Comparative effects of two beta-blockers on cardiovascular reactivity and type A behavior in hypertensives

This study compared the effects of beta-blockers differing in degree of central nervous system penetration on Type A behavior and cardiovascular reactivity to mental stress. Forty-six male hypertensives were assigned randomly to receive either highly lipophilic and nonselective propranolol, hydrophilic and cardioselective atenolol, the diuretic hydrochlorothiazide, or placebo. Subjects were administered parallel forms of the Structured Interview (SI) and performed mental arithmetic and a cognitive task prior to and after 6 weeks of therapy. Results indicated that diuretic and placebo subjects (subsequently combined into a single control group) did not differ and that both beta-blockers reduced heart rate but not blood pressure reactivity to mental stress (p less than 0.02), an effect that was strongest during the mental arithmetic test. Analysis of SI components indicated a reduction only in explosive speech for beta-blockers versus controls (p less than 0.05). For global SI classifications, seven out of 12 subjects (58%) receiving propranolol, three of 12 (25%) receiving atenolol, and four of 22 control subjects (18%) became less Type A (p less than 0.05). These data do not replicate results of a prior study obtained with atenolol and suggest that only a subset of hypertensive individuals show reduced Type A behavior with propranolol. Central nervous system mechanisms may be important in producing these effects.     

Physical fitness of blind and sighted children

Summary Twenty-seven children (age 7–17 years) with varying degrees of blindness but with no other known disorder were assessed for physical fitness. Twenty-seven randomly selected children with normal eyesight were also assessed. Maximum oxygen uptake ( ) was measured directly during a progressive exercise test on a treadmill. There was a significant and substantial reduction in in totally blind children (mean ± standard deviation 35.0±7.5 ml · min^–1 · kg^–1) compared with normal children (45.9±6.6 ml · min^–1 · kg^–1). Partially sighted children had a significant but smaller reduction in . Fitness assessed by a step-test was significantly reduced in the visually impaired children, and skin-fold thickness was also significantly greater in totally blind children.The level of habitual physical activity for each child, as assessed by a questionnaire, correlated with (r=0.53,p<0.0001). Blind children were significantly less active than normal children, and the difference between mean for blind and normal children became non-significant when their different activity levels were taken into account. It is concluded that totally blind children are less fit than other children at least partly because of their lower level of habitual activity.     

Evaluation of formalin-inactivated Clostridium difficile vaccines administered by parenteral and mucosal routes of immunization in hamsters.

Clostridium difficile produces toxins that cause inflammation, necrosis, and fluid in the intestine and is the most important cause of nosocomial antibiotic-associated diarrhea and colitis. We evaluated C. difficile antigens as vaccines to protect against systemic and intestinal disease in a hamster model of clindamycin colitis. Formalin-inactivated culture filtrates from a highly toxigenic strain were administered by mucosal routes (intranasal, intragastric, and rectal) with cholera toxin as a mucosal adjuvant. A preparation of culture filtrate and killed whole cells was also tested rectally. The toxoid was also tested parenterally (subcutaneously and intraperitoneally) and by a combination of three intranasal immunizations followed by a combined intranasal-intraperitoneal boost. Serum antibodies against toxins A and B and whole-cell antigen were measured by enzyme-linked immunosorbent assay, neutralization of cytotoxic activity, and bacterial agglutination. The two rectal immunization regimens induced low antibody responses and protected only 20% of hamsters against death and 0% against diarrhea. The intragastric regimen induced high antibody responses but low protection, 40% against death and 0% against diarrhea. Hamsters immunized by the intranasal, intraperitoneal, and subcutaneous routes were 100% protected against death and partially protected (40, 40, and 20%, respectively) against diarrhea. Among the latter groups, intraperitoneally immunized animals had the highest serum anticytotoxic activity and the highest agglutinating antibody responses. Hamsters immunized intranasally and revaccinated intraperitoneally were 100% protected against both death and diarrhea. Protection against death and diarrhea correlated with antibody responses to all antigens tested. The results indicate that optimal protection against C. difficile disease can be achieved with combined parenteral and mucosal immunization.     

