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Early school times clash with the late sleep of adolescents, leading to wide-spread sleep restriction in students. Evidence suggests that delaying school starts is beneficial for sleep and recent studies investigated whether this also translates into improved academic achievement. We thus conducted a systematic review of the literature on school start times, grades and test scores in middle and high-school students. We reviewed 21 studies following the PRISMA guidelines and assessed the evidence quality using a pre-defined risk of bias tool. Nine studies reported no association of later starts with achievement, while the remaining reported mixed (5), positive (5), negative (1) or unclear (1) results. Considering the heterogeneity in academic outcomes, study types, amount of delay and exposure, and the substantial risk of bias, a meta-analysis was not warranted - instead we provide grouped reviews and discussion. Overall, no generalisable improvements in achievement with later starts emerge beyond the level of single studies. This does not necessarily preclude improvements in students' learning but highlights shortcomings of the literature and the challenges of using grades and test scores to operationalise academic achievement. Given other previously reported positive outcomes, our results suggest that schools could start later while achievement is likely maintained.

This work presents an approach to the macroscopic field-controlled mechanics of magnetoactive elastomers of mixed content, which are a special type of smart materials made of an elastic composite and a combination of two essentially different ferromagnetic fillers. High-coercive particles of NdFeB-alloy powder for the magnetically hard (MH) filler and carbonyl iron powder particles with nearly zero coercivity for the magnetically soft (MS) filler are usually used. The MH particles are tens-of-micron in size and impart to the elastomer a remanent magnetisation, whereas due to the MS particles of several microns in size, the elastomer acquires a high magnetic susceptibility. Since large MH particles once magnetised in a strong field possess their own fields to which the MS particles are susceptible, the overall elastomer magnetisation as well as its mechanical response greatly depends on the relative concentration of both fillers. This work particularly studies the bending deformation of horizontally fixed magnetoactive cantilevers with the permanent magnetisation along the length axis under the action of gravity and a vertically applied uniform magnetic field. The cantilevers of the same geometry and fixed NdFeB content but different carbonyl iron concentration are considered. The magnetomechanical model is developed based on the finite-strain theory assuming the plane-stress approximation of the two-dimensional cantilever of infinite width. The magnetic energy comprises two magnetic terms, one of which is qualitatively linear and the other one is quadratic in the applied field strength. The numerically calculated field-programmed equilibrium bending shapes of the cantilevers are compared with the experimentally observed shapes. The model provides good agreement with the experiment up to moderate concentrations of the MS filler, when the coefficients of customary interpolation formulas for the concentration dependencies of elastic modulus and magnetic susceptibility are properly adjusted.

Early school times fundamentally clash with the late sleep of teenagers. This mismatch results in chronic sleep deprivation, which poses acute and long-term health risks and impairs students’ learning. Despite conclusive evidence that delaying school times has immediate benefits for sleep, the long-term effects on sleep are unresolved due to a shortage of longitudinal data. Here, we studied whether a flexible school start system, with the daily choice of an 8AM or 08:50AM-start, allowed secondary school students to improve their sleep and psychological functioning in a longitudinal pre-post design over exactly 1 year. Based on 2 waves, each with 6-9 weeks of daily sleep diary, we found that students maintained their 1-hour-sleep gain on days with later starts, both longitudinally (n=28) and cross-sectionally (n=79). This sleep gain was independent of chronotype and frequency of later starts but differed between genders. Girls were more successful in keeping early sleep onsets despite later sleep offsets, whereas boys delayed their onsets and thus had reduced sleep gains after 1 year. Students also reported psychological benefits (n=93), increased sleep quality and reduced alarm-driven waking on later school days. Despite these benefits on later schooldays, overall sleep duration was not extended in the flexible system. This was likely due to the persistently low uptake of the late-start option. If uptake can be further promoted, the flexible system is an appealing alternative to a fixed delay of school starts owing to possible circadian advantages (speculatively through prevention of phase-delays) and psychological mechanisms (e.g. sense of control).Significance statementTeenage sleep becomes progressively later during adolescence but school starts do not accommodate this shifted sleep window. This mismatch results in chronic sleep deprivation in teenagers worldwide, which is a pervasive public health concern. Delaying school starts could counteract this misalignment if students keep sleep onsets stable. However, few studies have investigated long-term effects of delayed starts on sleep. We observed here that students slept persistently longer and better when school started later in a flexible start system. Girls were especially successful in keeping stable onsets. Students also benefitted psychologically and liked the flexible system despite only a modest uptake of later starts. The flexible system is an interesting alternative to a fixed delay and should receive more scientific attention.

