Effects of atenolol,labetalol and propranolol on the peripheral circulation in hypertensive patients without obstructive vascular disease

Summary In an observer-blind, randomised cross-over trial, in 12 patients, the effects on the peripheral circulation of antihypertensive doses of atenolol, labetalol and propranolol and placebo were compared. After a placebo period of at least 4 weeks, patients were allocated at random to one of the three active drug treatments. After active treatment for at least 6 weeks and a fall in diastolic pressure (DP) to less than 90 mmHg subjects were switched to the next medication. At the end of each period, photoelectric plethysmography (PHELP) was done on all fingers of one hand cooled over 4 min in water in steps of 3°C from 33° to 12°C, and subsequently warmed in room air (20°C) for a period of 10 min. Blood flow changes during cooling were expressed as a percentage of the initial PHELP value (% PHELP). Areas under the curves, representing the % PHELP/cooling period and % PHELP/warming-up period, showed that within the temperature range normally encountered in daily life, labetalol preserved finger blood flow significantly better than propranolol and marginally better than placebo. With atenolol, finger blood flow was not significantly different from that during the three other regimens, but there were significantly fewer other side-effects. It is concluded that labetalol may be the drug of choice for hypertensive patients treated with beta-blocking agents whose peripheral arterial circulation seems inadequate at low temperatures.     

Assessment of pesticide exposure in the agricultural population of Costa Rica

We describe a model for the retrospective assessment of parental exposure to 26 pesticides, selected by toxicity-based prioritization, in a population-based case-control study of childhood leukaemia in Costa Rica (301 cases, 582 controls). The model was applied to a subset of 227 parents who had been employed or self-employed in agriculture or livestock breeding. It combines external data on pesticide use for 14 crops, 21 calendar years and 14 regions, and individual interview data on determinants (task and technology, personal protective equipment, field reentry, storing of pesticides, personal hygiene) of exposure. Recall was enhanced by use of checklists of pesticides in the interview. An external database provided information on the application rate (proxy for intensity of potential exposure) for each pesticide. The calendar time was individually converted to five time windows (year before conception, first, second and third trimester, and first year of the child). Time-windowed individual data on determinants of exposure and their expert-based general weights and their category-specific hazard values jointly provided an individual determinant score. This score was multiplied by the application rate to obtain an individual index of exposure intensity during application. Finally, average exposure intensity during entire time windows was estimated by incorporating in the model the individual time fraction of exposure during application. Estimates of exposure intensities were proxies assumed to be proportional to dermal exposure intensity, which represents the major pathway of occupational exposure to pesticides. A simulated sensitivity analysis resulted in a correlation coefficient of 0.91 between two sets of 10 000 values of individual exposure indices, based on two different but realistic sets expert-assigned weights. Lack of measurement data on concurrent exposures in comparable circumstances precluded direct validation of the model.     

Arterial haemodynamic parameters derived from noninvasively recorded pulsewaves,using parameter estimation

A parameter-estimation technique has been developed to derive haemodynamic parameters from pulsewaves, at a number of positions along a peripheral artery. The technique is entirely noninvasive, and uses pulsewaves recorded simultaneously from the brachial and radial arteries, which are fed into an analogue-computer model of the arm arteries. As the pulsewave amplitudes are uncalibrated, a novel technique was developed for comparing the model pulses with the pulsations of the actual artery. A least-squares error criterion was used in preference to an absolute-value criterion. As pressure but no flow waveforms were used, the impedance level, and thus the arterial cross-sections, in the model are, at first sight, undetermined. Linking the Poiseuille resistance of each segment of artery to its blood-mass parameter via the length of the arterial segment nevertheless gives unique per-segment values for radius. Parameters estimated with an acceptable result include the arterial internal radius, arterial compliance and the magnitude of the amplification effect of the pulsewave. Values for peripheral resistance are consistently understimated, owing to the use of an arterial model lacking viscous wall damping. Although the model parameter values are not exact, for various reasons explained in the text, they may still be useful for comparison between normal and abnormal conditions.     

Effect of sulphonylureas (tolazamide,tolbutamide and chlorpropamide) on the metabolism of diphenylhydantoin in the rat

The blood sugar lowering sulphonylureas chlorpropamide, tolazamide and tolbutamide showed competitive inhibition of diphenylhydantoin hydroxylation by the 9000 g-supernatant of rat liver homogenates. Tolbutamide was the strongest inhibitor and chlorpropamide the weakest. The enzyme kinetics could not be presented satisfactory by Lineweaver-Burk plots; therefore log-dose response curves were used and the potency of the inhibitors was calculated according to the method of Arunlakshana and Schild. The relative inhibitory potency of the three sulphonylureas chlorpropamide-tolazamide-tolbutamide was 1:2·5:4·3.     

Expression pattern of apoptosis-related markers in Huntington’s disease

Inappropriate apoptosis has been implicated in the mechanism of neuronal death in Huntingtons disease (HD). In this study, we report the expression of apoptotic markers in HD caudate nucleus (grades 1–4) and compare this with controls without neurological disease. Terminal transferase-mediated biotinylated-UTP nick end-labeling (TUNEL)-positive cells were detected in both control and HD brains. However, typical apoptotic cells were present only in HD, especially in grade 3 and 4 specimens. Expression of the pro-apoptotic protein Bax was increased in HD brains compared to controls, demonstrating a cytoplasmic expression pattern in predominantly shrunken and dark neurons, which were most frequently seen in grades 2 and 3. Control brains displayed weak perinuclear expression of the anti-apoptotic protein Bcl-2, whereas in HD brains Bcl-2 immunoreactivity was markedly enhanced, especially in severely affected grade 4 brains, and was observed in both healthy neurons and dark neurons. Caspase-3, an executioner protease, was only found in four HD brains of different grades and was not expressed in controls. A strong neuronal and glial expression of poly(ADP-ribose) polymerase (PARP)-immunoreactivity was observed in HD brains. These data strongly suggest the involvement of apoptosis in HD. The exact apoptotic pathway occurring in HD neurodegeneration remains yet unclear. However, the presence of late apoptotic events, such as enhanced PARP expression and many TUNEL-positive cells accompanied with weak caspase-3 immunoreactivity in severely affected HD brains, suggests that caspase-mediated neuronal death only plays a minor role in HD.     

