During hypoxic exercise some vasoconstriction is needed to match O2 delivery with O2 demand at the microcirculatory level.

To test the hypothesis that the increased sympathetic tonus elicited by chronic hypoxia is needed to match O(2) delivery with O(2) demand at the microvascular level eight male subjects were investigated at 4559 m altitude during maximal exercise with and without infusion of ATP (80 mug (kg body mass)(-1) min(-1)) into the right femoral artery. Compared to sea level peak leg vascular conductance was reduced by 39% at altitude. However, the infusion of ATP at altitude did not alter femoral vein blood flow (7.6 +/- 1.0 versus 7.9 +/- 1.0 l min(-1)) and femoral arterial oxygen delivery (1.2 +/- 0.2 versus 1.3 +/- 0.2 l min(-1); control and ATP, respectively). Despite the fact that with ATP mean arterial blood pressure decreased (106.9 +/- 14.2 versus 83.3 +/- 16.0 mmHg, P < 0.05), peak cardiac output remained unchanged. Arterial oxygen extraction fraction was reduced from 85.9 +/- 5.3 to 72.0 +/- 10.2% (P < 0.05), and the corresponding venous O(2) content was increased from 25.5 +/- 10.0 to 46.3 +/- 18.5 ml l(-1) (control and ATP, respectively, P < 0.05). With ATP, leg arterial-venous O(2) difference was decreased (P < 0.05) from 139.3 +/- 9.0 to 116.9 +/- 8.4(-1) and leg .VO(2max) was 20% lower compared to the control trial (1.1 +/- 0.2 versus 0.9 +/- 0.1 l min(-1)) (P = 0.069). In summary, at altitude, some degree of vasoconstriction is needed to match O(2) delivery with O(2) demand. Peak cardiac output at altitude is not limited by excessive mean arterial pressure. Exercising leg .VO(2peak) is not limited by restricted vasodilatation in the altitude-acclimatized human.     

Prolactin levels in paternal striped mouse (Rhabdomys pumilio) fathers

Paternal behavior is associated with an increase in prolactin levels in fish, birds and mammals, including rodents. The striped mouse (Rhabdomys pumilio) from southern Africa shows highly developed paternal care. We investigated whether striped mouse fathers have higher prolactin levels than nonfathers, and whether there is a relationship between tactile stimulation with pups and prolactin secretion in fathers. We measured serum prolactin in 42 male striped mice assigned to one of four different experimental groups (single males, paired males, fathers housed with mother and pups, and fathers separated from their family by a wire-mesh partition). Our results revealed no increases in prolactin levels in fathers, and fathers with tactile contact with pups did not have higher prolactin levels than the fathers that were prevented from making tactile contact with pups. In contrast, experienced males had higher prolactin levels than inexperienced males. Male striped mice are polygynous in nature, living in groups, with three breeding females, and are permanently associated with pups during the breeding season. In a field study, males had higher prolactin levels during the breeding season than during the nonbreeding season. Thus, prolactin secretion in the polygynous striped mouse might be regulated by environmental stimuli, whereas social stimuli might be important for monogamous species. This is the first study to demonstrate seasonal changes in prolactin levels in a free-living male mammal.     

Immunohistochemical and molecular analysis of p53, RB,and PTEN in malignant peripheral nerve sheath tumors

The molecular basis of both sporadic and neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNSTs) is yet largely undetermined. Therefore, we analyzed a series of 12 MPNSTs - including two cases which arose in the setting of NF1 - for molecular alterations in the p53, retinoblastoma ( Rb), and PTEN tumor suppressor genes. Furthermore, the immunohistochemical expression of p53, RB, and PTEN protein was examined in these tumors. One mutation (8%), an A to T transversion leading to an amino acid exchange, was found in exon 5 of the p53 gene in a sporadic MPNST. In two other sporadic tumors (20%), loss of heterozygosity (LOH) of the p53 gene occurred. Nuclear overexpression of p53 protein was observed in ten tumors (83%). Loss of RB protein expression was seen in two MPNSTs (17%), and LOH of the Rb gene was detected in four tumors (44%), including the two NF1-associated MPNSTs, one of them showing concomitant loss of RB protein expression. No mutation in the PTEN gene was detected, and cytoplasmic immunoreactivity for the PTEN protein was maintained in eight MPNSTs (67%). We suggest that alterations in the p53 and RB pathway, both are essential in controlling the cell-cycle progression, are critical points in the tumorigenesis of sporadic and NF1-associated MPNSTs, whereas the PTEN gene seems to play no significant role in this process.     

