Hibernating astronauts-science or fiction?

For long-duration manned space missions to Mars and beyond, reduction of astronaut metabolism by torpor, the metabolic state during hibernation of animals, would be a game changer: Water and food intake could be reduced by up to 75% and thus reducing payload of the spacecraft. Metabolic rate reduction in natural torpor is linked to profound changes in biochemical processes, i.e., shift from glycolysis to lipolysis and ketone utilization, intensive but reversible alterations in organs like the brain and kidney, and in heart rate control via Ca2+. This state would prevent degenerative processes due to organ disuse and increase resistance against radiation defects. Neuro-endocrine factors have been identified as main targets to induce torpor although the exact mechanisms are not known yet. The widespread occurrence of torpor in mammals and examples of human hypometabolic states support the idea of human torpor and its beneficial applications in medicine and space exploration.

How confident are physicians in deprescribing for the elderly and what barriers prevent deprescribing?

WHAT IS KNOWN AND OBJECTIVE: Deprescribing is the process of discontinuing or reducing the dosage of medications that are no longer appropriate or aligned with goals of care, which is paramount in elderly patients with multiple comorbidities and polypharmacy. The objective of this study was to assess the perceptions of primary care physicians on deprescribing for elderly patients and potential barriers to deprescribing that physicians experience in the Local Health Authority (LHA) of Parma, Emilia-Romagna, Italy. METHODS: One hundred and sixty physicians (57% of the total number of primary care physicians in Parma) attended an educational session related to deprescribing and were asked to anonymously complete a paper survey. Participants were asked to assess their level of agreement on nine questions about their perception of deprescribing and potential factors affecting the deprescribing process using a seven-point Likert-type scale. A correlation coefficient was calculated to assess the association between physicians' confidence in deprescribing and attitudes or barriers associated with deprescribing. RESULTS AND DISCUSSION: Many physicians (72%) reported general confidence in their ability to deprescribe. Most respondents (78%) reported they were comfortable deprescribing preventive medications, yet only half (53%) were comfortable deprescribing guideline-recommended therapies. Lack of evidence on discontinuing preventive medicines and concern about withdrawal side effects were reported to impede deprescribing by more than one-third of physicians. When medications were initially prescribed by another physician, 40% of physicians reported hesitance in deprescribing them. About half of physicians (45%) did not feel comfortable deprescribing when patients/caregivers believed that continuation of the medication was needed. Lack of time and difficulty engaging patients/caregivers in the deprescribing process were cited as barriers by about one in four physicians. There was no strong correlation between physicians' confidence and attitudes or barriers associated with deprescribing. WHAT IS NEW AND CONCLUSION: The study results show that physicians believe they are generally comfortable with deprescribing, although there are still several factors that hamper their ability to engage in the process. An improved understanding of physicians' views on deprescribing may help guide further research, and policies to help patients remain healthy while streamlining their medication regimen.

[Acute Kidney Failure Due to Urachal Cyst?] / Akutes Nierenversagen bei Urachuszyste?

A 34-year-old para V woman was referred to our centre at 35+1 weeks of gestation for an assumed fetal malformation with prenatal renal impairment and anhydramnios. Prenatal ultrasound demonstrated unilateral renal agenesis; the bladder was not detectable. The baby was born by caesarian section at 36+2 weeks of gestation because of placental insufficiency. Postnatal adaptation was uneventful, but the newborn presented external stigmas of trisomy 21 and progressive renal impairment with anuria. Nevertheless, the postnatal ultrasound showed two enlarged kidneys in loco typico with impaired perfusion but without signs of malformations. In the lower abdomen, a rosette-shaped structure of unknown origin was noted. Its origin could not be cleared by imaging including voiding cystourethrography and colon contrast radiography. Explorative laparotomy identified the structure as a persistent urachal cyst with secondary obstruction of the upper urinary tract. After removal of the urachus with reconstruction of the bladder dome, renal function recovered completely while urine was drained continuously via suprapubic catheter. A voiding cystourethrogram 3 weeks later showed a posterior urethral valve as an additional unexpected diagnosis. The valve was slit at the age of 6 months without complications, the renal function remained stable in the further course. In retrospect, the main cause for the renal failure remains unclear. It appears to be the obstruction due to the space-consuming character of the urachal cyst, especially because the megacystis typically associated with urethral valve was not viewable. Alternatively, the additional proximal stenosis may have only masked the typical findings of PUV.

Prospective validation study of transorbital Doppler ultrasound imaging for the detection of transient cerebral microemboli.

