Botulinum toxin abolishes sweating via impaired sweat gland responsiveness to exogenous acetylcholine.

BACKGROUND: Botulinum toxin A (BTX) disrupts neurotransmitter release from cholinergic nerves. The effective duration of impaired sweat secretion with BTX is longer relative to that of impaired muscle contraction, suggesting different mechanisms in these tissues. OBJECTIVES: The aim of this study was to test the hypothesis that BTX is capable of altering sweating by reducing the responsiveness of the sweat gland to acetylcholine. METHODS: BTX was injected into the dorsal forearm skin of healthy subjects at least 3 days before subsequent assessment. On the day of the experiment, intradermal microdialysis probes were placed within the BTX-treated area and in an adjacent untreated area. Incremental doses of acetylcholine were administered through the microdialysis membranes while the sweat rate (protocol 1; n = 8) or a combination of sweat rate and skin blood flow (protocol 2; n = 8) were assessed. RESULTS: A relative absence of sweating was observed at the BTX site for both protocols (protocol 1: 0.05 +/- 0.09 mg cm(-2) min(-1); protocol 2: 0.03 +/- 0.04 mg cm(-2) min(-1), both at the highest dose of acetylcholine), while the sweat rate increased appropriately at the control sites (protocol 1: 0.90 +/- 0.46 mg cm(-2) min(-1); protocol 2: 1.07 +/- 0.67 mg cm(-2) min(-1)). Cutaneous vascular conductance increased to a similar level at both the BTX and control sites. CONCLUSIONS: These results demonstrate that BTX is capable of inhibiting sweat secretion by reducing the responsiveness of the sweat gland to acetylcholine, while not altering acetylcholine-mediated cutaneous vasodilatation.

Heat stress enhances arterial baroreflex control of muscle sympathetic nerve activity via increased sensitivity of burst gating, not burst area, in humans.

The relationship between muscle sympathetic nerve activity (MSNA) and diastolic blood pressure has been used to describe two sites for arterial baroreflex control of MSNA. By determining both the likelihood of occurrence for sympathetic bursts and the area of each burst for a given diastolic blood pressure, both a 'gating' and an 'area' control site has been described in normothermic humans. Assessing the effect of heat stress on these mechanisms will improve the understanding of baroreflex control of arterial blood pressure under this thermal condition. Therefore, the purpose of this study was to test the hypothesis that heat stress enhances arterial baroreflex control of burst gating and area. In 10 normotensive subjects (age, 32+/-2 years; mean+/-s.e.m.), MSNA (peroneal) was assessed using standard microneurographic techniques. Five minute periods of data were examined during normothermic and whole-body heating conditions. The burst incidence (i.e. number of sympathetic bursts per 100 cardiac cycles) and the area of each burst were determined for each cardiac cycle and were placed into 3 mmHg intervals of diastolic blood pressure. During normotheric conditions, there was a moderate, negative relationship between burst incidence and diastolic blood pressure (slope=-2.49+/-0.38; r(2)=0.73+/-0.06; mean+/-s.e.m.), while area per burst relative to diastolic blood pressure exhibited a less strong relationship (slope=-1.13+/-0.46; r(2)=0.45+/-0.09). During whole-body heating there was an increase in the slope of the relationship between burst incidence and diastolic blood pressure (slope=-4.69+/-0.44; r(2)=0.84+/-0.03) compared to normothermia (P<0.05), while the relationship between area per burst and diastolic blood pressure was unchanged (slope=-0.92+/-0.29; r(2)=0.41+/-0.08) (P=0.50). The primary finding of this investigation is that, at rest, whole-body heating enhanced arterial baroreflex control of MSNA through increased sensitivity of a 'gating' mechanism, as indicated by an increase in the slope of the relationship between burst incidence and diastolic blood pressure. This occurrence is likely to afford protection against potential decreases in arterial blood pressure in an effort to preserve orthostatic tolerance during heat stress.

Carotid baroreflex function during and following voluntary apnea in humans.

