Somatotropic axis in hypocretin-deficient narcoleptic humans: altered circadian distribution of GH-secretory events

Narcolepsy is a sleep disorder caused by impaired hypocretin (orexin) neurotransmission. Growth hormone (GH) secretion may be altered in narcolepsy for various reasons. Slow-wave sleep episodes, which are closely associated with GH-secretory events, are more randomly dispersed over 24 h in narcoleptics. Furthermore, hypocretins may inhibit pituitary GH release. We assessed the function of the somatotropic axis in narcolepsy by deconvolving 24-h (10-min sampling interval) plasma GH concentration profiles in seven hypocretin-deficient narcoleptic patients and in seven healthy controls matched for age, sex, and body weight. Both basal and pulsatile GH secretion rate and secretagogue-induced GH release were similar in patients and controls. However, narcoleptics secreted approximately 50% of their total production during the daytime, whereas controls secreted only 25% during the day. Also, the GH output pattern of narcoleptics was significantly less regular. We propose that hypocretin deficiency disrupts the circadian distribution of hypothalamic GH-releasing hormone release in narcoleptic patients to simultaneously cause daytime GH release and promote their propensity to fall asleep during the day.     

Rapid Rather than Gradual Weight Reduction Impairs Hemorheological Parameters of Taekwondo Athletes through Reduction in RBC-NOS Activation

Purpose

Rapid weight reduction is part of the pre-competition routine and has been shown to negatively affect psychological and physiological performance of Taekwondo (TKD) athletes. This is caused by a reduction of the body water and an electrolyte imbalance. So far, it is unknown whether weight reduction also affects hemorheological properties and hemorheology-influencing nitric oxide (NO) signaling, important for oxygen supply to the muscles and organs.

Methods

For this purpose, ten male TKD athletes reduced their body weight by 5% within four days (rapid weight reduction, RWR). After a recovery phase, athletes reduced body weight by 5% within four weeks (gradual weight reduction, GWR). Each intervention was preceded by two baseline measurements and followed by a simulated competition. Basal blood parameters (red blood cell (RBC) count, hemoglobin concentration, hematocrit, mean corpuscular volume, mean cellular hemoglobin and mean cellular hemoglobin concentration), RBC-NO synthase activation, RBC nitrite as marker for NO synthesis, RBC deformability and aggregation parameters were determined on a total of eight investigation days.

Results

Basal blood parameters were not affected by the two interventions. In contrast to GWR, RWR decreased activation of RBC-NO synthase, RBC nitrite, respective NO concentration and RBC deformability. Additionally, RWR increased RBC aggregation and disaggregation threshold.

Conclusion

The results point out that a rapid weight reduction negatively affects hemorheological parameters and NO signaling in RBC which might limit performance capacity. Thus, GWR should be preferred to achieve the desired weight prior to a competition to avoid these negative effects.     

Apoptotic Platelet Events Are Not Observed in Severe von Willebrand Disease-Type 2B Mutation p.V1316M

Thrombocytopenia and increased platelet clearance observed in von Willebrand disease-type 2B (VWD-2B) may be explained by platelet apoptosis triggered by the constitutive binding of VWF to its receptor, glycoprotein Ib (GPIb). Apoptosis was assessed in platelets from two patients with a severe VWD-2B mutation VWF/p.V1316M and from mice transiently expressing VWF/p.V1316M. We now report that the VWD-2B mutation VWF/p.V1316M which binds spontaneously to its receptor GPIbα does not induce apoptosis. In 2 unrelated patients (P1 and P2) exhibiting different VWF plasma levels (70% and 36%, respectively, compared with normal pooled human plasma given as 100%), inner transmembrane depolarization of mitochondria, characteristic of apoptotic events was undetectable in platelets, whether washed or in whole blood. No or a moderate phosphatidyl serine (PS) exposure as measured by annexin-V staining was observed for P1 and P2, respectively. Expression of pro-apoptotic proteins Bak and Bax, and caspase-3 activity were similar to control platelets. In the VWD-2B mouse model expressing high levels of mVWF/p.V1316M (423%), similar to what is found in inflammatory pathologies, no significant difference was observed between mice expressing mVWF/WT and mVWF/p.V1316M. These results strongly argue against apoptosis as a mechanism for the thrombocytopenia of severe VWD-2B exhibiting the VWF/p.V1316M mutation.     

Increase in Red Blood Cell-Nitric Oxide Synthase Dependent Nitric Oxide Production during Red Blood Cell Aging in Health and Disease: A Study on Age Dependent Changes of Rheologic and Enzymatic Properties in Red Blood Cells

Aim

To investigate RBC-NOS dependent NO signaling during in vivo RBC aging in health and disease.