BACKGROUND: Transient cerebral microemboli are independent biomarkers of early risk of ischaemic stroke in acute carotid syndromes. Transcranial Doppler imaging (TCD) through the temporal bone is the standard method for detection of cerebral microemboli, but an acoustic temporal bone window for TCD is not available in around one in seven patients. Transorbital Doppler imaging (TOD) has been used when TCD is not possible. The aim of this study was to validate the use of TOD against TCD for detecting cerebral microemboli. METHODS: The study included patients undergoing elective carotid endarterectomy; all had confirmed temporal and orbital acoustic windows. Subjects gave written informed consent to postoperative TCD and TOD monitoring, which was performed simultaneously for 30 min by two vascular scientists. RESULTS: The study included 100 patients (mean(s.e.m.) age 72(1) years; 65 men). Microemboli were detected by one or both methods in 40·0 per cent of patients: by TOD and TCD in 24 patients, by TOD alone in ten and by TCD alone in six. For detecting microemboli, TOD had a sensitivity of 80·0 per cent, specificity of 86·1 per cent, positive predictive value of 71·6 per cent and negative predictive value of 91·2 per cent. Bland-Altman analysis revealed no significant bias (bias 0·11 (95 per cent c.i. -0·52 to 0·74) microemboli; P = 0·810) with upper and lower limits of agreement of +6 and -6 microemboli. CONCLUSION: TOD appears a valid alternative to TCD for detecting microembolic signals in patients with no suitable temporal acoustic window.

FACS-sorted particles reduce the data variance in optical tweezers-assisted dynamic force spectroscopy measurements.

By combining optical tweezers-assisted dynamic force spectroscopy experiments with fluorescence activated cell sorting (FACS), we demonstrate a new approach to reducing the data variance in measuring receptor-ligand interactions on a single molecule level by ensuring similar coating densities. Therefore, the carboxyfluorescein-labelled monophosphorylated peptide tau226-240[pThr231] is anchored on melamine resin beads and these beads are sorted by FACS to achieve a homogeneous surface coverage. To quantify the impact of the fluorescence dye on the bond parameters between the phosphorylated peptide and the corresponding phosphorylation specific anti-human tau monoclonal antibody HPT-104, we perform dynamic force spectroscopy and compare the results to data using unsorted beads covered with the non-fluorescence peptide analogue. Finally, we demonstrate that the data variance of the relative binding frequency is significantly decreased by a factor of 3.4 using pre-sorted colloids with a homogeneous ligand coating compared to using unsorted colloids.

Psychosocial adjustment in women with premature menopause: a cross-sectional survey.

OBJECTIVES: Previous studies have found that women with premature menopause often report fertility problems, menopause symptoms and negative experiences of medical services. This study aims to measure the prevalence of these problems and explore whether they have negative impacts on psychosocial adjustment (symptom experience and quality of life). METHODS: A cross-sectional survey was mailed to women who had been diagnosed with premature menopause, recruited from hospital clinics in West London and from a patient support website (the Daisy Network). The survey measured participant characteristics, fertility problems, hot flushes and night sweats, experience of diagnosis, patient satisfaction with medical services, the Women's Health Questionnaire and the General Health Survey SF-36. Responses were described and multiple linear regressions were used to explore predictors of psychosocial functioning and quality of life. RESULTS: A total of 136 women were included in the analysis. Psychosocial functioning was relatively poor compared to typical aged menopausal women. Fertility concerns were prevalent (reported by 71% of the sample), 35% reported experiencing hot flushes and/or nights sweats, and, on average, women were neither satisfied nor unsatisfied with medical services (mean =3.00, standard deviation =0.98). Age, experiencing hot flushes and/or night sweats and patient satisfaction predicted psychosocial functioning, but only explained a small amount of the variance (3-11%). CONCLUSIONS: Women with premature menopause would benefit from interventions that improve psychosocial functioning and quality of life, including improving patient experience and effective treatment of menopause symptoms. Assumptions about treatment needs could not reliably be made based on patient characteristics, suggesting that individually tailored treatments may be more effective.

[Long-term survival of preterm neonates]. / Langzeitüberleben von Frühgeborenen.

In view of the increased survival rate of very preterm neonates, several longitudinal studies were done to assess the quality of life of the survivors. They revealed a fairly constant rate of 25-30% of sensorineural and/or motor impairment. Beyond those "major handicaps," further problems may arise in every single period of life, which, albeit less severe, add to the burden of prematurity. These include growth retardation and cognitive delay in the school age, affected psychosocial behavior during adolescence, and the "metabolic syndrome" of formerly malnourished fetuses in adulthood. Thus, the epidemiologic studies not only confirmed the role of regionalization in the quality of perinatology, but also supported a more farsighted approach to the sequelae of prematurity. Like in young adults who grew up with congenital heart defects, also in former preterm neonates, appropriate medical care has to be provided for an increasing number of long-term survivors. Moreover, the life-long effects of metabolic imprinting in growth-retarded fetuses underline the primary-preventive role of perinatal medicine, extending far beyond the "baby" stage of human development.

The silent grief: psychosocial aspects of premature ovarian failure.