School start times have been at the centre of many scientific and political debates given the accumulating evidence that bell times are generally too early, and thus lead to an epidemic of sleep restriction in the student population. Recent media attention has conveyed the message that later school starts not only improve sleep but also result in better academic achievement. Several studies have been recently published on this topic requiring a comprehensive review of the results to clarify the relationship between later school start times and academic achievement to inform the general public and policy makers.To this end, we conducted a systematic review of the current literature on school starting times and academic achievement in middle and high school students, considering grades and standardised test scores as achievement measures. We followed the PRISMA guidelines for searching, including, and reporting relevant literature and identified 21 studies for detailed analysis. Evidence quality of included studies was assessed with a pre-defined risk of bias assessment using modified items from the GRADE scheme and ROBINS-I tool.About half of the reviewed studies reported no (positive or negative) effect of delaying school times on grades and test scores, while the other half reported either mixed or positive results. Given the strong heterogeneity of included studies, we grouped them according to various characteristics, such as academic outcomes, dose of delay, evidence quality, or study design to identify potential hidden effects. Despite this, we could not identify any generalisable effect beyond single studies as to whether delaying school times has clear beneficial effects on academic performance.Given that grades and scores determine future career trajectories and predict future success, the question whether school start times contribute to academic achievement is of great interest for the general public and needs to be further clarified. Mechanistically, it is very likely that improved sleep leads to or mediates improved cognitive performance and learning, but definitive conclusions on whether this also translates into better grades and scores across all students requires better evidence at this stage. Importantly, this does not preclude other positive outcomes of later start times such as improved sleep (quality), motivation or learning but draws attention on current gaps and shortcomings. To this end, we also highlight critical methodological aspects and provide suggestions to increase the evidence-level and to guide the direction of research in future studies.

Sleep deprivation in teenage students is pervasive and a public health concern, but evidence is accumulating that delaying school start times may be an effective countermeasure. Most studies so far assessed static changes in schools start time, using cross-sectional comparisons and one-off sleep measures. When a high school in Germany introduced flexible start times for their senior students—allowing them to choose daily between an 8 am or 9 am start (≥08:50)—we monitored students’ sleep longitudinally using subjective and objective measures. Students (10–12th grade, 14–19 y) were followed 3 weeks prior and 6 weeks into the flexible system via daily sleep diaries (n = 65) and a subcohort via continuous wrist-actimetry (n = 37). Satisfaction and perceived cognitive outcomes were surveyed at study end. Comparisons between 8 am and ≥9 am-starts within the flexible system demonstrated that students slept 1.1 h longer when starting school later—independent of gender, grade, chronotype, and frequency of later starts; sleep offsets were delayed but, importantly, onsets remained unchanged. Sleep quality was increased and alarm-driven waking reduced. However, overall sleep duration in the flexible system was not extended compared to baseline—likely because students did not start later frequently enough. Nonetheless, students were highly satisfied with the flexible system and reported cognitive and sleep improvements. Therefore, flexible systems may present a viable alternative for implementing later school starts to improve teenage sleep if students can be encouraged to use the late-option frequently enough. Flexibility may increase acceptance of school start changes and speculatively even prevent delays in sleep onsets through occasional early starts.

Cramp-fasciculation syndrome (CFS) is a rare muscle hyperexcitability syndrome that presents with muscle cramps, fasciculations, and stiffness, as well as pain, fatigue, anxiety, hyperreflexia, and paresthesias. Although familial cases have been reported, a genetic etiology has not yet been identified. We performed whole-exome sequencing followed by validation and cosegregation analyses on a father-son pair with CFS. Both subjects manifested other hypersensitivity-hyperexcitability symptoms, including asthma, gastroesophageal reflux, migraine, restless legs syndrome, tremor, cold hyperalgesia, and cardiac conduction defects. Most symptoms improved with carbamazepine, consistent with an underlying cation channelopathy. We identified a variant in the transient receptor potential ankyrin A1 channel (TRPA1) gene that selectively cosegregated with CFS and the other hypersensitivity-hyperexcitability symptoms. This variant (c.2755C>T) resulted in a premature stop codon at amino acid 919 (p.Arg919*) in the outer pore of the channel. TRPA1 is a widely distributed, promiscuous plasmalemmal cation channel that is strongly implicated in the pathophysiology of the specific hypersensitivity-hyperexcitability symptoms observed in these subjects. Thus, we have identified a novel TRPA1 variant that is associated with CFS as part of a generalized hypersensitivity-hyperexcitability disorder. These findings clarify the diverse functional roles of TRPA1, and underscore the importance of this channel as a potential therapeutic target.

Introduction: In Parkinson’s disease (PD), postural imbalance and gait disorders (PIGD) are predictors of decreased quality of life and survival. PIGD often become unresponsive to pharmacological treatments and are commonly associated with cognitive dysfunction. Physical therapy (PT) training and falls prevention education are considered effective treatments; however, improvements are generally short-lived and only partially maintained. In this population, cognitive dysfunction hampering the consolidation of new motor skills (motor learning) is one principal reason. Transcranial magnetic stimulation (TMS) is an emerging tool for neuro-rehabilitation and growing evidence supports its potential to improve motor learning. Prompted by a shared location between our TMS lab and the PT rehabilitation center, we aimed to test whether adjuvant repetitive TMS combined with PT for PIGD is a feasible neuro-rehabilitation paradigm in patients with PD. Methods: Double blind, randomized, sham-controlled, pilot trial to evaluate the feasibility of recruitment, randomization, retention, assessment procedures and implementation of adjuvant TMS paired back-toback with PT in PD patients with PIGD. Result: 41 paired sessions were completed with 100% adherence. All sessions were tolerated. There were no severe adverse events. One subject withdrew consent. Blinding of study was deemed adequate. The average time between PT and TMS administration was 13.9 (SD 7.3) minutes. After completion of the 5th enrolled subject, the study was early terminated due to relocation of the PD center away from the PT facility. Clinical outcome mean values improved at follow up; however, the small sample size prevented further analysis of efficacy. Conclusions: When the TMS device is located in the proximity of a rehabilitation setting, adjuvant TMS appears to be feasible, safe, and well tolerated in PD. The efficacy of this modality of neuro-rehabilitation and its generalizability remain to be determined.

