Genetics of GHRH, GHRH-receptor, GH and GH-receptor: its impact on pharmacogenetics

When a child is not following the normal, predicted growth curve, an evaluation for underlying illnesses and central nervous system abnormalities is required and, appropriate consideration should be given to genetic defects causing GH deficiency (GHD). Because Insulin-like-Growth Factor-I (IGF-I) plays a pivotal role, GHD could also be considered as a form of IGF-I deficiency (IGFD). Although IGFD can develop at any level of the GHRH-GH-IGF axis, a differentiation should be made between GHD (absent to low GH in circulation) and IGFD (normal to high GH in circulation). The main focus of this review is on the GH-gene, the various gene alterations and their possible impact on the pituitary gland. However, although transcription factors regulating the pituitary gland development may cause multiple pituitary hormone deficiency they may present initially as GHD. These defects are discussed in various different chapters within this book, whereas, the impact of alterations of the GHRH-, GHRH-receptor- --as well as the GH-receptor (GHR) gene--will be discussed here.

Scheduler-dependent inter-cell interference and its impact on LTE uplink performance at flow level

The Long Term Evolution (LTE) cellular technology is expected to extend the capacity and improve the performance of current 3G cellular networks. Among the key mechanisms in LTE responsible for traffic management is the packet scheduler, which handles the allocation of resources to active flows in both the frequency and time dimension. This paper investigates for various scheduling scheme how they affect the inter-cell interference characteristics and how the interference in turn affects the user’s performance. A special focus in the analysis is on the impact of flow-level dynamics resulting from the random user behaviour. For this we use a hybrid analytical/simulation approach which enables fast evaluation of flow-level performance measures. Most interestingly, our findings show that the scheduling policy significantly affects the inter-cell interference pattern but that the scheduler specific pattern has little impact on the flow-level performance.

The Impact of Gender and Pedagogy on the Development of Self-Regulated Learning Strategies in Undergraduate Engineering Classrooms

The purpose of this paper is to examine ways in which pedagogy and gender of instructor impact the development of self-regulated learning strategies as assessed by the Motivated Strategies for Learning Questionnaire (MSLQ) in male and female undergraduate engineering students. Pedagogy was operationalized as two general formats: lecture plus active learning techniques or problem-base/project-based learning. One hundred seventy-six students from four universities participated in the study. Within-group analyses found significant differences with regard to pedagogy, instructors’ gender, and student gender on the learning strategies and motivation subscales as operationalized by the MSLQ. Male and females students reported significant post-test differences with regard to the gender of instructor and the style of pedagogy. The results of this study showed a pattern where more positive responses for students of both genders were found with the same-gendered instructor. The results also suggested that male students responded more positively to project and problem-based courses with changes evidenced in motivation strategies and resource management. Female students showed decreases in resource management in these two types of courses. Further, female students reported increases in the lecture with active learning courses.

Intra-articular calcium phosphate cement: Its fate and impact on joint tissues in a rabbit model

Clinical application of injectable ceramic cement in comminuted fractures revealed penetration of the viscous paste into the joint space. Not much is known on the fate of this cement and its influence on articular tissues. The purpose of this experimental study was to assess these unknown alterations of joint tissues after intra-articular injection of cement in a rabbit knee. Observation periods were from 1 week up to 24 months, with three rabbits per group. Norian SRS cement was injected into one knee joint, the contralateral side receiving the same volume of Ringers' solution. Light microscopic evaluation of histologic sections was performed, investigating the appearance of the cement, inflammatory reactions, and degenerative changes of the articular surface. No signs of pronounced acute or chronic inflammation were visible. The injected cement was mainly found as a single particle, anterior to the cruciate ligaments. It became surrounded by synovial tissues within 4 weeks and showed signs of superficial resorption. In some specimens, bone formation was seen around the cement. Degeneration of the articular surface showed no differences between experimental and control side, and no changes over time became apparent. No major degenerative changes were induced by the injected cement. The prolonged presence of cement still seems to make it advisable to remove radiologically visible amounts from the joint space.

Seasonal variation in orthopedic health services utilization in Switzerland: the impact of winter sport tourism

BACKGROUND: Climate- or holiday-related seasonality in hospital admission rates is well known for many diseases. However, little research has addressed the impact of tourism on seasonality in admission rates. We therefore investigated the influence of tourism on emergency admission rates in Switzerland, where winter and summer leisure sport activities in large mountain regions can generate orthopedic injuries. METHODS: Using small area analysis, orthopedic hospital service areas (HSAo) were evaluated for seasonality in emergency admission rates. Winter sport areas were defined using guest bed accommodation rate patterns of guest houses and hotels located above 1000 meters altitude that show clear winter and summer peak seasons. Emergency admissions (years 2000-2002, n = 135'460) of local and nonlocal HSAo residents were evaluated. HSAo were grouped according to their area type (regular or winter sport area) and monthly analyses of admission rates were performed. RESULTS: Of HSAo within the defined winter sport areas 70.8% show a seasonal, summer-winter peak hospital admission rate pattern and only 1 HSAo outside the defined winter sport areas shows such a pattern. Seasonal hospital admission rates in HSAo in winter sport areas can be up to 4 times higher in winter than the intermediate seasons, and they are almost entirely due to admissions of nonlocal residents. These nonlocal residents are in general -and especially in winter- younger than local residents, and nonlocal residents have a shorter length of stay in winter sport than in regular areas. The overall geographic distribution of nonlocal residents admitted for emergencies shows highest rates during the winter as well as the summer in the winter sport areas. CONCLUSION: Small area analysis using orthopedic hospital service areas is a reliable method for the evaluation of seasonality in hospital admission rates. In Switzerland, HSAo defined as winter sport areas show a clear seasonal fluctuation in admission rates of only nonlocal residents, whereas HSAo defined as regular, non-winter sport areas do not show such seasonality. We conclude that leisure sport, and especially ski/snowboard tourism demands great flexibility in hospital beds, staff and resource planning in these areas.