Young adults’ recollections of parental bonds

Abstract. Background: Recollections of cold and overprotective behaviors from parents have been hypothesized to lead to the presence of mental disorders in young adulthood through their detrimental effects on individuals satisfaction in later partner relationships. Previous studies have not explicitly tested, however, whether partner relationship satisfaction mediates the longitudinal relationship from parental bonds to DSMIII-R disorders in young adults. Methods: We examined: (1) whether recollections of parental bonds in the first 16 years of life were related to the prevalence of DSMIII-R mental disorders in young adulthood, and (2) whether young adults satisfaction with current partner relationships mediated these links. Data were used from 1,581 Dutch young adults aged 18–34 years, who were interviewed in three waves (1996, 1997, and 1999) of a nationwide epidemiological study Results: Structural Equation Models demonstrated that recollections of caring, non-intrusive parenting behaviors were significantly, negatively associated with the prevalence of mood and anxiety disorders (but not substance disorders) in young adulthood. The satisfaction with current partner relationships did not mediate these negative associations. Conclusion: Results replicate and extend earlier findings from the National Comorbidity Survey (Enns et al. 2002), demonstrating that mental disorders are directly related to peoples recollections of parental care and overprotection. Low-quality parental bonds were only related to internalizing types of psychopathology, however, and were of a modest strength. Results may indicate that there is relatively little cross-relationship continuity in the experience of intimacy between relationships with parents and with partners.     

Absence of heparan sulfate proteoglycans in Lewy bodies and Lewy neurites in Parkinson's disease brains

alpha-Synuclein is the major constituent of Lewy bodies and Lewy neurites in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Relatively little is known about the exact mechanism of alpha-synuclein deposition and fibrillization in these alpha-synucleinopathies. In order to better understand the pathogenesis of alpha-synucleinopathies it is important to identify molecules that regulate the fibrillization of alpha-synuclein. Since it has been demonstrated that heparan sulfate proteoglycans (HSPGs) and glycosaminoglycans (GAGs) promote the conversion of non-fibrillar amyloid beta-protein (Abeta) into neurotoxic fibrillar Abeta in Alzheimer's disease, they might also be involved in alpha-synuclein aggregation. It was the aim of our study to examine the distribution pattern of these macromolecules in PD brains and the possible association with Lewy bodies and Lewy neurites. Although HSPGs clearly colocalized with senile plaques, we were unable to identify HSPGs or GAGs in Lewy bodies and Lewy neurites and therefore concluded that it is likely that alpha-synuclein fibrillization and stabilization occurs independently of the presence of HSPGs or GAGs.     

Central nervous system effects of acute organophosphate poisoning in a two-year follow-up

OBJECTIVES: Patients hospitalized for acute organophosphate poisoning in León, Nicaragua, were followed for effects on the central nervous system (CNS) over a 2-year period. METHODS: Immediate verbal memory (Rey verbal learning), visuomotor performance (digit symbol), and neuropsychiatric symptoms (Q-16) were assessed for 53 poisoned persons at the time of hospital discharge, 7 weeks postpoisoning, and 2 years postpoisoning, and, at the same time intervals, for 28 persons who had never been poisoned. The poisonings were classified as moderate occupational (31), severe occupational (15), and severe through the oral route (7), representing low, medium, and high exposure, respectively. Longitudinal confounder-adjusted between-category comparisons and longitudinal analyses of variance and covariance were used to assess the effects of the exposure. RESULTS :Immediate verbal learning showed deficits in the high-exposure group, in particular at the time of discharge, but the estimate of the difference when compared with the values of the unexposed was imprecise. Visuomotor performance showed a deficit at 7 weeks in the medium-exposure group, but it had improved after 2 years relative to that of the unexposed, for whom improvement had occurred at 7 weeks and persisted during the 2 years of follow-up, possibly a test-retest effect. Neuropsychiatric symptoms were in excess 2 years after the hospital discharge in the low- and medium-exposure groups and all the groups combined. All the results were imprecise for the small high-exposure group. CONCLUSIONS: Visuomotor performance and possibly short-term verbal memory seem to be affected early after severe acute organophosphate poisoning and recover, either truly or by some compensatory mechanism. Neuropsychiatric symptoms seem to increase after a longer latency period.     

Heparan sulphate proteoglycans in Alzheimer's disease and amyloid-related disorders

Proteoglycans are associated with all kinds of amyloid deposits in the human body. These complex macromolecules, in particular heparan sulphate proteoglycans, have also been implicated in several features of the pathogenesis of Alzheimer's disease (AD), including the genesis of senile plaques, cerebrovascular amyloid, and neurofibrillary tangles. In this review we focus on the role of proteoglycans and glycosaminoglycans in amyloidogenesis in general and in AD in particular. Heparan sulphate proteoglycans may promote amyloid-beta peptide (Abeta) or tau fibrillisation on the one hand, and provide resistance against proteolytic breakdown on the other. Knowledge about the role of proteoglycans in AD pathology may eventually be of therapeutic use, because small polysulphated compounds, which can interfere with the interaction between proteoglycan and Abeta, have been shown to stop or even prevent amyloidogenesis.