Method

RBC from fifteen healthy volunteers (HC) and four patients with type 2 diabetes mellitus (DM) were separated in seven subpopulations by Percoll density gradient centrifugation.

Results

The proportion of old RBC was significantly higher in DM compared to HC. In both groups, in vivo aging was marked by changes in RBC shape and decreased cell volume. RBC nitrite, as marker for NO, was higher in DM and increased in both HC and DM during aging. RBC deformability was lower in DM and significantly decreased in old compared to young RBC in both HC and DM. RBC-NOS Serine¹¹⁷⁷ phosphorylation, indicating enzyme activation, increased during aging in both HC and DM. Arginase I activity remained unchanged during aging in HC. In DM, arginase I activity was significantly higher in young RBC compared to HC but decreased during aging. In HC, concentration of L-arginine, the substrate of RBC-NOS and arginase I, significantly dropped from young to old RBC. In DM, L-arginine concentration was significantly higher in young RBC compared to HC and significantly decreased during aging. In blood from healthy subjects, RBC-NOS activation was additionally inhibited by N⁵-(1-iminoethyl)-L-Ornithine dihydrochloride which decreased RBC nitrite, and impaired RBC deformability of all but the oldest RBC subpopulation.

Conclusion

This study first-time showed highest RBC-NOS activation and NO production in old RBC, possibly to counteract the negative impact of cell shrinkage on RBC deformability. This was even more pronounced in DM. It is further suggested that highly produced NO only insufficiently affects cell function of old RBC maybe because of isolated RBC-NOS in old RBC thus decreasing NO bioavailability. Thus, increasing NO availability may improve RBC function and may extend cell life span in old RBC.     

Loss of SLC38A5 and FTSJ1 at Xp11.23 in three brothers with non-syndromic mental retardation due to a microdeletion in an unstable genomic region

Using high resolution X chromosome array-CGH we identified an interstitial microdeletion at Xp11.23 in three brothers with moderate to severe mental retardation (MR) without dysmorphic features. The extent of the deletion was subsequently delineated to about 50 kb by regular PCR and included only the SLC38A5 and FTSJ1 genes. The loss of the FTSJ1 MR gene in males is expected to result in the observed phenotype but the contribution of the deletion of the solute carrier SLC38A5 gene is less clear. Their mother also carries the deletion and completely inactivates the aberrant X chromosome. Interestingly, the distal breakpoint is situated within a 200 kb SSX repeat region that appears to stimulate recombination since subtle copy number changes often occur at this location and it is frequently involved in translocations in tumours. Since this apparent SSX unstable structure is flanked proximally by FTSJ1 and PQBP1, subtle deletions or duplications at this location would be expected to cause MR, as in our family. So far, we have screened a cohort of 300 patients but did not find additional aberrations at the FTSJ1 locus indicating that the frequency is likely to be low.     

Large-conductance calcium-activated potassium channel activity is absent in human and mouse neutrophils and is not required for innate immunity

Large-conductance Ca²⁺-activated K⁺ (BK) channels are reported to be essential for NADPH oxidase-dependent microbial killing and innate immunity in leukocytes. Using human peripheral blood and mouse bone marrow neutrophils, pharmacological targeting, and BK channel gene-deficient (BK^–/–) mice, we stimulated NADPH oxidase activity with 12-O-tetradecanoylphorbol-13-acetate (PMA) and performed patch-clamp recordings on isolated neutrophils. Although PMA stimulated NADPH oxidase activity as assessed by O₂^– and H₂O₂ production, our patch-clamp experiments failed to show PMA-activated BK channel currents in neutrophils. In our studies, PMA induced slowly activating currents, which were insensitive to the BK channel inhibitor iberiotoxin. Instead, the currents were blocked by Zn²⁺, which indicates activation of proton channel currents. BK channels are gated by elevated intracellular Ca²⁺ and membrane depolarization. We did not observe BK channel currents, even during extreme depolarization to +140 mV and after elevation of intracellular Ca²⁺ by N-formyl-L-methionyl-L-leucyl-phenylalanine. As a control, we examined BK channel currents in cerebral and tibial artery smooth muscle cells, which showed characteristic BK channel current pharmacology. Iberiotoxin did not block killing of Staphylococcus aureus or Candida albicans. Moreover, we addressed the role of BK channels in a systemic S. aureus and Yersinia enterocolitica mouse infection model. After 3 and 5 days of infection, we found no differences in the number of bacteria in spleen and kidney between BK^–/– and BK^+/+ mice. In conclusion, our experiments failed to identify functional BK channels in neutrophils. We therefore conclude that BK channels are not essential for innate immunity. killing assay; reactive oxygen species; BK-deficient mice; mice infection     

