Alpha-receptor restriction of coronary blood flow during atrial fibrillation

The effects of atrial fibrillation (AF) on coronary circulation before and after alpha-receptor blockade were studied in 14 anesthetized, open-chest dogs. AF was induced by electrical stimulation of the left atrial appendage; identical rhythmic heart rates were adjusted by left atrial pacing. During atrial pacing, coronary vascular resistance (CVR) was 0.97 +/- 0.10 mm Hg X min X 100 g/ml (resistance units [RU]), coronary blood flow (CBF) 125 +/- 14 ml/min X 100 g, and oxygen saturation 30 +/- 2%; plasma epinephrine was 193 +/- 42 pg/ml and norepinephrine 584 +/- 111 pg/ml. During AF, CVR was higher (1.16 +/- 0.11 RU, p less than 0.0005), whereas CBF (92 +/- 9 ml/min X 100 g, p less than 0.001) and coronary sinus oxygen saturation (24 +/- 2%, p less than 0.0025) were lower than during atrial pacing. When AF was induced, epinephrine increased to 333 +/- 98 pg/ml (p less than 0.05) and norepinephrine to 1,005 +/- 214 pg/ml (p less than 0.005). The large increase in plasma catecholamines suggested an activation of the sympathoadrenal system during AF. In addition, the alpha-receptor blocker phenoxybenzamine (10 mg/kg, intravenously) abolished the differences in CVR, CBF and oxygen saturation between AF and atrial pacing. The data suggest that the decrease in CBF and increase in CVR during experimentally induced AF are caused by coronary vasoconstriction, mediated by sympathetic activation of alpha receptors in the coronary vascular bed.     

Bone marrow‐on‐a‐chip: Long‐term culture of human haematopoietic stem cells in a three‐dimensional microfluidic environment

Multipotent haematopoietic stem and progenitor cells (HSPCs) are the source for all blood cell types. The bone marrow stem cell niche in which the HSPCs are maintained is known to be vital for their maintenance. Unfortunately, to date, no in vitro model exists that accurately mimics the aspects of the bone marrow niche and simultaneously allows the long‐term culture of HSPCs. In this study, a novel three‐dimensional coculture model is presented, based on a hydroxyapatite coated zirconium oxide scaffold, comprising of human mesenchymal stromal cells (MSCs) and cord blood derived HSPCs, enabling successful HSPC culture for a time span of 28 days within the microfluidic multiorgan chip. The HSPCs were found to stay in their primitive state (CD34⁺CD38^?) and capable of granulocyte, erythrocyte, macrophage, megakaryocyte colony formation. Furthermore, a microenvironment was formed bearing molecular and structural similarity to the in vivo bone marrow niche containing extracellular matrix and signalling molecules known to play an important role in HSPC homeostasis. Here, a novel human in vitro bone marrow model is presented for the first time, capable of long‐term culture of primitive HSPCs in a microfluidic environment.     

Halving the volume of AnaConDa: initial clinical experience with a new small-volume anaesthetic reflector in critically ill patients—a quality improvement project

AnaConDa-100 ml (ACD-100, Sedana Medical, Uppsala, Sweden) is well established for inhalation sedation in the intensive care unit. But because of its large dead space, the system can retain carbon dioxide (CO₂) and increase ventilatory demands. We therefore evaluated whether AnaConDa-50 ml (ACD-50), a device with half the internal volume, reduces CO₂ retention and ventilatory demands during sedation of invasively ventilated, critically ill patients. Ten patients participated in this cross-over protocol. After sedation with isoflurane via ACD-100 for 24 h, the 5-h observation period started. During the first hour, ACD-100 was used; for the next 2 h, ACD-50; and for the last 2 h, ACD-100 was used again. Sedation was titrated to Richmond Agitation and Sedation Scale (RASS) score ??3 to ??4 and a processed electroencephalogram (Narcotrend Index, Narcotrend-Gruppe, Hannover, Germany) was recorded. Minute ventilation, CO₂ elimination, and isoflurane consumption were compared. All patients were deeply sedated (Narcotrend Index, mean?±?SD: 38?±?10; RASS scores ??3 to ??5) and breathed spontaneously with pressure support throughout the observation period. Infusion rates of isoflurane and opioid, either remifentanil or sufentanil, as well as ventilator settings were unchanged. Minute ventilation and end-tidal CO₂ were significantly reduced with the ACD-50, respiratory rate remained unchanged, and tidal volume decreased by 66?±?43 ml. End-tidal isoflurane concentrations were also slightly reduced while haemodynamic measures remained constant. The ACD-50 reduces the tidal volume needed to eliminate carbon dioxide without augmenting isoflurane consumption.     

How to define pathologic pelvic floor descent in MR defecography during defecation?

Abdominal Radiology - To assess the extents of pelvic floor descent both during the maximal straining phase and the defecation phase in healthy volunteers and in patients with pelvic floor...     