Muscle sympathetic nerve activity (MSNA) and arterial pressure increase concomitantly during apnea, suggesting a possible overriding of arterial baroreflex inhibitory input to sympathoregulatory centers by apnea-induced excitatory mechanisms. Apnea termination is accompanied by strong sympathoinhibition while arterial pressure remains elevated. Therefore, we hypothesized that the sensitivity of carotid baroreflex control of MSNA would decrease during apnea and return upon apnea termination. MSNA and heart rate responses to -60-Torr neck suction (NS) were evaluated during baseline and throughout apnea. Responses to +30-Torr neck pressure (NP) were evaluated during baseline and throughout 1 min postapnea. Apnea did not affect the sympathoinhibitory or bradycardic response to NS (P > 0.05); however, whereas the cardiac response to NP was maintained postapnea, the sympathoexcitatory response was reduced for 50 s (P < 0.05). These data demonstrate that the sensitivity of carotid baroreflex control of MSNA is not attenuated during apnea. We propose a transient rightward and upward resetting of the carotid baroreflex-MSNA function curve during apnea and that return of the function curve to, or more likely beyond, baseline (i.e., a downward and leftward shift) upon apnea termination may importantly contribute to the reduced sympathoexcitatory response to NP.

Role of central command in carotid baroreflex resetting in humans during static exercise.

The purpose of the experiments was to examine the role of central command in the exercise-induced resetting of the carotid baroreflex. Eight subjects performed 30 % maximal voluntary contraction (MVC) static knee extension and flexion with manipulation of central command (CC) by patellar tendon vibration (PTV). The same subjects also performed static knee extension and flexion exercise without PTV at a force development that elicited the same ratings of perceived exertion (RPE) as those observed during exercise with PTV in order to assess involvement of the exercise pressor reflex. Carotid baroreflex (CBR) function curves were modelled from the heart rate (HR) and mean arterial pressure (MAP) responses to rapid changes in neck pressure and suction during steady state static exercise. Knee extension exercise with PTV (decreased CC activation) reset the CBR-HR and CBR-MAP to a lower operating pressure (P < 0.05) and knee flexion exercise with PTV (increased CC activation) reset the CBR-HR and CBR-MAP to a higher operating pressure (P < 0.05). Comparison between knee extension and flexion exercise at the same RPE with and without PTV found no difference in the resetting of the CBR-HR function curves (P > 0.05) suggesting the response was determined primarily by CC activation. However, the CBR-MAP function curves were reset to operating pressures determined by both exercise pressor reflex (EPR) and central command activation. Thus the physiological response to exercise requires CC activation to reset the carotid-cardiac reflex but requires either CC or EPR to reset the carotid-vasomotor reflex.

A DNA damage-induced p53 serine 392 kinase complex contains CK2, hSpt16, and SSRP1.

Phosphorylation of the human p53 protein at Ser-392 has been shown to be responsive to UV but not gamma irradiation. Here we describe identification and purification of a mammalian UV-activated protein kinase complex that phosphorylates Ser-392 of p53 in vitro. This kinase complex contains casein kinase 2 (CK2) and the chromatin transcriptional elongation factor FACT (a heterodimer of hSpt16 and SSRP1). In vitro studies show that FACT alters the specificity of CK2 in the complex such that it selectively phosphorylates p53 over other substrates including casein. In addition, phosphorylation by the kinase complex enhances p53 activity. These results thus provide a potential mechanism for p53 activation by UV irradiation.

Prevalence of AD among whites: a summary by levels of severity.

OBJECTIVE: To determine age- and sex-specific AD prevalence rates for whites using each of four severity-based definitions of a case: a person diagnosed as having at least questionable AD, one diagnosed as having at least mild AD, one diagnosed as having moderate or severe AD, and one diagnosed as having severe AD. METHODS: Data from 21 studies of Europeans and North Americans were pooled. RESULTS: Empirically, one study, from East Boston, is an outlier. Applied to the US population of 1996, the obtained estimates yield a prevalence of 1.7 to 1.9 million cases, depending on whether the outlier study is excluded or included. CONCLUSIONS: With disease severity taken into account, estimates of AD prevalence from white populations are more consistent than is usually acknowledged. By including disease severity in the case definition, variations in reported rates are much reduced. The outlier status of the East Boston study appears to result from the use of a definition of AD that differs from that used in the other 20 studies. Alternative explanations of the discrepancy between these estimates and the common estimate of 4 million cases are discussed.

Suppressive effects of fish oil on mesangial cell proliferation in vitro and in vivo.