Social,contextual, and individual factors affecting the occurrence and acoustic structure of drumming bouts in wild chimpanzees (Pan troglodytes)

The production of structured and repetitive sounds by striking objects is a behavior found not only in humans, but also in a variety of animal species, including chimpanzees (Pan troglodytes). In this study we examined individual and social factors that may influence the frequency with which individuals engage in drumming behavior when producing long distance pant hoot vocalizations, and analyzed the temporal structure of those drumming bouts. Male chimpanzees from Budongo Forest, Uganda, drummed significantly more frequently during travel than feeding or resting and older individuals were significantly more likely to produce drumming bouts than younger ones. In contrast, we found no evidence that the presence of estrus females, high ranking males and preferred social partners in the caller's vicinty had an effect on the frequency with which an individual accompanied their pant hoot vocalization with drumming. Through acoustic analyses, we demonstrated that drumming sequences produced with pant hoots may have contained information on individual identity and that qualitatively, there was individual variation in the complexity of the temporal patterns produced. We conclude that drumming patterns may act as individually distinctive long‐distance signals that, together with pant hoot vocalizations, function to coordinate the movement and spacing of dispersed individuals within a community, rather than as signals to group members in the immediate audience. Am J Phys Anthropol 156:125–134, 2015 © 2014 Wiley Periodicals, Inc.     

Effects of multidisciplinary integrated care on quality of care in residential care facilities for elderly people: a cluster randomized trial

Background:

Sophisticated approaches are needed to improve the quality of care for elderly people living in residential care facilities. We determined the effects of multidisciplinary integrated care on the quality of care and quality of life for elderly people in residential care facilities.

Methods:

We performed a cluster randomized controlled trial involving 10 residential care facilities in the Netherlands that included 340 participating residents with physical or cognitive disabilities. Five of the facilities applied multidisciplinary integrated care, and five provided usual care. The intervention, inspired by the disease management model, consisted of a geriatric assessment of functional health every three months. The assessment included use of the Long-term Care Facility version of the Resident Assessment Instrument by trained nurse-assistants to guide the design of an individualized care plan; discussion of outcomes and care priorities with the family physician, the resident and his or her family; and monthly multidisciplinary meetings with the nurse-assistant, family physician, psychologist and geriatrician to discuss residents with complex needs. The primary outcome was the sum score of 32 risk-adjusted quality-of-care indicators.

Results:

Compared with the facilities that provided usual care, the intervention facilities had a significantly higher sum score of the 32 quality-of-care indicators (mean difference − 6.7, p = 0.009; a medium effect size of 0.72). They also had significantly higher scores for 11 of the 32 indicators of good care in the areas of communication, delirium, behaviour, continence, pain and use of antipsychotic agents.

Interpretation:

Multidisciplinary integrated care resulted in improved quality of care for elderly people in residential care facilities compared with usual care.

Trial registration:

www.controlled-trials.com trial register no. ISRCTN11076857.The quality of care provided in residential care facilities is under pressure worldwide.¹ Facilities are frequently understaffed, and the complexity of care needed by residents increases while expertise of staff does not necessarily keep pace.^2,3 Although most care organizations want to innovate and improve quality of care, many lack expertise or financial resources needed to do so.^4,5 Family physicians are responsible for medical care in residential care facilities in the Netherlands. However, they do not regard themselves as suited for systematic management of chronic diseases and disabilities associated with frail health.⁶About 10% of elderly people aged 75 or older in the Netherlands live in residential care facilities.^7,8 These facilities were established to offer sheltered living for elderly people who are disabled but still relatively healthy. Because of the growing elderly population, the characteristics of elderly people living in residential care facilities have become more comparable to those of people in nursing homes, who need complex care. Residential care facilities in the Netherlands are comparable to residential care facilities in Canada, are publicly funded and are subject to government inspection and approval. Over 70% of the residents need professional care, such as assistance with activities of daily living, nursing care (e.g., medication, wound care) and housekeeping. They have multiple chronic diseases and associated disabilities.^9–12Effective interventions for chronic illnesses generally rely on a multidisciplinary team approach. The elements of this approach include structured geriatric assessment, protocol-based regulation of medications, support for self-reliance and intensive follow-up. The closely related disease management model comprises coordination of care, steering of the care process and patient empowerment.¹³ This model is strongly recommended by Bodenheimer and colleagues to improve the health and quality of life of chronically ill patients.¹⁴ However, no studies have as yet been undertaken to evaluate the effects of disease management on functional health and quality of care for elderly people in residential care facilities who have physical or cognitive disabilities.We developed an approach to multidisciplinary integrated care inspired by the disease management model. The objective of our study was to determine the effects of multidisciplinary integrated care on quality of care and quality of life for elderly people in residential care facilities.