The behavior of a pair of magnetizable spherical particles embedded in a viscoelastic elastomer is studied for the case, where an AC magnetic field is applied along the center-to-center line of the particles. This system is considered as a small-scale (mesoscopic) structure element of a magnetorheological elastomer. Under a quasistatic cycle of the field, the system in question is prone to hysteretic behavior. Namely, the particles initially positioned well apart, at some finite field strength, fall onto one another (cluster) and reside in this state until the field decreases well below the value at which the cluster has been formed. Under dynamic cycling of the field, the viscous friction interferes with the particle displacement process and impedes the occurrence of the magnetodeformational hysteresis of the element. Starting from small-amplitude overdamped oscillations and enhancing the role of magnetic forces over viscous ones, we show how the anharmonicity of the system grows while it approaches the transition threshold, above which the dynamics of the element includes the cluster state. The dynamic hysteresis of magnetization that accompanies the mechanical oscillations of the particles is presented as well.

Patients with osteoarthritis experience pain when moving or, sometimes, touching the affected joints. Raouf et al. identified proteins that bound to a toxin that inhibits mechanically induced pain, including the membrane-binding protein annexin A6. Mice lacking annexin A6 were more sensitive to mechanically induced pain, whereas overexpression of annexin A6 in sensory neurons reduced pain in a mouse model of osteoarthritis. These results suggest that strategies that increase the abundance of annexin A6 could alleviate the chronic pain of osteoarthritis.Mechanically activated, slowly adapting currents in sensory neurons have been linked to noxious mechanosensation. The conotoxin NMB-1 (noxious mechanosensation blocker-1) blocks such currents and inhibits mechanical pain. Using a biotinylated form of NMB-1 in mass spectrometry analysis, we identified 67 binding proteins in sensory neurons and a sensory neuron–derived cell line, of which the top candidate was annexin A6, a membrane-associated calcium-binding protein. Annexin A6–deficient mice showed increased sensitivity to mechanical stimuli. Sensory neurons from these mice showed increased activity of the cation channel Piezo2, which mediates a rapidly adapting mechano-gated current linked to proprioception and touch, and a decrease in mechanically activated, slowly adapting currents. Conversely, overexpression of annexin A6 in sensory neurons inhibited rapidly adapting currents that were partially mediated by Piezo2. Furthermore, overexpression of annexin A6 in sensory neurons attenuated mechanical pain in a mouse model of osteoarthritis, a disease in which mechanically evoked pain is particularly problematic. These data suggest that annexin A6 can be exploited to inhibit chronic mechanical pain.

Sensory neuron mechanically-activated slowly adapting currents have been linked to noxious mechanosensation. We identified a Conotoxin, Noxious Mechanosensation Blocker -1, that blocks such currents selectively and inhibits mechanical pain Using an active biotinylated form of the toxin we identified 67 binding proteins in sensory neurons and sensory neuron-derived cell lines using mass spectrometry. Annexin A6 was the most frequently identified binding protein. Annexin A6 knockout mice showed an enhanced sensitivity to mechanical stimuli. An increase in rapidly adapting currents was observed in sensory neurons alongside a decrease in slowly adapting currents. Conversely, overexpression of Annexin A6 in sensory neurons inhibited rapidly adapting currents and augmented slowly adapting currents. Furthermore, co-expression of Annexin A6 with Piezo2 led to an inhibition of Piezo-mediated rapidly adapting currents. AAV-mediated overexpression of Annexin A6 in sensory neurons attenuated mechanical pain in a mouse model of osteoarthritis. These data demonstrate a modulatory role for Annexin A6 in somatosensory mechanotransduction.

This paper investigates the protection system of a German 20kV distribution grid in terms of fault clearing times for volatile short-circuit conditions. For this purpose, an automated protection security assessment software tool is deployed. Firstly, the fault clearing times for 250 faults in two protection areas in the prevailing grid are attained for a case with no distributed generation infeed. Two subcases are investigated: In the first step, the short-circuit power of the subtransmission network is as it has been in year 2012. In the next step, the short-circuit power is reduced to 70% to depict the scheduled shutdown of several nuclear power plants in Germany. Secondly, the functionality of the same protection system is tested for DG share in the distributed system as it is assumed to be in year 2020. This forecast is merged from several studies. To overcome overloadings and to reduce losses without conventional grid expansion, meshing by closing normally open disconnectors can be suitable. This new grid topology is investigated in the same way as the other configurations. Fort the new topology, simulation results for a protection system equipped with distance protection relays are compared to a loose coupling strategy where the open loop topology is restored in case of fault.