BACKGROUND: Mesangial cell proliferation is a characteristic feature of IgA nephropathy and many other forms of glomerulonephritis. Recent clinical studies have shown that dietary fish oil supplementation retards renal disease progression in patients with IgA nephropathy. The mechanism by which this effect occurs is unknown. METHODS: The anti-Thy 1.1 (ATS) model of mesangial proliferative glomerulonephritis was employed to test the hypothesis that dietary fish oil supplementation reduces mesangial cell proliferation following acute injury. Subcultured rat mesangial cells were used to determine the in vitro effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the primary components of fish oil, on proliferation. RESULTS: Following antithymocyte serum (ATS) administration, proteinuria was significantly decreased in animals treated with fish oil compared with sesame oil-treated controls. In ATS rats given fish oil, there was less mesangial cell and matrix expansion, mesangiolysis, or basement membrane disruption (delta% = -40%). ATS rats receiving fish oil had less glomerular cell proliferation (PCNA-delta% = -50%) and a reduction of alpha-smooth muscle actin expression (delta% = -27%) by mesangial cells. In subcultured rat mesangial cells, DHA, but not EPA, significantly inhibited proliferation. CONCLUSIONS: Fish oil inhibits mesangial cell activation and proliferation in ATS glomerulonephritis, reduces proteinuria, and decreases histologic evidence of glomerular damage. In vitro, the antiproliferative effects of fish oil are more likely related to the action of DHA. We suggest that orally administered fish oil, or purified DHA, may have a suppressive effect in acute phases or relapses of glomerulopathies by inhibiting activation and proliferation of mesangial cells.

Understanding and preventing substance abuse by adolescents: a guide for primary care clinicians.

Psychoactive drug use by teens is a common occurrence. This article examines the influences that promote and deter experimentation with and hazardous use of psychoactive substances. Clinical guidance is offered on how to assess and intervene with teens and their parents at various developmental phases and levels of involvement with drugs. Understanding how youth make decisions to change their behavior can assist a clinician in helping a teenager avoid these problems.

Survival rates for four forms of cancer in the United States and Ontario.

OBJECTIVES: In this study, cancer survival rates for patients diagnosed in Ontario and selected areas within the United States were compared. METHODS: Relative survival rates were computed for patients aged 15 through 84 years diagnosed with any of four forms of cancer (breast, colon, lung, and Hodgkin's disease). The cohorts represented those diagnosed over the years 1978 through 1986 in the Canadian province of Ontario and in nine regions covered by the US National Cancer Institute's Surveillance Epidemiology and End Results program. Patients were followed through the end of 1990. RESULTS: The cumulative relative survival rates were similar for American and Canadian patients. The largest difference was observed for breast cancer, where patients in the United States enjoyed a survival advantage throughout the follow-up period. CONCLUSIONS: Patients in the United States and Ontario with the diseases studied, except for breast cancer, experience very similar survival. The greater use of mammographic screening in the United States could account for that country's higher breast cancer survival rate by promoting earlier and therefore more efficacious treatment, by introducing bias, or by a combination of both treatment and bias factors.

Prevalence of urinary tract infection in febrile infants.

Urinary tract infection (UTI), a relatively common cause of fever in infancy, usually consists of pyelonephritis and may cause permanent renal damage. This study assessed (1) the prevalence of UTI in febrile infants (temperature > or = 38.3 degrees C) with differing demographic and clinical characteristics and (2) the usefulness of urinalysis in diagnosing UTI. We diagnosed UTI in 50 (5.3%) of 945 febrile infants if we found > or = 10,000 colony-forming units of a single pathogen per milliliter in a urine specimen obtained by catheterization. Prevalences were similar in (1) infants aged < or = 2 months undergoing examination for sepsis (4.6%), (2) infants aged > 2 months in whom UTI was suspected, usually because no source of fever was apparent (5.9%), and (3) infants with no suspected UTI, most of whom had other illnesses (5.1%). Female and white infants had significantly more UTIs, respectively, than male and black infants. In all, 17% of white female infants with temperature > or = 39 degrees C had UTI, significantly more (p < 0.05) than any other grouping of infants by sex, race, and temperature. Febrile infants with no apparent source of fever were twice as likely to have UTI (7.5%) as those with a possible source of fever such as otitis media (3.5%) (p = 0.02). Only 1 (1.6%) of 62 subjects with an unequivocal source of fever, such as meningitis, had UTI. As indicators of UTI, pyuria and bacteriuria had sensitivities of 54% and 86% and specificities of 96% and 63%, respectively. In infants with fever, clinicians should consider UTI a potential source and consider a urine culture as part of the diagnostic evaluation.

Effect of exercise level on the diagnostic accuracy of thallium-201 SPECT scintigraphy.

The sensitivity of electrocardiographic ST analysis for detecting coronary artery disease is markedly decreased in patients unable to exercise vigorously. To determine the diagnostic accuracy of Thallium-201 SPECT scintigraphy at various exercise levels, we evaluated 179 patients without evidence of prior myocardial infarction or other confounding factors who performed symptom-limited exercise with Thallium-201 SPECT scintigraphy. Sensitivity decreased from 89% in those patients achieving greater than or equal to 85% of maximal heart rate to 63% in those achieving less than 65%. Like ST segment analysis, Thallium 201 SPECT scintigraphy has decreased diagnostic yield at low levels of exertion.