GH mutant (R77C) in a pedigree presenting with the delay of growth and pubertal development: structural analysis of the mutant and evaluation of the biological activity

A heterozygous missense mutation in the GH-1 gene converting codon 77 from arginine (R) to cysteine (C), which was previously reported to have some GH antagonistic effect, was identified in a Syrian family. The index patient, a boy, was referred for assessment of his short stature (-2.5 SDS) at the age of 6 years. His mother and grandfather were also carrying the same mutation, but did not differ in adult height from the other unaffected family members. Hormonal examination in all affected subjects revealed increased basal GH, low IGF-I concentrations, and subnormal IGF-I response in generation test leading to the diagnosis of partial GH insensitivity. However, GH receptor gene (GHR) sequencing demonstrated no abnormalities. As other family members carrying the GH-R77C form showed similar alterations at the hormonal level, but presented with normal final height, no GH therapy was given to the boy, but he was followed through his pubertal development which was delayed. At the age of 20 years he reached his final height, which was normal within his parental target height. Functional characterization of the GH-R77C, assessed through activation of Jak2/Stat5 pathway, revealed no differences in the bioactivity between wild-type-GH (wt-GH) and GH-R77C. Detailed structural analysis indicated that the structure of GH-R77C, in terms of disulfide bond formation, is almost identical to that of the wt-GH despite the introduced mutation (Cys77). Previous studies from our group demonstrated a reduced capability of GH-R77C to induce GHR/GH-binding protein (GHBP) gene transcription rate when compared with wt-GH. Therefore, reduced GHR/GHBP expression might well be the possible cause for the partial GH insensitivity found in our patients. In addition, this group of patients deserve further attention because they could represent a distinct clinical entity underlining that an altered GH peptide may also have a direct impact on GHR/GHBP gene expression causing partial GH insensitivity. This might be responsible for the delay of growth and pubertal development. Finally, we clearly demonstrate that GH-R77C is not invariably associated with short stature, but that great care needs to be taken in ascribing growth failure to various heterozygous mutations affecting the GH-IGF axis and that careful functional studies are mandatory.

Statistical evaluation of time-dependent metabolite concentrations: estimation of post-mortem intervals based on in situ 1H-MRS of the brain

Knowledge of the time interval from death (post-mortem interval, PMI) has an enormous legal, criminological and psychological impact. Aiming to find an objective method for the determination of PMIs in forensic medicine, 1H-MR spectroscopy (1H-MRS) was used in a sheep head model to follow changes in brain metabolite concentrations after death. Following the characterization of newly observed metabolites (Ith et al., Magn. Reson. Med. 2002; 5: 915-920), the full set of acquired spectra was analyzed statistically to provide a quantitative estimation of PMIs with their respective confidence limits. In a first step, analytical mathematical functions are proposed to describe the time courses of 10 metabolites in the decomposing brain up to 3 weeks post-mortem. Subsequently, the inverted functions are used to predict PMIs based on the measured metabolite concentrations. Individual PMIs calculated from five different metabolites are then pooled, being weighted by their inverse variances. The predicted PMIs from all individual examinations in the sheep model are compared with known true times. In addition, four human cases with forensically estimated PMIs are compared with predictions based on single in situ MRS measurements. Interpretation of the individual sheep examinations gave a good correlation up to 250 h post-mortem, demonstrating that the predicted PMIs are consistent with the data used to generate the model. Comparison of the estimated PMIs with the forensically determined PMIs in the four human cases shows an adequate correlation. Current PMI estimations based on forensic methods typically suffer from uncertainties in the order of days to weeks without mathematically defined confidence information. In turn, a single 1H-MRS measurement of brain tissue in situ results in PMIs with defined and favorable confidence intervals in the range of hours, thus offering a quantitative and objective method for the determination of PMIs.