The results of modelling the behaviour of a pair of magnetisable spherical particles embedded in a viscoelastic elastomer with Kelvin rheology are presented for the case, where an ac magnetic field is exerted along the intercenter line of the particles. This system is considered as a small-scale (mesoscopic) structure element of a magnetorheological elastomer. The system in question is known to be able for hysteretic behaviour under the quasistatic cycle of the field. The particles initially positioned well apart, at some finite field strength, fall onto one another (cluster) and dwell in this state until the field decreases well below the value at which the cluster has been formed. Under dynamic cycling of the field, the viscous friction interferes the particle displacement process and impedes occurrence of the magnetodeformational hysteresis of the element. Starting from small-amplitude overdamped oscillations and enhancing the role of magnetic forces over viscous ones, we show how the anharmonicity of the system grows while it approaches the transition threshold, above which the dynamics of the element includes the cluster state. The dynamic hysteresis of magnetisation that accompanies the mechanical oscillations of the particles is presented as well.

Several functions have been assigned to the extensive glycosylation of HIV-1 envelope glycoprotein gp120, especially immune escape mechanisms, but the intramolecular interactions between gp120 and its carbohydrate complement are not well understood. To analyse this phenomenon we established a new microwell deglycosylation assay for determining N-linked glycan accessibility after binding of gp120-specific agents. Orientation-specific exposition of gp120 in ELISA microplates was achieved by catching with either anti-C5 antibody D7324 or anti-V3 antibody NEA-9205. We found that soluble CD4 inhibited the deglycosylation of gp120 only when gp120 was caught by D7324 and not by NEA9205. In contrast, antibodies from HIV-infected individuals inhibited the deglycosylation best when gp120 was caught by NEA9205. These results demonstrated that both the CD4-binding site and the epitopes recognised by antibodies from HIV-infected individuals have N-glycans in the close vicinity. However, the difference in gp120 orientation indicates that antibodies in HIV-infected individuals, at least partly, bind to epitopes different from the CD4-binding site. Finally, we determined the structural class of the glycan of one V1 glycosylation site of prototype HIV-1 LAI gp120, which remained unsolved from previous studies, and found that it belonged to the complex type of glycans.

Cardiovascular diabetology 12, 117 (2013). doi:10.1186/1475-2840-12-117, Published by BioMed Central, London

Introduction Inflammatory stimuli are causative for insulin resistance in obesity as well as in acute inflammatory reactions. Ongoing research has identified a variety of secreted proteins that are released from immune cells and adipocytes as mediators of insulin resistance; however, knowledge about their relevance for acute inflammatory insulin resistance remains limited. In this study we aimed for a clarification of the relevance of different insulin resistance mediating factors in an acute inflammatory situation. Methods Insulin resistance was measured in a cohort of 37 non-diabetic patients undergoing cardiac surgery by assessment of insulin requirement to maintain euglycaemia and repeated measurements of an insulin glycaemic index. The kinetics of cortisol, interleukin 6 (IL6), tumour necrosis factor α (TNFα), resistin, leptin and adiponectin were assessed by repeated measurements in a period of 48 h. Results Insulin resistance increased during the observation period and peaked 22 h after the beginning of the operation. IL6 and TNFα displayed an early increase with peak concentrations at the 4-h time point. Serum levels of cortisol, resistin and leptin increased more slowly and peaked at the 22-h time point, while adiponectin declined, reaching a base at the 22-h time point. Model assessment identified cortisol as the best predictor of insulin resistance, followed by IL6, leptin and adiponectin. No additional information was gained by modelling for TNFα, resistin, catecholamine infusion rate, sex, age, body mass index (BMI), operation time or medication. Conclusions Serum cortisol levels are the best predictor for inflammatory insulin resistance followed by IL6, leptin and adiponectin. TNFα, and resistin have minor relevance as predictors of stress dependent insulin resistance.

The interaction between two particles made of an isotropic linearly polarizable magnetic material and embedded in an elastomer matrix is studied. In this case, when an external field is imposed, the magnetic attraction of the particles, contrary to point dipoles, is almost wraparound. The exact solution of the magnetic problem in the linear polarization case, although existing, is not practical; to circumvent its use, an interpolation formula is proposed. One more interpolation expression is developed for the resistance of the elastic matrix to the field-induced particle displacements. Minimization of the total energy of the pair reveals its configurational bistability in a certain field range. One of the possible equilibrium states corresponds to the particles dwelling at a distance, the other—to their collapse in a tight dimer. This mesoscopic bistability causes magnetomechanical hysteresis which has important implications for the macroscopic behavior of magnetorheological elastomers.

DNA encoding HIV-1 env is a poorly efficient B-cell immunogen and one probable explanation is that the numerous gp120 N-linked glycans gp120 may interfere with B-cell epitope presentation. The N306 glycan in gp120 shields HIV-1 from neutralizing antibodies. A DNA immunogen lacking the N306 glycosylation signal (T308A) was constructed to determine whether this glycan affected the immune response. Mice were immunized intranasally twice with DNA containing either the wild type or the mutant env. Two additional groups were primed with wild type or mutant env and boosted with rgp160 protein, containing the complete set of N-linked glycans. Immunization with DNA alone resulted in priming of B-cell clones but was not sufficient to induce a complete antibody response. Animals primed with the N306 mutant and subsequently boosted with rgp160 protein displayed higher serum IgG-binding titers to gp120 than animals primed with wild type env DNA. The manipulation of the glycosylation sites of the env DNA strongly primes antibody responses (but non-neutralizing) as well as T-cell responses to the wild type strain gp160. However, priming with mutant plasmid did not result in higher neutralization titers to wild type or T308A-mutated virus than did the wild type plasmid. With the N306 mutant DNA we thus immunized a non-neutralization epitope, but obtained strong env-binding IgG after rgp160 boosting.