Components of burden: interventive implications.

A study of 127 informal caregivers of Alzheimer's disease patients in Florida's Tampa Bay area was undertaken to determine the correlates of the five components of burden, as measured by the Cost of Care Index, a multidimensional measure of caregiving burden. Significant relationships between predictor variables and burden components suggest that global scores and measures of burden do not identify specific problem areas relative to the various components of burden.

Resting platelets contain a substantial centrally located pool of glycoprotein IIb-IIIa complex which may be accessible to some but not other extracellular proteins.

Recent evidence suggests the presence in resting platelets of centrally located compartments of glycoprotein (GP) IIb-IIIa. We have employed an experimental procedure which dissociates and antigenically denatures the surface compartment of GP IIb-IIIa and allows internal compartments of GP IIb-IIIa to be studied immunochemically and functionally in intact platelets. When gel-filtered platelets are incubated with 0.25 mM EGTA at 37 degrees C for 30 min, and then supplemented for 30 min with 5 mM calcium, they lose their ability to bind GP IIb-IIIa complex-specific monoclonal antibody Fab fragments. However, when such platelets are subsequently stimulated with thrombin, GP IIb-IIIa-specific Fabs are again able to bind in large amounts to the platelet surface, in concert with the appearance of substantial amounts of receptors for fibrinogen and fibronectin. In immunoprecipitation experiments, we have found that this thrombin-displayed pool of GP IIb-IIIa originates from a pool that is not labeled by lactoperoxidase-catalyzed radioiodination of intact resting platelets. In immunofluorescence experiments, we have found that EGTA-incubated platelets contain a large sequestered internal pool of GP IIb-IIIa which upon thrombin stimulation is translocated to the platelet surface. Additional experiments suggest that this centrally located compartment may be surface connected in resting platelets and that it is accessible to some extracellular proteins, but not others.

Localization of internal pools of membrane glycoproteins involved in platelet adhesive responses.

To investigate the existence of intracellular pools of membrane glycoproteins involved in platelet adhesive reactions, the authors have studied the distribution of glycoprotein (GP) Ib and IIb/IIIa by immunofluorescence and immunoelectron microscopy. Studies on whole cells and frozen thick sections revealed a rim pattern of fluorescence for GPIb and GPIIb/IIIa consistent with a surface distribution. In addition, extensive staining occupying the entire cell interior was observed for anti-GPIIb/IIIa, whereas anti-GPIb revealed staining of large intracellular structures that contained no stainable fibrinogen. On the ultrastructural level, the extracellular face of the plasma membrane and the intraluminal face of vacuolar structures were stained with both anti-GPIb and anti-GPIIb/IIIa. Additionally, GPIIb/IIIa antigen was localized to alpha-granule membranes. To determine whether alpha-granule GPIIb/IIIa could be transported to the cell surface, the authors employed a calcium-dependent monoclonal anti-GPIIb/IIIa antibody. Incubation of platelets with EGTA at 37 C abolished staining of plasma membrane and vacuolar but not alpha-granule GPIIb/IIIa. Recalcification of these cells failed to restore the epitope; however, thrombin treatment of recalcified cells reconstituted surface staining with a concurrent loss of internal staining. These data suggest that GPIIb/IIIa is present in alpha-granule membranes and may be transported to the cell surface in response to thrombin treatment. In addition, both GPIb and GPIIb/IIIa antigens are present in intracellular membrane-bounded vacuolar structures which are closed to antibody probes in fixed cells. Redistribution of these internal pools of adhesive protein "receptors" may participate in the regulation of platelet adhesive properties.

Computer simulation of Freud's counterwill theory: extension to elementary social behavior.

A model is presented describing decision processes of a living system at the level of the individual, together with its interpersonal relationship context (organism, subsystems, and suprasystem). The beginning point was the 1977 system dynamics model of Wegman, which was itself characterized by quantitative cross-level hypotheses concerning both physiological and psychological levels of functioning within the individual personality system. The extension process was accomplished by synthesizing concepts from many different theories in personality and social psychology into equations linking two multiple-loop feedback systems to form a suprasystem. Each individual model was found to have several distinct operational modes, and the dyadic model had a number of interesting combinations of these modes which correlated with clinical descriptions of steady-state behavior and subjective experience in human marital dyads. For example, under certain conditions an individual operating in an unstable mode could achieve personal system stability within a dyadic relationship. In some cases, two unstable individuals could form a stable system. The process of extending the original model supports the utility of a synthetic approach to the construction of quantitative theories concerning small social systems. This process also suggests new approaches to planning future empirical research on small social systems using methods more appropriate to the study of complex, dynamic systems.

