Evaluation of blood flow parameters in addition to blood pressure and electrocardiogram in the conscious telemetered beagle dog

INTRODUCTION: The objective of this study was to evaluate a model for measuring blood flow parameters in addition to blood pressure, heart rate and electrocardiogram (ECG) in conscious telemetered restrained and unrestrained beagle dogs. METHODS: Male beagle dogs were instrumented with fully implantable ITS radio telemetry devices for the measurement of blood pressure and ECG. In addition, the dogs were instrumented with a probe around the pulmonary artery for the measurement of blood flow by ultrasound. Dobutamine at 5, 10 and 20 mug/kg/min, given intravenously to sling restrained animals (n=4), and minoxidil at 2 mg/kg, given orally to unrestrained animals (n=4), were selected as test compounds known to cause changes in the cardiovascular parameters of interest in this work. RESULTS: Dobutamine produced a small increase in mean (9%) and systolic blood pressure (5%), and an increase in pulse pressure (37%) and heart rate (30%). The additional blood flow parameters showed that dobutamine also increased stroke volume (21%) and cardiac output (58%) and reduced total peripheral resistance (52%). Minoxidil treatment resulted in a prolonged reduction in mean, systolic and diastolic blood pressure (up to 24%). Additionally, a prolonged increase in heart rate (169%) and cardiac output (120%) were observed along with a reduction in total peripheral resistance (62%). The effects of both compounds were consistent with their known pharmacology. DISCUSSION: The results show that measurement of blood flow parameters can be successfully added to the standard telemetered cardiovascular dog model to provide valuable additional information on the effects of compounds on the cardiovascular system.     

Does glycoprotein IIIa gene (Pl(A)) polymorphism influence clopidogrel resistance? : a study in older patients

BACKGROUND: Clopidogrel is a potent antiplatelet drug used for secondary prevention after ischaemic cardiovascular or cerebrovascular events. In patients with aspirin (acetylsalicylic acid) intolerance or resistance, it is used as monotherapy. Recent data report that Pl(A) polymorphism of the glycoprotein IIIa gene may account for differences in aspirin-induced antiplatelet effects. An increased degree of platelet reactivity was also reported in Pl(A2) carriers compared with Pl(A1/A1) patients after administration of a clopidogrel 300mg loading dose. OBJECTIVES: The aim of this study was to assess the modulatory effect of the Pl(A2) allele on platelet aggregation in patients taking long-term clopidogrel. M ETHODS: The prevalence of the Pl(A2) allele was assessed in 38 (21 males, 17 females; mean age 63 +/- 13 years) clopidogrel-resistant and 59 (26 males, 33 females; mean age 63 +/- 11 years) clopidogrel-responsive patients. The polymerase chain reaction-restriction fragment length polymorphism method was utilised to evaluate Pl(A) polymorphism. A Carat TX4 optical platelet aggregometer (Carat Diagnostics Ltd, Budapest, Hungary) was used to measure 5 and 10 micromol/L adenosine diphosphate-induced platelet aggregation. RESULTS: Significantly more patients were taking combination antiplatelet therapy in the clopidogrel-resistant group than in the clopidogrel-responsive group (50% vs 30%, respectively). The prevalence of the Pl(A2) allele did not differ significantly between the two groups (0.09 vs 0.13), even after adjustment for combination therapy and various risk factors. CONCLUSIONS: Our results show that carriers of the Pl(A2) allele do not have an increased risk of clopidogrel resistance. These findings and data from our previous studies suggest that patients with a Pl(A2) allele homozygosity may benefit from antiplatelet therapy based on clopidogrel rather than aspirin.     

Depolarizing GABAergic synaptic input triggers endocannabinoid‐mediated retrograde synaptic signaling