OBJECTIVE: Premature ovarian failure in women under 40 years is uncommon, but not rare (1-3%), with up to 2.5% of adolescents affected. This study aims to investigate women's experiences of diagnosis, perception of cause, treatment, main concerns, long-term consequences and impact on self-esteem, sexual functioning and health-related quality of life. DESIGN: This was a cross-sectional study, using a single-group design, including quantitative and qualitative measures. Two hundred and twenty questionnaires were sent to women recruited from the databases of two London specialist multidisciplinary clinics and from a national premature menopause self-help website. The questionnaire included the Rosenberg's Self Esteem Questionnaire, SF 36 Health Survey (quality of life), the Sexual Personal Experiences Questionnaire and the Young Menopause Assessment questionnaire, following a pilot to assess acceptability and feasibility. RESULTS: The response rate was 62% in women aged 19-61 years. The majority of women felt that they had been offered inadequate information; 53% did not know the reason for their condition, 30% obtained a diagnosis within 6 months, and the diagnosis for 22% took up to 3 years. Fertility and bone health were main concerns, followed by emotional well-being. Libido and vaginal dryness were perceived as the main long-term effects by 79% of the women. The internet was the main source of information. The majority requested more information targeted to their age group and 49% requested psychological support, citing a negative impact on their self-esteem. CONCLUSIONS: This study examined women's perceptions of premature ovarian failure, its impact and the services they received. The results can be used to inform service reconfiguration and improvement.

The relationship between antigen concentration, antigen internalization, and antigenic complexes: modeling insights into antigen processing and presentation.

Native antigen is processed and subsequently presented on the surface of antigen-presenting cells, an important step in the elicitation of an immune response. The early events of antigen processing and presentation include: ingestion of a native antigen, intracellular degradation to expose an antigenic peptide fragment, binding of this fragment with an MHC class II molecule, and display of this newly formed complex on the cell surface. Through the development of a mathematical model, a set of mathematical equations which describes the time-dependent appearance, disappearance, and movement of individual molecules, quantitative insight can be gained into the pathways and rate-limiting steps of antigen presentation. The credibility of the model has been verified by comparison to literature data. For example, it has been shown experimentally that macrophages require 60 min for effective antigen presentation, whereas B cells require 6-8 h. The mathematical model predicts these presentation times and identifies the difference in the cell's respective pinocytic rates and sizes as important parameters. B cells capture antigen in their environment through nonspecific fluid-phase pinocytosis as well as by binding antigen to their surface immunoglobulin, allowing receptor-mediated uptake. Uptake of antigen via receptor-mediated endocytosis has been reported to require 1,000-fold less antigen than uptake via nonspecific pinocytosis. The mathematical model clearly predicts this decrease in concentration. The model also makes quantitative predictions for the number of MHC class II-antigen complexes needed to produce T cell stimulation.

Resistance of MHC class I-deficient mice to experimental systemic lupus erythematosus.

Experimental systemic lupus erythematosus (SLE) can be induced in mice by immunization with a human monoclonal antibody to DNA that bears a common idiotype (16/6Id). These mice generate antibodies to 16/6Id, antibodies to DNA, and antibodies directed against nuclear antigens. Subsequently, manifestations of SLE develop, including leukopenia, proteinuria, and immune complex deposits in the kidney. In contrast, after immunization with 16/6Id, mice lacking major histocompatibility complex (MHC) class I molecules generated antibodies to 16/6Id but did not generate antibodies to DNA or to nuclear antigen. Furthermore, they did not develop any of the above clinical manifestations. These results reveal an unexpected function of MHC class I in the induction of autoimmune SLE.

The roles of the subunits in the function of the calcium channel.

Dihydropyridine-sensitive voltage-dependent L-type calcium channels are critical to excitation-secretion and excitation-contraction coupling. The channel molecule is a complex of the main, pore-forming subunit alpha 1 and four additional subunits: alpha 2, delta, beta, and gamma (alpha 2 and delta are encoded by a single messenger RNA). The alpha 1 subunit messenger RNA alone directs expression of functional calcium channels in Xenopus oocytes, and coexpression of the alpha 2/delta and beta subunits enhances the amplitude of the current. The alpha 2, delta, and gamma subunits also have pronounced effects on its macroscopic characteristics, such as kinetics, voltage dependence of activation and inactivation, and enhancement by a dihydropyridine agonist. In some cases, specific modulatory functions can be assigned to individual subunits, whereas in other cases the different subunits appear to act in concert to modulate the properties of the channel.

Repression of MHC class I gene promoter activity by two-exon Tat of HIV.

Major histocompatibility complex (MHC) class I molecules are the major receptors for viral peptides and serve as targets for specific cytotoxic T lymphocytes. Human immunodeficiency virus-type 1 (HIV-1) specifically decreased activity of an MHC class I gene promoter up to 12-fold. Repression was effected by the HIV-1 Tat protein derived from a spliced viral transcript (two-exon Tat). These studies define an activity for two-exon Tat distinct from that of one-exon Tat and suggest a mechanism whereby HIV-1-infected cells might be able to avoid immune surveillance, allowing the virus to persist in the infected host.