Increased pulmonary prostacyclin synthesis in rats with chronic hypoxic pulmonary hypertension

OBJECTIVE: The regulation of pulmonary prostacyclin synthesis is not completely understood. We tested the hypothesis that prostacyclin production is predominantly stimulated by hemodynamic factors, such as increased shear-stress, and is thus increased in rats with chronic hypoxic pulmonary hypertension. METHODS: To this end, we determined pulmonary prostacyclin synthase (PGIS) gene expression, circulating levels of the stable prostacyclin metabolite 6-keto prostaglandin F(1alpha) (6-keto-PGF(1alpha)), pulmonary endothelin (ET)-1 gene expression, and ET-1 plasma levels in rats exposed to 4 weeks of hypoxia (10% O(2)) in the presence or absence of either the nitric oxide (NO) donor molsidomine (MD, 15 mg/kg/day) or the ET-A receptor antagonist LU135252 (LU, 50 mg/kg/day). RESULTS: Right ventricular systolic pressure (RVSP), the cross-sectional medial vascular wall area of pulmonary arteries, and ET-1 production increased significantly during hypoxia. PGIS mRNA levels increased 1.7-fold, and 6-keto-PGF(1alpha) plasma levels rose from 8.2+/-0.8 to 12.2+/-2.2 ng/ml during hypoxia (each P<0.05 vs. normoxic controls). MD and LU reduced RVSP and pulmonary vascular remodeling similarly (each P<0.05 vs. hypoxia), but only MD inhibited pulmonary ET-1 formation (P<0.05 vs. hypoxia). Nevertheless, both drugs attenuated the increase in PGIS gene expression and plasma 6-keto-PGF(1alpha) levels (each P<0.05 vs. hypoxia). CONCLUSION: Our data suggest that prostacyclin production in hypertensive rat lungs is predominantly increased by hemodynamic factors while hypoxia, NO and ET-1 per are less important stimuli, and that this increase may serve as a compensatory mechanism to partially negate the hypoxia-induced elevation in pulmonary vascular tone.     

Management of bisphosphonate‐related osteonecrosis of the jaw: a literature review

Osteonecrosis of the jaw (ONJ) is a serious side effect of bisphosphonate use in patients with osteoporosis, Paget's disease, hypercalcemia of malignancy, metastatic bone disease and multiple myeloma, although recently this complication has also been reported in patients under non‐bisphosphonate medication, such as denosumab and bevacizumab. The occurrence of ONJ is higher in oncology patients treated with high‐dose iv bisphosphonates than in osteoporosis patients treated with oral bisphosphonates. Although multiple hypotheses have been proposed, the exact pathogenic mechanism of ONJ still remains unclear. As treatment protocols based on randomized controlled trials (RCTs) do not exist, we critically reviewed the existing data concerning the management of bisphosphonate‐related osteonecrosis of the jaw, including the most recent data for the use of teriparatide and hyperbaric oxygen.     

Monitoring of direct alcohol markers in alcohol use disorder patients during withdrawal treatment and successive rehabilitation

Direct and indirect biomarkers are widely applied for the determination of alcohol consumption. They help to assess past or present alcohol consumption. Depending on the window of detection and sensitivity of the investigated marker, punctual alcohol consumption may remain undetected. In this study, different sampling strategies for the intermediary long‐term marker phosphatidylethanol (PEth) are evaluated and compared to the determination of the short‐term markers ethyl glucuronide (EtG) and ethyl sulfate (EtS) in urine. Samples from 19 patients undergoing alcohol use disorder treatment were collected during the withdrawal treatment and successive rehabilitation (33 ± 26 days (range: 3–74 days)). With liquid chromatography–tandem mass spectrometry (LC–MS/MS) EtG and EtS in urine, PEth in blood, PEth in dried blood spot (DBS) from venous blood, and PEth in DBS from capillary blood were quantified and compared. The use of volumetric capillary DBS, prepared from 20 μL of blood, provided the same results as the use of venous DBS (95% ± 10%, R² 0.9899 for PEth 16:0/18:1). Capillary DBS sampling has the advantage that it can be performed without venipuncture. The use of PEth in DBS proved to prevent post‐sampling degradation, providing a longer detection in comparison to PEth in liquid blood, which only showed 67% ± 24% of the PEth DBS 16:0/18:1 concentration. When compared with EtG and EtS in urine, PEth monitoring proved to be advantageous for the detection of relapse situations, as the accumulation of PEth in blood prolongs the detectability. In conclusion, volumetric capillary DBS sampling for PEth is a simple and useful tool for compliance monitoring, and avoids hematocrit issues.     

Versagen der Atempumpe

The total anatomical and functional apparatus which allows normal ventilation of the lungs is known as the respiratory pump. An insufficiency of this system, which can be caused by a multitude of reasons, primarily affects the inspiratory musculature and especially the diaphragm. One of the essential clinical characteristics is rapid shallow breathing. Exhaustion of the repiratory musculature due to acute respiratory insufficiency is normally clinically registered but can also be functionally determined in particular by the maximum static inspiratory closed mouth pressure. A further option is invasive measurement of the transdiaphragmal pressure, which however is not suitable as a routine procedure. Mechanical ventilation is used as treatment of respiratory pump insufficiency independent of the cause. This is initially a non-invasive procedure but if unsuccessful intubation and invasive ventilation are indicated. The technical developments in the field of extracorporeal gas exchange systems are very promising. However, in view of the insufficient data, ventilation procedures using masks and tubes still remain the first choice methods.     

The phenotype of human STK4 deficiency

We describe a novel clinical phenotype associating T- and B-cell lymphopenia, intermittent neutropenia, and atrial septal defects in 3 members of a consanguineous kindred. Their clinical histories included recurrent bacterial infections, viral infections, mucocutaneous candidiasis, cutaneous warts, and skin abscesses. Homozygosity mapping and candidate gene sequencing revealed a homozygous premature termination mutation in the gene STK4 (serine threonine kinase 4, formerly having the symbol MST1). STK4 is the human ortholog of Drosophila Hippo, the central constituent of a highly conserved pathway controlling cell growth and apoptosis. STK4-deficient lymphocytes and neutrophils exhibit enhanced loss of mitochondrial membrane potential and increased susceptibility to apoptosis. STK4 deficiency is a novel human primary immunodeficiency syndrome.     

The management of trauma victims with head injury: a study by the national confidential enquiry into patient outcome and death

Introduction

In 2006 the National Confidential Enquiry into Patient Outcome and Death undertook a large prospective study of trauma care, which revealed several findings pertaining to the management of head injuries in a sample of 493 patients.

Methods

Case note data were collected for all trauma patients admitted to all hospitals accepting emergencies in England, Wales, Northern Ireland and the Channel Islands over a three-month period. Severely injured patients with an injury severity score (ISS) of ≥16 were included in the study. The case notes for these patients were peer reviewed by a multidisciplinary group of clinicians, who rated the overall level of care the patient received.

Results

Of the 795 patients who met the inclusion criteria for the study, 493 were admitted with a head injury. Room for improvement in the level of care was found in a substantial number of patients (265/493). Good practice was found to be highest in high volume centres. The overall head injury management was found to be satisfactory in 84% of cases (319/381).

Conclusions

This study has shown that care for trauma patients with head injury is frequently rated as less than good and suggests potential long-term remedies for the problem, including a reconfiguration of trauma services and better provision of neurocritical care facilities.