication, cultural factors and lack of privacy. Discussion concerning sex should be initiated as soon as the patient is stable and pertinent advice is the key to better sexual adjustment after myocardial infarction.

Torsade de pointes and syncopal attacks in a 26-year old woman with congenital complete heart block and prolonged QT interval.

A 26-year old woman with congenital complete heart block and prolonged QT interval presented for the first time with syncopal attacks associated with torsade de pointes in adulthood. Cardioversion followed by overdrive pacing was needed to finally control the unstable rhythm. During episodes of non-capture, paraoxysms of torsade de pointes leading to ventricular flutter were recorded by a 24-hour ambulatory electrocardiographic monitoring. Beta-blockade and permanent ventricular pacing finally abolished both the syncopal attacks and the torsade phenomena. The prognosis of congenital complete heart block associated with QT prolongation resembles that of the Romano-Ward syndrome. Recognition of this variant would facilitate earlier treatment of this rare but potentially lethal disorder.

Neuroleptic malignant syndrome with renal and respiratory complications--a case report.

The neuroleptic malignant syndrome is an idiosyncratic reaction to neuroleptic therapy which sometimes can be fatal because of the various associated complications. We describe a schizophrenic patient who, after commencement of haloperidol, developed this reaction which was complicated by acute oliguric renal failure and aspiration pneumonia. It is mandatory that the patient is treated in a medical intensive care unit once the syndrome is recognised. The management of the neuroleptic malignant syndrome and its complications is discussed.

Massive pericardial effusion in primary hypothyroidism.

A 44 year old lady with primary hypothyroidism presented with massive pericardial effusion without cardiac tamponade. Pericardial tap was done twice and the effusion resolved as the hypothyroid state improved. She remained hypertensive despite the euthyroid state. She was discharged well with L-thyroxine and anti-hypertensive therapy.

Cigarette smoking and the risk of myocardial infarction, and acute non-infarct coronary events among Malaysian women.

In a prospective case-control study over a two-year period involving 1006 women, 264 women with acute myocardial infarction (AMI), 305 with non-infarct acute coronary syndromes (CAD) were compared with 437 women with no coronary heart disease (Controls), to determine the relationship between cigarette smoking and other risks factors with coronary heart disease. A history of current cigarette smoking was strongly associated with the risk of coronary events for both AMI And CAD (p less than 0.001). 23.9% of patients with acute coronary syndromes were current smokers, compared with only 12.8% among controls. Overall, women smokers had about a two-fold increase in risk for all coronary events. Younger women smokers (less than 40 years) and those between 61-70 years had particularly higher risks (10.3 and 2.7 times respectively (p less than 0.01, p less than 0.02). A dose-response pattern of increased AMI risks (from 2.0 to 2.9 times) among women smokers was also found, corresponding to the number of cigarettes smoked per day (p less than 0.05). Other significant coronary risk factors established were: postmenopausal status (OR 6.5), diabetes mellitus (OR 5.1), hypertension (OR 1.6), family history of premature coronary heart disease less than 50 years (OR 1.3) and use of oral contraceptive pills (OR 1.4). Our results thus emphasize that cigarette smoking is an important determinant of acute coronary events even among Malaysian women.

Myocardial infarction, circadian rhythm and delay in hospital admission.

Circadian variations have been observed in the onset of acute coronary syndromes including acute myocardial infarction. We studied 422 acute myocardial infarction patients who presented to the coronary care unit of General Hospital Kuala Lumpur. Of the 318 (75.4%) patients whose data was complete, a circadian rhythm with bimodal peak was demonstrated. The second quarter of the day i.e. 6.00 a.m. to 12 noon was shown to have a significantly increased frequency of onset of acute myocardial infarction (p less than 0.05). Time delay in presenting to the hospital was also determined. This showed that 56.8% of acute myocardial infarction patients presented early, within four hours of the onset of symptoms. By six hours, more than 71% had sought hospital care. This early presentation to the hospital may offer a realistic opportunity for optimal thrombolytic therapy should this treatment modality be offered as routine to infarct patients.

Malaysian child psychiatric practice: a pragmatic and rational approach.

A pragmatic and rational approach to the management of five child psychiatric cases in Malaysia is briefly reviewed. The significance of sociocultural factors in treating these cases within the context of a rapidly developing plural society is emphasized. The implications of overemphasis on educational and material achievements are noted.

Viral agents of acute respiratory infections in young children in Kuala Lumpur.

The results of this study indicate that the important viral agents associated with lower respiratory tract infections in young children are respiratory syncytial virus, rhinovirus, and parainfluenza virus, particularly in those under 2 years of age. This is in close agreement with studies done in temperate climates. Influenza A virus is seasonal and plays an important role in upper respiratory tract infections in older children.

A double-blind comparison of nomifensine and amitriptyline in the treatment of depression.

A double-blind study was carried out to compare the efficacy and tolerability of nomifensine and amitriptyline in 17 Malaysian patients with moderate to severe depression. The two drugs did not differ with regard to antidepressant effect but nomifensine-treated subjects report fewer side-effects with no complaints of palpitations. Nomifensine also increases capacity for work and activity.