Endocannabinoids released by postsynaptic neurons inhibit neurotransmitter release from presynaptic axon terminals. One typical stimulus of endocannabinoid production is an increase of calcium concentration in postsynaptic neurons. The aim of the present study was to clarify whether depolarizing GABAergic synaptic input, by increasing calcium concentration in postsynaptic neurons, can trigger endocannabinoid production. Spontaneous GABAergic inhibitory postsynaptic currents (sIPSCs) were recorded in Purkinje cells in mouse cerebellar slices with patch‐clamp pipettes containing 151 mM chloride (a usual recording mode). sIPSCs were depolarizing inward currents under this condition. Combined electrophysiological and fluorometric calcium imaging experiments indicated that sIPSCs frequently triggered calcium spikes. After the calcium spikes, a short‐term suppression of sIPSCs occurred. This suppression was prevented by the CB₁ cannabinoid receptor antagonist rimonabant and the diacylglycerol lipase inhibitor orlistat, but not changed by URB597, an inhibitor of anandamide degradation. It is, therefore, likely that CB₁ receptors and 2‐arachidonoylglycerol were involved. For testing the physiological significance of the above observation, we carried out experiments on brains of 3‐ to 5‐day‐old mice. The gramicidin‐induced perforated patch‐clamp mode was used for preserving the physiological intracellular chloride concentration of the neurons. Depolarizing GABAergic sIPSCs occurred under this condition, but at a very low rate. Rimonabant did not change the frequency of these sIPSCs, arguing against the persistence of an endocannabinoid tone. The results point to a new kind of trigger of endocannabinoid production: depolarizing GABAergic synaptic input can elicit endocannabinoid production in postsynaptic neurons by activating calcium channels. The produced endocannabinoid suppresses GABA release from presynaptic axon terminals. Synapse 63:643–652, 2009. © 2009 Wiley‐Liss, Inc.     

Evaluation of systemic and dermal toxicity and dermal photoprotection by sour cherry kernels

The present report describes outcomes of animal studies conducted to determine the systemic and dermal toxicity of Prunus cerasus (sour cherry) seed kernel contents; and a separate evaluation of the photoprotective capacity of the kernel oil fraction. B6 mice and Hartley guinea‐pigs were used for these experiments. Dosage groups of 6–8 animals were administered whole kernel meal in a dose range of 0–3000 mg/kg by gavage for 8 days, following which they were killed. The liver and kidney weights were recorded and histological examination performed on sections of these organs. Kidney function was assessed as blood urea nitrogen and creatinine and liver function by measurement of serum glutamic oxaloacetic transaminase, glutamic pyruvic transaminase and alkaline phosphatase. Dermal toxicity was evaluated in a Hartley guinea‐pig model by comparing UVB‐irradiated shaved skin to which the kernel oil had been applied with distilled water controls. In conclusion, no evidence of toxicity was observed to result from the consumption or dermal application of sour cherry seed kernel in the dose range at which it is likely to be used in foods or healthcare. Moreover, it was shown to have a powerful capacity to protect skin from UV damage. These results suggest it will prove to be a highly safe and effective addition to a wide range of products for general use. Copyright © 2011 John Wiley & Sons, Ltd.     

Differences in T-helper polarizing capability between human monocyte-derived dendritic cells and monocyte-derived Langerhans'-like cells

Langerhans' cells (LCs) represent a specific subset of dendritic cells (DCs) which are important for detecting and processing pathogens that penetrate the skin and epithelial barriers. The aim of our study was to explain what makes their in vitro counterparts - monocyte-derived Langerhans'-like cells (MoLCs) - unique compared with monocyte-derived dendritic cells (MoDCs). Immature MoDCs were generated by incubating peripheral blood monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4. The addition of transforming growth factor-β (TGF-β) to this cytokine cocktail resulted in the generation of MoLCs. MoLCs showed a lower expression of CD83, CD86, HLA-DR and CCR7 compared with MoDCs, regardless of their maturational status. Both immature and mature MoLCs secreted higher quantities of IL-23 compared with MoDCs and this finding correlated with a higher secretion of IL-17 in co-culture of MoLCs with allogeneic CD4(+) T cells. Mature MoLCs, which produced higher levels of IL-12 and lower levels of IL-10 compared with mature MoDCs, were more potent at inducing interferon-γ (IFN-γ) production by CD4(+) T cells in the co-culture system. In conclusion, the finding that mature MoLCs stimulate stronger T-helper 1 and T-helper 17 immune responses than mature MoDCs, makes them better candidates for use in the preparation of anti-tumour DC vaccines.     

Anxiety in the pediatric medical setting

The relationship between pediatric anxiety disorders and physical health is not well-understood, but appreciation of the importance of this relationship is growing. Significant functional impairment may accompany a chronic physical health condition such as asthma, diabetes, or epilepsy, and anxiety may complicate the course. In addition, physical disease can present with symptoms of anxiety, and anxiety disorders may present or be associated with physical symptoms such as functional abdominal pain, headache, and fatigue. This article describes anxiety and its association with physical disease, outlines assessment, and presents a treatment overview including psychotherapy and pharmacotherapy.     