Neuronal activity regulated pentraxin (narp) and GluA4 subunit of AMPA receptor may be targets for fluoxetine modulation

Fluoxetine is the foremost prescribed antidepressant. Drugs acting on monoaminergic system may also regulate glutamatergic system. Indeed, the investigation of proteins associated with this system, such as Narp (neuronal activity-dependent pentraxin) and GluA4 subunit of AMPA receptor may reveal poorly explored modulations triggered by conventional antidepressants. This study aimed to uncover neurochemical mechanisms underlying the chronic fluoxetine treatment, mainly by evaluating these protein targets in the prefrontal cortex and in the hippocampus. Mice received a daily administration of fluoxetine (0.1, 1 or 10 mg/kg, p.o.) or potable water (vehicle group) for 21 days. These animals were submitted to the forced swim test (FST) to verify antidepressant-like responses and the open-field test (OFT) to assess locomotor activity. Modulation of signaling proteins was analyzed by western blot. Chronic treatment with fluoxetine (1 and 10 mg/kg) was effective, since it reduced the immobility time in the FST, without altering locomotor activity. Fluoxetine 10 mg/kg increased CREB phosphorylation and BDNF expression in the prefrontal cortex and hippocampus. Noteworthy, in the hippocampus fluoxetine also promoted Akt activation and augmented Narp expression. In the prefrontal cortex, a significant decrease in the expression of the GluA4 subunit and Narp were observed following fluoxetine administration (10 mg/kg). The results provide evidence of novel molecular targets potentially involved in the antidepressant effects of fluoxetine, since in mature rodents Narp and GluA4 are mainly expressed in the GABAergic parvalbumin-positive (PV+) interneurons. This may bring new insights into the molecular elements involved in the mechanisms underlying the antidepressant effects of fluoxetine.

     

Effectiveness of different intervention measures in children and adolescents with hypertension and lipid metabolism disorders

141 children and adolescents (7-21 years, mean age 14.2 years) showed values of blood pressure, total cholesterol and triglycerides greater than or equal to 90 percentile and HDL-cholesterol values less than or equal to 10 during an examination of 639 children of parents with distinct coronary risk factors or early percentile infarction. By randomization they were subdivided into two groups. (A and B) and underwent intervention measures of different intensity. While group B got only a unique recommendation concerning the preventive measures, in group A a regular, non medicamentous individual treatment was performed. After one year a decrease of blood pressure could be proved in the two groups. A significant decrease of total and HDL cholesterol was found only in group A. While the blood pressure was most clearly reduced in 7-13-year-old children, the most distinct lipid changes were shown in 14-17-year-old adolescents. An influence on body-weight and triglycerides could not be established. Our results confirm the possibilities and also the limits of preventive measures in childhood and adolescence. Apart from the intended decrease of blood pressure and total cholesterol the simultaneous decrease of HDL-cholesterol refers to open questions in the conception of the primary prevention, particularly in children.     

Low-density lipoprotein apheresis in children with familial hypercholesterolemia: follow-up to 21 years

Twenty-seven patients (14 girls, 13 boys) affected by familial hypercholesterolemia who had begun low-density lipoprotein (LDL) apheresis treatment before the age of 15 were studied. The median age at diagnosis was 4 years and the blood LDL cholesterol level was 704 +/- 163 mg/dL. Screening was performed for homozygous or double heterozygous mutations of the LDL cholesterol receptor gene and mutations were found in 24 of the patients. The mean age at the beginning of treatment was 8.5 years and the mean length of follow up was 12.6 years. The two main procedures used were direct adsorption of lipoproteins and dextran sulfate cellulose adsorption. Nine patients experienced anaphylactic reactions due to bradykinin and six had to have their treatment changed. The LDL cholesterol level before the session was lowered by 45 +/- 11% of the value at diagnosis. The LDL cholesterol reduction in a session was 72 +/- 10%. Tendinous xanthomas disappeared or diminished dramatically in 62% of the children. In 22 patients no cardiovascular event occurred during LDL apheresis treatment. Three had angina pectoris; two others had surgical management of aortic stenosis, but no clinical manifestations. Seven children had normal cardiovascular pictures while on treatment. Eleven had abnormalities of the aortic root or coronary arteries, which in six cases had appeared before treatment; the other five children did not undergo prior cardiac evaluation. In five children the abnormalities appeared during treatment. Based on these data, LDL-apheresis can be recommended for the treatment of homozygous familial hypercholesterolemia, even in young children, with good efficiency on biological parameters, cutaneous lesions and cardiovascular events.     

Dose-reduced antihypertensive agents--use in complex nonmedicamentous therapy of hypertension

In order to estimate the influence of a non-medicamentous therapy (CNT) on the consumption of medicaments and coronary risk in high blood pressure 73 hypertensives of a medicamentously stabilized CNT-group were examined in comparison to a group of the same size of patients with hypertension who were managed exclusively medicamentously for behaviour of blood pressure, need of antihypertensive drugs and changes of hypertension-associated risk factors. After an exactly controlled 6-month treatment hypertensives with additionally recommended far-reaching CNT showed an economization of medicaments by scarcely the half in comparison to the reference group. By means of suitable control methods a causal non-medicamentously conditioned decrease of blood pressure could be excluded. A different need of antihypertensive drugs was simulated by the exacter intake of medicaments in the index-patients. Notwithstanding the metabolic effects of the additional therapy have induced a positive change of atherogenic lipids. The examinations indicate in general the difficulty of the judgement of efficacy of non-medicamentous therapeutic measures in connection with a rational dose-reduced long-term therapy with antihypertensive drugs.     

Association of hormone replacement therapy with bronchial hyper-responsiveness

Postmenopausal hormone replacement therapy (HRT) has been linked to asthma in women, however, with inconsistent conclusions. This study examined the association of HRT with bronchial hyper-responsiveness (BHR). Eighty-five postmenopausal women completed a women-specific questionnaire and underwent methacholine challenge testing according to the protocol of the European community respiratory health survey. Associations of HRT use with BHR (based on a 20% fall in FEV1), mild BHR (10% fall in FEV1) or dichotomized dose-response slopes were analyzed by logistic regression, controlling for age, education, smoking and overweight. The 27 HRT users were less likely to show BHR compared to the 58 non-users (11% vs. 41%), multiply adjusted odds ratio (95% confidence interval) 0.12 (0.03, 0.55). Results for dose-response slopes were similar, while mild BHR showed no association with HRT use. These results point to a relaxing effect of estrogens on bronchial smooth muscle.