GH deficiency is associated with increased cardiovascular mortality and early manifestations of atherosclerosis. Elevated serum homocyst(e)ine levels have been found to be associated with increased cardiovascular risk. The effect of GH replacement on homocyst(e)ine has not been investigated to date. We evaluated the effect of GH replacement on fasting homocyst(e)inemia in a group of men with adult-onset GH deficiency in a randomized, single blind, placebo-controlled trial. Forty men with adult-onset GH deficiency were randomized to GH or placebo for 18 months, with dose adjustments made according to serum insulin-like growth factor I (IGF-I) levels. Fasting serum homocyst(e)ine, folate, vitamin B12, and total T(3) levels were determined at baseline and 6 and 18 months. Anthropometry, IGF-I levels, insulin, and glucose were measured at 1, 3, 6, 12, and 18 months. Nutritional assessment, body composition, total T(4), thyroid hormone binding index, and free T(4) index were assessed every 6 months. Homocyst(e)ine decreased in the GH-treated group compared with that in the placebo group (net difference, -1.2 +/- 0.6 micromol/L; confidence interval, -2.4, -0.02 micromol/L; P = 0.047). Homocyst(e)ine at baseline was negatively correlated with plasma levels of folate (r = -0.41; P = 0.0087). Total T(3) increased in the GH-treated group vs. that in the placebo group (net difference, 0.17 +/- 0.046 ng/dL; confidence interval, 0.071, 0.26 nmol/L; P = 0.0012). Folate and vitamin B12 levels did not significantly change between groups. Changes in homocyst(e)ine were negatively correlated with changes in IGF-I. For each 1 nmol/L increase in IGF-I, homocyst(e)ine decreased by 0.04 +/- 0.02 micromol/L (P = 0.029). In contrast, changes in homocyst(e)ine did not correlate with changes in folate, vitamin B12, total T(3), C-reactive protein, interleukin-6, or insulin levels. This study shows that GH replacement decreases fasting homocyst(e)ine levels compared with placebo. This may be one of the mechanisms involved in the putative modulation of atherosclerosis and cardiovascular risk by GH replacement.

Data published in the past decade have demonstrated that adults who are deficient in growth hormone (GH) experience deleterious clinical consequences without treatment. In 1996, the Food and Drug Administration approved the use of GH in adults who were GH deficient as a result of hypothalamic or pituitary disease. However, there are other conditions in adults for which GH treatment has also been approved (acquired immune deficiency syndrome [AIDS]-related wasting) or for which it is being considered, such as aging, catabolic states, and cardiomyopathy. Clinical issues revolve around the rationale for treatment; the diagnostic evaluation; the effects of GH therapy on body composition, bone density, lipids, and cardiac function; and appropriate dosing and follow up. Clearly, the use of GH in adults raises reimbursement issues as well. In this article, Dr. Beverly M.K. Biller provides an overview of the rationale for the treatment of adult-onset GH deficiency and reviews its etiology and clinical features as well as reimbursement and utilization issues related to treatment. Dr. Mary Lee Vance discusses various assays and criteria used in the diagnostic evaluation of the patient with adult-onset GH deficiency. Dr. David L. Kleinberg focuses on the effects of GH therapy on body composition, bone density, lipid profiles, and cardiac function, as well as on reimbursement issues regarding body composition studies. To complete the clinical portion of this session, Dr. David M. Cook addresses dosing and follow up. To address economic implications, Dr. Terry Gordon provides the payer's perspective on the diagnosis and treatment of adult-onset GH deficiency.

Hyperprolactinemia is the most common endocrine disorder of the hypothalamic-pituitary axis. While it can occur in men, it occurs more commonly in women. The prevalence of hyperprolactinemia ranges from 0.4% in an unselected normal adult population to as high as 9-17% in women with reproductive disorders. There are many possible causes of hyperprolactinemia, falling into three general categories: physiologic, pharmacologic and pathologic. When specific treatable underlying causes have been eliminated and in cases of severe hyperprolactinemia, the most likely cause is a prolactin (PRL)-secreting pituitary adenoma. Microadenomas should be treated medically, with a dopamine agonist, if there is an indication for therapy (such as amenorrhea, infertility or bothersome galactorrhea). If there is no indication for therapy, microadenomas may be followed conservatively, as growth is uncommon. Macroadenomas may grow larger; medical therapy is recommended initially, with neurosurgical evaluation reserved for specific clinical situations, such as failure of medical therapy and evidence of mass effect despite medical therapy. In the United States, the dopamine agonists indicated for treatment of hyperprolactinemia are bromocriptine and cabergoline. Bromocriptine is usually given once or twice daily, while cabergoline has a long duration of action and is given once or twice weekly. Results of comparative studies indicate that cabergoline is clearly superior to bromocriptine in efficacy (PRL suppression, restoration of gonadal function) and tolerability.