The vascularization of the hypothalamic-hypophyseal region of the eastern brook trout,Salvelinus fontinalis

The hypophysis of the brook trout is irrigated by blood vessels which originate from the internal carotid arteries. These are: (1) branches of the ventral hypothalamic arteries that give rise to an extensive capillary plexus in the neurohypophysis from which vessels extend into all regions of the adenohypophysis; (2) branches of the caudal hypothalamic artery that irrigate the saccus vasculosus and continue anteriorly to supply the ventral areas of the meta-adenohypophysis; (3) a caudal hypophyseal artery which vascularizes a portion of the meta-adenohypophysis however, this vessel is not always present; (4) a pair of small arteries which supply the peripheral regions of the gland directly from the carotids. Most of the neurosecretory fibers of the preoptic-hypophyseal tract terminate close to capillaries in the neurohypophysis. A few axons extend into meso-adenohypophyseal tissue. It is suggested that the secretory activities of the pro-, meso- and metaadenohypophyses are governed by hypothalamic factors that are chiefly transmitted to the gland cells via the vascular system (indirect control). However, the activity of the meso-adenohypophysis may also be regulated by factors which are transmitted directly to the cells from the endings of neurosecretory fibers which have traversed the neurohypophysis (direct control). The distribution and abundance of neurosecretion in the ventral hypophysis suggest the possibility of storage of hypothalamic products within this region.     

Model of intersegmental coordination in the leech heartbeat neuronal network

We have created a computational model of the timing network that paces the heartbeat of the medicinal leech, Hirudo medicinalis. The rhythmic activity of this network originates from two segmental oscillators located in the third and fourth midbody ganglia. In the intact nerve cord, these segmental oscillators are mutually entrained to the same cycle period. Although experiments have shown that the segmental oscillators are coupled by inhibitory coordinating interneurons, the underlying mechanisms of intersegmental coordination have not yet been elucidated. To help understand this coordination, we have created a simple computational model with two variants: symmetric and asymmetric. In the symmetric model, neurons within each segmental oscillator called oscillator interneurons, inhibit the coordinating interneurons. In contrast, in the asymmetric model only the oscillator interneurons of one segmental oscillator inhibit the coordinating interneurons. In the symmetric model, when two segmental oscillators with different inherent periods are coupled, the faster one leads in phase, and the period of the coupled system is equal to the period of the faster oscillator. This behavior arises because, during each oscillation cycle, the oscillator interneurons of the faster segmental oscillator begin to burst before those of the slower oscillator, thereby terminating spike activity in the coordinating interneurons. Thus there is a brief period of time in each cycle when the oscillator interneurons of the slower segmental oscillator are relieved of inhibition from the coordinating interneurons. This "removal of synaptic inhibition" allows, within certain limits, the slower segmental oscillator to be sped to the period of the faster one. Thus the symmetric model demonstrates a plausible biophysical mechanism by which one segmental oscillator can entrain the other. In general the asymmetric model, in which only one segmental oscillator has the ability to inhibit the coordinating interneurons, behaves similarly, except only one segmental oscillator can control the period of the system. In addition, we simulated physiological experiments in which a "driving" stimulus, consisting of alternating positive and negative current steps, was used to control a single oscillator interneuron and thereby entrain the activity of the entire timing network.     

Reduction of [125I]Bolton Hunter CCK8 and [3H]MK-329 (devazepide) binding to CCK receptors in the substantia nigra/VTA complex and its forebrain projection areas following MPTP-induced hemi-parkinsonism in the monkey.

Cholecystokinin (CCK) receptors were visualized autoradiographically using [125I]Bolton Hunter CCK8 ([125I]BHCCK8) in the fore- and midbrain of 3 monkeys rendered hemi-parkinsonian by unilateral intra-carotid infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). More specifically, CCK-A receptors were detected using [3H]MK-329 (devazepide), a peripheral-type (CCK-A) receptor antagonist. In the substantia nigra pars compacta, ipsilateral to the toxin infusion, where dopamine D2 receptors (labelled with [3H]sulpiride) were lost, there was a decrease in the binding of both [125I]BHCCK8 and [3H]MK-329. Binding of the two CCK ligands was also reduced in the ipsilateral nucleus accumbens and most medial part of the caudate nucleus, whereas 3H-sulpiride binding was increased in the lateral caudate nucleus and putamen. These results indicate that CCK-A receptors may be located on dopaminergic cells within the substantia nigra, which are lost in the parkinsonian brain, and may also be present on dopaminergic terminals within restricted regions of nigral/ventral tegmental area projection sites.     