Offshore telemedicine emergency service: a 1-year experience

Journal of Public Health - Offshore wind energy is a fast growing market. Accordingly, a correspondingly large number of employees are working at the wind farms. Owing to the harsh operating...     

Tezacaftor/ivacaftor in people with cystic fibrosis who stopped lumacaftor/ivacaftor due to respiratory adverse events

BackgroundIncreased rates of respiratory adverse events have been observed in people ≥12 years of age with cystic fibrosis homozygous for the Phe508del-CFTR mutation treated with lumacaftor/ivacaftor, particularly in those with percent predicted forced expiratory volume in 1 s (ppFEV₁) of <40%. We evaluated the safety, tolerability, and efficacy of tezacaftor/ivacaftor in people with cystic fibrosis homozygous for Phe508del-CFTR who discontinued lumacaftor/ivacaftor due to treatment-related respiratory signs or symptoms.MethodsParticipants ≥12 years of age with cystic fibrosis homozygous for Phe508del-CFTR with ppFEV₁ of ≥25% and ≤90% were randomized 1:1 and treated with tezacaftor/ivacaftor or placebo for 56 days.ResultsOf 97 participants, 94 (96.9%) completed the study. The primary endpoint was incidence of predefined respiratory adverse events of special interest (chest discomfort, dyspnea, respiration abnormal, asthma, bronchial hyperreactivity, bronchospasm, and wheezing): tezacaftor/ivacaftor, 14.0%; placebo, 21.3%. The adverse events were mild or moderate in severity. None were serious or led to treatment interruption or discontinuation. Overall, the discontinuation rate was similar between groups. The mean (SD) ppFEV₁ at baseline was 44.6% (16.1%) with tezacaftor/ivacaftor and 48.0% (18.1%) with placebo. The posterior mean difference in absolute change in ppFEV₁ from baseline to the average value of days 28 and 56 was 2.7 percentage points with tezacaftor/ivacaftor vs placebo.ConclusionsTezacaftor/ivacaftor was generally safe, well tolerated, and efficacious in people ≥12 years of age with cystic fibrosis homozygous for Phe508del-CFTR with ppFEV₁ of ≥25% and ≤90% who previously discontinued lumacaftor/ivacaftor due to treatment-related respiratory signs or symptoms.     

Rapid rise in plasma glucagon induced by acute cold exposure in man and rat

The effect of acute cold exposure on the concentration of glucagon in the blood was investigated in man and in intact and adrenalectomized rats.In man fasted overnight acute cold exposure, which caused a twofold increase in O₂-consumption resulted in a rapid rise in plasma glucagon. The levels of insulin and blood glucose remained unaltered, while the concentration of serum free fatty acids and -hydroxybutyrate increased.In fasted intact rats acute cold exposure lead to similar effects. A close parallelism between the rise in plasma glucagon and the concentration of hepatic cycloAMP was observed. Adrenalectomy did not impair the cold induced rise in plasma glucagon and hepatic cycloAMP.It is concluded that acute cold exposure caused a rapid rise in the concentration of plasma glucagon leading to an increase in the concentration of hepatic cycloAMP, thus enhancing the rate of hepatic gluconeogenesis and ketogenesis. As these alterations were similar in the absence of glucocorticoids and medulla-derived catecholamines, it is suggested that glucagon may play a role in the metabolic adaptation to acute cold exposure.     