A serum prolactin (PRL) level is obtained in response to a specific clinical presentation, including symptoms of hyperprolactinemia (such as amenorrhea and galactorrhea); serum PRL measurement may also be performed as part of an infertility evaluation. An initial level above the normal range should be followed by a repeat level from a blood sample drawn in the morning with the patient in a fasting state. The medical history and a few laboratory tests can eliminate the most common physiologic and pharmacologic causes of hyperprolactinemia, including pregnancy, primary hypothyroidism and treatment with drugs (such as neuroleptics) that reduce dopaminergic effects on the pituitary. In the absence of such causes, radiologic imaging of the sella turcica is necessary to establish whether a PRL-secreting pituitary adenoma or other lesion is present. The vast majority of patients are treated medically, with dopamine agonist drugs. Surgery is reserved for the patient with the uncommon tumor that does not respond to medical therapy or has a large cystic component or for the occasional patient who cannot tolerate dopamine agonists or who experiences pituitary apoplexy.

Prolactinomas are the most common pituitary tumors. Hyperprolactinemia is characterized by increased production of prolactin, often leading to reproductive dysfunction and galactorrhea. Prolactinomas may also cause male-factor infertility by producing hypogonadism. In addition, if large, they can produce neurologic symptoms by mass effect in the sellar area. The diagnostic evaluation first requires exclusion of other causes of hyperprolactinemia, such as pregnancy, primary hypothyroidism, numerous medications, and miscellaneous causes. The second step in the diagnostic evaluation is to perform a head scan, preferably an MRI. This is essential in order to exclude a "pseudoprolactinoma" which would require surgery. Following diagnostic evaluation, the next step is to determine whether a patient with hyperprolactinemia has an indication for therapy, such as a macroprolactinoma (tumor1 cm), hypogonadism (risk of osteoporosis), infertility, significant galactorrhea, acne, hirsutism, or headache. The treatment of choice for nearly all patients with hyperprolactinemic disorders is medical. In most cases, dopamine agonists (bromocriptine, pergolide, cabergoline) are extremely effective in lowering serum prolactin, restoring gonadal function, decreasing tumor size, and improving visual fields. The main limitation is side effects, particularly nausea or orthostatic dizziness. The newest dopamine agonist, cabergoline, can be given just once or twice a week, is more effective in normalizing prolactin and restoring menses than bromocriptine, and is significantly better tolerated. However, it is not yet recommended as first-line therapy for patients seeking fertility, because adequate safety data in pregnancy are not available. For the infrequent patient unable to tolerate, or resistant to, medical therapy, neurosurgical transsphenoidal resection may be necessary, particularly if the patient has a large lesion jeopardizing the optic chiasm. Hyperprolactinemia is a rewarding disorder to manage because patients typically respond well to medication, with restoration of menses and fertility.

GH replacement of adults with acquired GH deficiency (GHD) results in body composition changes including increases in lean mass and bone mineral density. However, the effects of long-term GH therapy on cognitive function are largely unknown, and there are conflicting data regarding quality of life. We performed a randomized, double-blind, placebo-controlled study of GH replacement in adults with GHD and measured cognition and sense of well-being using standardized psychometric tests before and after therapy. Forty men (median age 51 yr, range 24-64 yr) with a history of pituitary disease were randomized to GH therapy (starting dose, 10 +/- 0.3 micrograms/kg per day: mean treatment dose, 4 +/- 2 micrograms/kg per day) vs. placebo for 18 months, and GH doses were adjusted according to serum insulin growth factor-I levels. At baseline, the patients displayed a full-scale intelligence quotient (IQ) score nearly 1 SD above the normal mean. Mean scores on all cognitive tests fell within normal limits, and on many tests, fell above the mean. On tests of verbal learning and delayed visual memory, mean test scores fell below the mean (although within normal limits), suggestive of a relative compromise in the area of memory performance. Following 18 months of GH replacement therapy, there were no significant changes in cognitive function or quality of life. We conclude that acquired GHD in adult men is not associated with significant alterations in cognitive function as assessed by standardized tests, and chronic low-dose GH replacement therapy does not result in significant beneficial effects on cognitive function or quality of life. Although previous studies have suggested that GH replacement in adults with acquired GHD may improve quality of life, our data do not support the use of physiological GH replacement in GHD men for this indication.