The potentiating effect of rheumatoid arthritis serum in the immediate phase of nephrotoxic nephritis

Nephrotoxic nephritis induced in rats was employed as an experimental model to investigate the possible effects of rheumatoid factor on in vivo antigen–antibody reactions. Rats injected simultaneously with rheumatoid arthritis serum and rabbit nephrotoxic globulin showed a three-fold increase in immediate proteinuria compared with rats injected with nephrotoxic globulin alone. This potentiating effect of rheumatoid arthritis serum was evident even when the serum was injected 48 hr after the nephrotoxic globulin and was also apparent to a lesser extent in rats decomplemented by a prior injection of aggregated human IgG. Normal human serum had no effect on the proteinuria produced by a standard dose of nephrotoxic globulin while rheumatoid arthritis serum injected with normal rabbit globulin did not increase urinary protein excretion above baseline levels. In rats injected with rheumatoid arthritis serum and nephrotoxic globulin, human IgM (presumably rheumatoid factor) was detected by immunofluorescence on the glomerular basement membrane along with the nephrotoxic globulin and rat complement and persisted at this site for as long as 42 days after the initial injections. Rheumatoid factor activity was also recovered by elution from glomeruli isolated from rat kidneys 24 hr after the injection of rheumatoid arthritis serum and nephrotoxic globulin.     

Priming of the oxidative burst in human neutrophils by physiological agonists or cytochalasin B results from the recruitment of previously non-responsive cells.

Using a sensitive flow cytometric assay, which measures the intracellular oxidation of 2'7' dichlorofluorescein (DCFH) by H2O2, we have assessed, at a single-cell level, the effects of a variety of physiological priming agonists and cytochalasin B (CB) on purified populations of neutrophils stimulated at different points along the signal response transduction pathway. Pretreatment of purified neutrophils with the physiological priming agonists monocyte interleukin-8 (IL-8), granulocyte-monocyte colony-stimulating factor (GM-CSF), platelet-activating factor (PAF), IL-1 beta, tumour necrosis factor-alpha (TNF-alpha), IL-6, and non-stimulatory doses of formyl-methionyl-leucyl-phenylalanine (FMLP), resulted in an increased percentage of cells generating an oxidative burst in response to subsequent receptor stimulation with FMLP. CB had a similar but much more pronounced effect on cellular recruitment to a receptor-mediated responsive state. Activation of protein kinase C (PKC) using the phorbol ester phorbol myristate acetate (PMA) resulted in a heterogeneous response, with all cells generating H2O2, but with two populations differing in their magnitude of response. Physiological priming agonists had no effect on the heterogeneity of the PMA response. However, pretreatment with CB dramatically altered the PMA response, producing a homogeneous population highly responsive to stimulation with PKC. In contrast, direct stimulation of G proteins with fluoride (A1F-4) was primed both by physiological priming agonists and by CB. These results demonstrate that priming of neutrophils by physiological agonists involves changes at the level of signal transduction which enable a previously non-responsive cell to respond to a secondary stimulus.(ABSTRACT TRUNCATED AT 250 WORDS)     

Incidence of intraglomerular platelets in steroid sensitive nephrotic syndrome.

Renal biopsies from 44 patients with steroid sensitive nephrotic syndrome were examined with respect to the content of their intraglomerular platelets and compared with 18 normal control patients and with 51 patients with membranous glomerulonephritis and the nephrotic syndrome. The results suggested that platelet activity was not involved in the pathogenesis of steroid sensitive nephrotic syndrome; in the active phase of the number of platelets in glomeruli is lower than that of normal controls, and this may be associated with increased sensitivity to aggregating agents as part of the nephrotic syndrome. After steroid treatment and disappearance of proteinuria, the number of intraglomerular platelets rises to normal values.