Urinary flow disturbance as an early sign of autonomic neuropathy in diabetic children and adolescents

AIMS: Urinary bladder dysfunction is a frequent complication of diabetes mellitus in adults. The aim of this study is to determine the early disturbances of the detrusor contractility in children, and adolescents with type 1 diabetes. MATERIALS AND METHODS: The bladder urine flow parameters were investigated in 37 children with type 1 diabetes, 10/37 with cardiovascular autonomic dysfunction (CAD) voided 482 +/- 128 mils (Group A), 27/37 without CAD voided 258 +/- 52 mils (Group B). From an earlier uroflow screening study 20 healthy children formed group control A, who had voided 488 +/- 94 mils, and another 30 healthy children formed group control B, who had voided 260 +/- 50 mils. The compared groups were matched for voided volume, age, weight, and height. There was no evidence of urinary tract abnormalities in any of the children. RESULTS: Time to maximum flow was longer in both diabetic groups as compared with controls (P < 0.01), and the acceleration (the ratio of maximum flow and the time to maximum flow) of diabetics was significantly lower (P < 0.01). Bladder emptying was complete in each subject. Bladder wall disturbances were not seen by ultrasound. CONCLUSIONS: The decreased acceleration of detrusor muscle contraction may be interpreted as an early sign of autonomic neuropathy in children and adolescent with type 1 diabetes, even in patients without CAD. Clinicians may be able to determine autonomic neuropathy by using uroflowmetry that is easy to perform, sensitive, reproducible, and needs only a child's minimal cooperation.     

Incidence of chest tube malposition in the critically ill: a prospective computed tomography study

BACKGROUND: Malposition of percutaneously inserted chest tubes is considered as a rare complication in critically ill patients. Its incidence, however, remains uncertain. The aims of the study were to assess the true incidence of chest tube malposition in critically ill patients and to identify predicting factors. METHODS: The authors prospectively studied 122 chest tubes percutaneously inserted in 75 consecutive critically ill patients. For clinical reasons independent of the study, thoracic computed tomography scanning was performed in 63 patients, allowing direct visualization of 106 chest tubes. Based on these findings, chest tube position was classified as intrapleural, intrafissural, or intraparenchymal. Factors predicting chest tube malposition were analyzed by univariate and multivariate analysis. RESULTS: The mean delay between chest tube placement and thoracic scan was 3.5+/-2.9 days. Twenty-two chest tubes were diagnosed as being intrafissural (21%), and 10 were diagnosed as being intraparenchymal (9%). The only predicting factor associated with the risk of malposition was the use of a trocar for the percutaneous insertion of the chest tube (P=0.032). CONCLUSIONS: Malposition was detected in 30% of percutaneously inserted chest tubes, a higher incidence than previously reported. Avoiding the use of a trocar may reduce significantly the incidence of chest tube malposition.     

Declining seroprevalence of HIV infection among paediatric inpatients

An unlinked anonymous testing for HIV infection among consecutive paediatric admissions at Cama and Albless Hospital, Mumbai, was performed in 1998-99 and again in 2003-04. The seroprevalence declined from 5.5% (24/535) to 2.2% (10/447). Greater awareness, enhanced antenatal detection and measures taken to prevent mother-to-child transmission (MTCT) seem to have contributed to the declining seroprevalence. We believe that paediatric inpatients reflect the extent of MTCT in the community.     

Morphological mechanism of the development of pulmonary emphysema in klotho mice

The concept of fractal geometry is useful for the analysis of irregular and complex structures often seen in nature. Here we apply this concept to investigate the structural mechanism of the development of pulmonary emphysema in the klotho mouse, which, after milk feeding, exhibits characteristics resembling aging and develops emphysema. We calculated the relationships between perimeter and size characterizing shape and between cumulative frequency and size of the terminal air spaces identified from histologic slides and found that both relations followed a power law with fractal properties. However, the fractal dimensions related to the shape and size (Dsn) in the klotho mice were significantly lower than in controls. Additionally, in the klotho mice, Dsn decreased with age without significant change in mean linear intercept. These abnormal morphological changes were restored when the klotho mice were fed with a vitamin D-deficient diet. Previously undescribed morphological model simulations showed that a random destruction, in which the destruction process occurs homogeneously in the lungs, was more consistent with the data than a correlated destruction that is usually seen in smoking-related human emphysema. These results suggest that the pathological changes in the lungs of the klotho mice are derived not from localized causes, but from systemic causes that are related to abnormal activation of vitamin D. The morphogenesis of emphysema in the klotho mice and morphological analyses using fractal geometry may contribute to the understanding of the progressive nature and cause of parenchymal destruction in human emphysema.