Die pharmazeutische Industrie fuhrt im internationalen Raum eine seit Beginn der 90er Jahre zunehmende Diskussion um sogenannte pharmakookonomische Studien. Angeheizt nicht zuletzt auch durch wissenschaftliche Institute und Consulting-Unternehmen liegt inzwischen eine kaum noch ubersehbare Fulle von Einzelstudien und Sekundaranalysen vor.1

The acquired immunodeficiency syndrome (AIDS) wasting syndrome is a devastating complication of human immunodeficiency virus (HIV) infection characterized by progressive weight loss and severe inanition. In men, the wasting syndrome is characterized by a disproportionate decrease in lean body mass and relative fat sparing. In contrast, relatively little is known about the gender-specific changes in body composition that characterize AIDS wasting in women. Three groups of women were studied to determine body composition and hormonal changes with respect to stage of wasting [nonwasting (NW; weight90% ideal body weight; weight loss10% of preillness maximum; n = 12), early wasting (EW; weight90% ideal body weight; weight loss10% of preillness maximum; n = 10), and late wasting (LW; weight90%; n = 9)] and compared with a control group of 12, healthy, age-matched women. Weight loss averaged 6 +/- 6% (NW), 15 +/- 6% (EW), and 20 +/- 8% (LW) in the three groups. Lean, fat, and muscle masses were determined by dual energy x-ray absorptiometry and urinary creatinine excretion. Subjects were 36 +/- 5 yr of age (mean +/- SD) with a CD4 cell count of 379 +/- 239 cells/mm3. The body mass index was 24.4 +/- 2.6 kg/m2 (NW), 22.2 +/- 1.2 kg/m2 (EW), 18.2 +/- 2.0 kg/m2 (LW), and 24.3 +/- 2.6 kg/m2 (controls; P0.01, NW vs. EW; P0.0001, NW vs. LW). Lean body mass indexed for height was 15.7 +/- 2.4 kg/m2 (NW), 14.8 +/- 2.0 kg/m2 (EW), and 13.7 +/- 1.2 kg/m2 (LW) and was decreased significantly only in the LW group (P0.05 vs. NW). Muscle mass was 96% (NW), 94% (EW), and 78% (LW) of that predicted for height (P0.05, NW vs. LW). In contrast, fat mass indexed for height was decreased significantly among patients in both the EW and LW groups [8.7 +/- 1.9 kg/m2 (NW), 6.5 +/- 1.9 kg/m2 (EW), and 3.7 +/- 1.4 kg/m2 (LW); P0.05, NW vs. EW; P0.001, NW vs. LW). Expressed as a percentage of the value in nonwasting HIV-positive controls (NW), the relative loss of fat was greater than the loss of lean mass with progressive degrees of wasting [EW, 25% vs. 6% (fat vs. lean); LW, 58% vs. 13%]. The prevalence of amenorrhea was 20% among study subjects [17% (NW), 10% (EW), and 38% (LW)]. The percent predicted muscle mass was significantly lower in subjects with amenorrhea (74 +/- 8%) compared to that in eumenorrheic HIV-positive subjects (94 +/- 4%; P0.05). Estradiol levels were lower among subjects with amenorrhea (17.6 +/- 21.8 pg/mL) compared to eumenorrheic HIV-positive (48.9 +/- 33.6 pg/mL) and control (68.3 +/- 47.6 pg/mL) subjects and did not correlate with body composition. Mean free testosterone, but not total testosterone, levels were decreased in subjects with EW and LW compared to those in age-matched healthy controls, but not compared with those in NW [0.9 +/- 0.6 ng/dL (NW), 0.7 +/- 0.4 ng/dL (EW), 0.6 +/- 0.3 ng/dL (LW), and 2.0 +/- 2.4 ng/dL (controls); P0.05, EW vs. controls and LW vs. controls] and correlated with muscle mass (r = 0.37; P0.05). The percentages of women with free testosterone levels below the age-adjusted normal range were 33% (NW), 50% (EW), and 66% (LW). Dehydroepiandrosterone sulfate levels were also low in the subjects with LW compared to those in the control group [98 +/- 85 microg/dL (NW), 102 +/- 53 microg/dL (EW), 55 +/- 46 microg/dL (LW), and 132 +/- 68 microg/dL (controls); P0.05 LW vs. controls] and were correlated highly with free testosterone levels (r = 0.73; P0.00001) and also with muscle mass (r = 0.48; P0.01). These data demonstrate that women lose significant lean body and muscle mass in the late stages of wasting. However, in contrast to men, women exhibit a progressive and disproportionate decrease in body fat relative to lean body mass at all stages of wasting, consistent with gender-specific effects in body composition in AIDS wasting. (ABSTRACT TRUNCATED)

Fucosylated N-linked glycans are important constituents of membrane glycoproteins, owing to their significance as biologically active ligands for several selectins and their role in modulating protein conformation of viral glycoproteins. The human immunodeficiency virus type 1 (HIV-1) glycoprotein contains more than 30 different glycan structures but so far fucose was found associated solely with the innermost GlcNAc of N-linked glycans. In the present report we determined whether fucose units also were linked to the distal GlcNAc via alpha(1-3) or alpha(1-4) linkages in N-linked glycans of gp 120. [3H]-fucose labelled gp 120 was subjected to endoglycosidase F digestion, releasing diantennary complex type N-linked glycans, but leaving the inner polypeptide-bound carbohydrates, GlcNAc and possibly associated fucose units, intact. Gel filtration of the digested material revealed that [3H]-fucose label was released from gp 120 by this treatment, indicating presence of peripheral fucose units. Furthermore, [3H]-focuse label was also released by treatment of the labelled gp 120 with an alpha-L-fucosidase specifically removing fucose in alpha(1-3) and alpha(1-4) linkages. Altogether the results indicated presence of fucose units linked to peripheral GlcNAc of gp 120 N-linked glycans. We have earlier shown that other peripheral carbohydrate determinants, i.e. beta(1-4)-galactose on N-linked glycans, maintain a correct antigenic conformation of gp 120. Using a coupled ELISA system, where changes in antigenic behaviour of a viral glycoprotein were correlated to stepwise elimination of peripheral monosaccharides from N-linked glycans, we found that treatment of gp 120 with a pan-specific alpha-fucosidase as well as an enzyme specific for alpha(1-3)- or alpha(1-4)-linked fucose disclosed a hidden linear epitope situated in the gp 120 C2 region. The effects of the general fucosidase on epitope exposure was more prominent than those obtained with the enzyme with narrow specificity, suggesting that peripheral and inner fucose units co-operate in the maintenance of gp 120 conformation.