The use of trimeric isoleucine-zipper fusion proteins to study surface-receptor-ligand interactions in natural killer cells

The ligands for several activating natural killer (NK) cell receptors have not been identified to date. Soluble receptor fusion proteins can be used to stain target cells for the presence of these unidentified ligands. Here, we describe the generation and use of soluble type I NK cell receptor isoleucine-zipper (ILZ) fusion proteins of the immunoglobulin (Ig) superfamily. ILZ-fusion proteins are easy to produce and purify. They form trimeric complexes in solution and display a higher binding avidity than classical immunoglobulin-fusion proteins. ILZ-fusion proteins do not interact with Fc-receptors and can therefore be used to block receptor-ligand interactions in cellular assays. This makes ILZ-fusion proteins a valuable tool to study receptor-ligand interactions in NK cells and other cellular systems.     

Increased frequency of HLA-DPw2 in pauciarticular onset juvenile chronic arthritis

Thirty-six unrelated Danish patients with pauciarticular Juvenile Chronic Arthritis (PJCA) and 120 controls were typed for HLA-DPw1-w6 and the local specificity CDPHEI with bulk-expanded Primed Lymphocyte Typing (PLT) cells. The frequency of HLA-DPw2 was 52.8% in PJCA patients and 16.7% in controls (relative risk, RR = 4.5; P less than 0.001). The antigens HLA-Dw5 and/or Dw8 were present in 50% of the patients and in 21.3% of the controls (RR = 4.2; p less than 10(-3)). DPw2 was not associated (in linkage disequilibrium) with Dw5/w8 in patients or in controls, and the DP and D associations with PJCA were independent of each other. However, the combined presence of DPw2 and Dw5 and/or Dw8 gave a significantly higher risk of PJCA than each antigen alone indicating interaction of DP and DR gene products. PJCA is the first disease definitely found to be associated with a DP antigen.     

Application of molecular and cytogenetic techniques to the detection of a de novo unbalanced t(11q;21q) in a patient previously diagnosed as having monosomy 21

Hertz B, Brandt CA, Petersen MB, Pedersen S, König U, Strømkjær H, Jensen PKA. Application of molecular and cytogenetic techniques to the detection of a de novo unbalanced t(11q;21q) in a patient previously diagnosed as having monosomy 21.
Clin Genet 1993: 44: 89–94. © Munksgaard, 1993
The occurrence of complete autosomal monosomy in man is extremely rare and generally considered to be incompatible with life. Since the introduction of banding techniques in human cytogenetics, several cases of presumptive monosomy for chromosome 21 have nevertheless been reported. However, it has been suggested that most, if not all, of these cases may represent unbalanced translocations or other structural aberrations resulting in only partial monosomy 21. Here we describe a patient in whom full monosomy 21 was initially diagnosed by routine karyotyping. Re-examination with a combination of high resolution banding technique, chromosome painting and DNA polymorphism analysis demonstrated the presence of an unbalanced translocation between the long arms of chromosome 11 and 21, respectively. Consequently, the case was re-classified as a partial monosomy for the proximal long arm of chromosome 21.     

Enolase 1 of Candida albicans binds human CD4+ T cells and modulates naïve and memory responses

To obtain a better understanding of the biology behind life-threatening fungal infections caused by Candida albicans, we recently conducted an in silico screening for fungal and host protein interaction partners. We report here that the extracellular domain of human CD4 binds to the moonlighting protein enolase 1 (Eno1) of C. albicans as predicted bioinformatically. By using different anti-CD4 monoclonal antibodies, we determined that C. albicans Eno1 (CaEno1) primarily binds to the extracellular domain 3 of CD4. Functionally, we observed that CaEno1 binding to CD4 activated lymphocyte-specific protein tyrosine kinase (LCK), which was also the case for anti-CD4 monoclonal antibodies tested in parallel. CaEno1 binding to naïve human CD4⁺ T cells skewed cytokine secretion toward a Th2 profile indicative of poor fungal control. Moreover, CaEno1 inhibited human memory CD4⁺ T-cell recall responses. Therapeutically, CD4⁺ T cells transduced with a p41/Crf1-specific T-cell receptor developed for adoptive T-cell therapy were not inhibited by CaEno1 in vitro. Together, the interaction of human CD4⁺ T cells with CaEno1 modulated host CD4⁺ T-cell responses in favor of the fungus. Thus, CaEno1 mediates not only immune evasion through its interference with complement regulators but also through the direct modulation of CD4⁺ T-cell responses.