An evaluation of the reliability and validity of the Functional Assessment Inventory.

The reliability of the Functional Assessment Inventory (FAI) was evaluated using a sample of VA domiciliary and nursing home patients. The interobserver and interrater reliability coefficients of the summary rating scales, based on a single assessment, tended to be higher than their test-retest reliability coefficients, based on two independent assessments separated by a modal four-week interval. Validity coefficients, using the OARS instrument ratings as criteria, also based on two independent assessments several weeks apart, were, on the average, as high as the test-retest reliability coefficients. More specifically, the mental health, physical health, and activities of daily living rating scales, along with the objectively scored Short Portable Mental Status Questionnaire and Short Psychiatric Evaluation Schedule, tended to yield relatively similar scores with repeated measurement, while the social resources and economic resources scales were somewhat less stable, a discrepancy possibly explained by the homogeneous nature of the social and economic status of most of the patients (institutionalized veterans). Thus the reliability and validity of the FAI are satisfactory, but the stability of some of its scales requires further investigation.

Adsorption of radium-226 by biological origin absorbents.

Selected samples of waste microbial biomass used in industrial fermentation processes and wastewater biological treatment plants have been studied for their radium biosorption ability from aqueous solutions. Equilibrium biosorption isotherms have been used to quantify the radium uptake capacity of the various types of biomass which were also compared to two types of activated carbon. Solution pH affected the observed uptake significantly. In general, the biomass types that showed appreciable sorption capacity exhibited maximum uptake between pH 7 and 10. The uptake was reduced considerably at pH 4 and little or no uptake was observed at pH 2. Radium biosorptive uptake capacities of the order of 4.5 x 10(4) nCi/g, at pH 7 and at an equilibrium radium concentration of 1000 pCi/L, were determined for a mixed culture, while the biomass of Penicillium chrysogenum adsorbed 5 x 10(4) nCi/g radium under the same conditions. The highest uptake value for a sample of F-400 granular activated carbon was 3600 nCi/g at pH 7 and 1000 pCi/L radium concentration. The biosorptive radium uptake of microbial biomass is compared to literature values for other types of adsorbents. The most effective biomass types studied exhibited radium removals in excess of 99% of the radium in solution.

Enzymatic adaptation by bacteria under pressure.

A study of enzymic adaptation under hydrostatic pressure by moderately barotolerant bacteria that can grow at pressure up to about 500 atm revealed that some adaptive processes are relatively insensitive to pressure, whereas others are sufficiently barosensitive to compromise survival capacity in situations requiring adaptation to new substrates under pressure. Examples of the former include adaptation of Escherichia coli to arabinose catabolism for growth and adaptation of Streptococcus faecalis to catabolism of lactose, ribose, or maltose. Examples of the latter include derepression of the lac operon in Escherichia coli and induction of penicillinase synthesis by Bacillus licheniformis. For both these barosensitive systems, pressure had little effect on enzyme levels in constitutive strains or in bacteria that had previously been induced at 1 atm. Moreover, it had no detectable effect on penicillinase secretion. However, pressures of 300 to 400 atm were found to reduce markedly rates and extents of enzyme synthesis by bacteria undergoing derepression or adaptation. This inhibitory effect of pressure was reflected in greater barosensitivity with extended lag and slower growth of initially unadapted Escherichia coli cells inoculated into minimal medium with lactose as sole source of carbon and fuel, and by major reductions in the minimal inhibitory concentrations of penicillin G for unadapted B. licheniformis cells inoculated into complex, antibiotic-containing media. Cyclic adenosine 5'-monophosphate did not reverse pressure inhibition of derepression of the lac operon, and catabolite repression was complete under pressure. However, derepression of the lac operon was more sensitive to pressure at low concentrations of inducer than at high concentrations. Apparent volume changes for derepression were 94 and 60 ml/mol at inducer concentrations of about 0.5 and 5 mM, respectively. Pressure was found not to be inhibitory for uptake of beta-galactosides; in fact, it was somewhat stimulatory. Therefore, results were interpreted in terms of inducer binding and subsequent conversion of an operator-inducer-repressor complex to inactive repressor and operator. Both reactions appeared to result in an increase in volume, the former more so than the latter. We found also that 200 atm was actually stimulatory for growth of Escherichia coli in minimal media, and the bacterium was in a sense barophilic.