There has been a long-standing controversy as to whether Cushing's syndrome is primarily a hypothalamic disorder, with the pituitary simply responding to excess of CRH or other factors, or whether the defect lies at the level of the pituitary. Current data suggest that in nearly all cases, the tumor is clonal, implying a genetic defect at the level of the pituitary. The specific abnormalities underlying the development of corticotroph adenomas remain to be determined. It is certainly possible that the historical controversy has created an artificial dichotomy in our thinking about the pathogenesis of Cushing's syndrome and that hypothalamic factors may play a permissive role in the clonal expansion of a mutated pituitary cell. Finally, the finding of polyclonality in hyperplastic corticotroph tissue from a patient with an ectopic CRH-secreting tumor suggests there may be a more direct role for CRH in the pathogenesis of Cushing's syndrome in rare cases.

Geographische Gegebenheiten und begrenzte, insbesondere intensivmedizinische Kapazitaten der neurochirurgischen Zentren, erfordern oft die definitive Behandlung Schadel-Hirn-verletzter Patienten in peripheren Kliniken. Aus einem 8 1/2-Jahres-Zeitraum wird uber die operative Versorgung von 137 SHT-Patienten, darunter 33 Verletzten mit epiduralem Hamatom, an einer allgemeinchirurgischen Krankenhausabteilung berichtet. Personelle und apparativ-technische Voraussetzungen, OP-Taktik einschlieslich Hirndruckmessung und postoperative Ergebnisse werden dargestellt.

Hypothalamic amenorrhea, a common disorder associated with abnormalities in gonadotropin pulsatility and subsequent estrogen deficiency, is usually transient, and treatment indications are unclear unless fertility is desired. To determine whether this disorder is associated with progressive bone loss, we studied 24 women with primary or secondary amenorrhea related to stress or simple weight loss, compared with 31 normal women of the same age. Amenorrheic women had significantly lower (P = .01) body fat (26.4 +/- 7.3 versus 30.6 +/- 4.7%) and higher (P = .0001) urine free cortisol levels (250 +/- 100 versus 140 +/- 50 nmol/day) than normals. Trabecular bone density in women with hypothalamic amenorrhea as assessed by spinal computed tomography was significantly (P = .001) lower than in normals (140.2 +/- 27.3 versus 175.1 +/- 24.6 mg K2HPO4/mL, respectively). Twenty of the 24 amenorrheic women had initial spinal bone density below the mean in normals, and in eight it was 2 standard deviations or more below the normal mean. Initial bone density correlated negatively with duration of amenorrhea (r = -0.489, P = .02) and positively with serum free testosterone levels (r = 0.517, P = .02). Prospective evaluation showed a decline in spinal bone density in those who were amenorrheic for fewer than 5 years. The slope of change in bone density correlated with initial weight, percent ideal body weight, and percent body fat (R2 = 0.597, P = .0003; R2 = 0.549, P = .0007; and R2 = 0.618, P = .0002, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

With the increased number of fiber-optic couplers in use in network applications, it is imperative that device reliability be ensured. Corning has developed flexible and accurate multi-channel test systems for monitoring performance during environmental testing. One such single-mode system utilizing 90 channels has been demonstrated with a one sigma stability of < 0.004dB over 136 hours of testing.

Commercially available, precoated plates of silica gel have been derivatized by reaction with (3-aminopropyl)triethoxysilane (3-APTS). The aminopropyl-bonded-phase plates prepared from Adsorbosil-Plus-1, soft-layer prekotes (Alltech Associates, Inc.2) provided optimal resolution of a variety of closely related sugars. Plates were immersed in a 1.0% solution of 3-APTS in hexane for 15 min, washed with hexane, and then dried. The resulting, bonded-phase silica contained 9.7% of 3-aminopropyl groups. Further derivatization could be obtained, but optimal resolution of sugars occurred at this level of aminopropyl substitution. Acetonitrile—water mixtures were used as mobile phases; normal phase chromatography resulted, because increasing the proportion of water resulted in increased mobility of the sugars. Closely related mono-, di-, and tri-saccharides have been resolved more effectively than in such traditional approaches as t.l.c. on plates of cellulose or underivatized silica. Also, significantly less time is required for irrigation of the plates than is normally encountered in the t.l.c. of sugars. “Anomalous” behavior was observed for aldotetroses, aldopentoses, and some aldohexoses and deoxy sugars; these remain at the origin. Two sugars of this series, xylose and rhamnose, have been shown to interact covalently with the amino groups on the derivatized plates.