Posttraumatic stress disorder after implantation of a mechanical assist device followed by heart transplantation: evaluation of patients and partners

AIM: We sought to investigate the prevalence of posttraumatic stress disorder, anxiety, and depression in patients and their partners after implantation of a mechanical assist device as a bridge to heart transplantation. METHODS: This was a retrospective assessment of 41 patients (age 46.3 +/- 12.0 years; male-female ratio, 38:3; time since transplantation, 55.3 +/- 34.2 months [range, 7-122 months) and 27 partners (male-female ratio 2:25) by standardized instruments (Impact of Event Scale, Hospital Anxiety and Depression Scale), in 2 University Heart Transplant Centers (Vienna, Austria, Munster, Germany). The duration of the support systems (MicroMed DeBakey-VAD in 17 patients, Novacor in 10, Thoratec in 8, TCI HeartMate in 5, and Berlin Heart Incor in 1 patient) ranged from 28 to 711 (176 +/- 146) days. RESULTS: None of the patients, but 23% of the partners (n = 6), met the criteria for posttraumatic stress disorder (Maercker cutoff >0). The Impact of Event Scale (IES) sum scales differed significantly between the 2 groups (21.2 +/- 15.1, mean +/- SD) for the patients versus 38.1 +/- 27.8 for the partners, respectively; P = .001). Two percent of the patients, but 19% of the partners, showed mild to moderate depression; 4% of patients, but 23% of their partners, reported mild to moderate anxiety. None of the results were significantly influenced by the time since transplantation, patient age, diagnoses, type of assist device, or indication for heart transplantation. CONCLUSIONS: Despite patients being much closer to a life threat, their partners experience significantly more psychologic distress even in the long run. Our findings highlight the need for attention to the supporting persons.

Multi-parametric classification of Alzheimer's disease and mild cognitive impairment: the impact of quantitative magnetization transfer MR imaging

Multi-parametric and quantitative magnetic resonance imaging (MRI) techniques have come into the focus of interest, both as a research and diagnostic modality for the evaluation of patients suffering from mild cognitive decline and overt dementia. In this study we address the question, if disease related quantitative magnetization transfer effects (qMT) within the intra- and extracellular matrices of the hippocampus may aid in the differentiation between clinically diagnosed patients with Alzheimer disease (AD), patients with mild cognitive impairment (MCI) and healthy controls. We evaluated 22 patients with AD (n=12) and MCI (n=10) and 22 healthy elderly (n=12) and younger (n=10) controls with multi-parametric MRI. Neuropsychological testing was performed in patients and elderly controls (n=34). In order to quantify the qMT effects, the absorption spectrum was sampled at relevant off-resonance frequencies. The qMT-parameters were calculated according to a two-pool spin-bath model including the T1- and T2 relaxation parameters of the free pool, determined in separate experiments. Histograms (fixed bin-size) of the normalized qMT-parameter values (z-scores) within the anterior and posterior hippocampus (hippocampal head and body) were subjected to a fuzzy-c-means classification algorithm with downstreamed PCA projection. The within-cluster sums of point-to-centroid distances were used to examine the effects of qMT- and diffusion anisotropy parameters on the discrimination of healthy volunteers, patients with Alzheimer and MCIs. The qMT-parameters T2(r) (T2 of the restricted pool) and F (fractional pool size) differentiated between the three groups (control, MCI and AD) in the anterior hippocampus. In our cohort, the MT ratio, as proposed in previous reports, did not differentiate between MCI and AD or healthy controls and MCI, but between healthy controls and AD.

[Mitochondrial dysfunction during sepsis, impact and possible regulating role of hypoxia-inducible factor-1alpha]

There is a direct correlation between the development of the multiple organ dysfunction syndrome (MODS) and the elevated mortality associated with sepsis. The mechanisms responsible for MODS development are being studied, however, the main efforts regarding MODS evaluation have focused on oxygen delivery optimization and on the modulation of the characteristic inflammatory cascade of sepsis, all with negative results. Recent studies have shown that there is development of tissue acidosis, even when there are normal oxygen conditions and limited presence of tissue cellular necrosis or apoptosis, which would indicate that cellular energetic dysfunction may be a central element in MODS pathogenesis. Mitochondrias are the main source of cellular energy, central regulators of cell death and the main source for reactive oxygen species. Several mechanisms contribute to mitochondrial dysfunction during sepsis, that is blockage of pyruvate entry into the Krebs cycle, oxidative phosphorylation substrate use in other enzymatic complexes, enzymatic complex inhibition and membrane damage mediated by oxidative stress, and reduction in mitochondrial content. Hypoxia-inducible factor-1alpha (HIF-1alpha) is a nuclear transcription factor with a central role in the regulation of cellular oxygen homeostasis. Its induction under hypoxic conditions is associated to the expression of hundreds of genes that coordinate the optimization of cellular oxygen delivery and the cellular energy metabolism. HIF-1alpha can also be stabilized under normoxic condition during inflammation and this activation seems to be associated with a prominent pro-inflammatory profile, with lymphocytes dysfunction, and to a reduction in cellular oxygen consumption. Further studies should establish a role for HIF-1alpha as a therapeutic target.

Evaluation of physical and mental recovery status after elective liver resection

BACKGROUND AND OBJECTIVE: This prospective, clinical pilot trial compared the Short Form 36 Health Survey (SF-36) and a nine-item quality of recovery [Quality of Recovery 9 (QoR-9)] survey to assess the 1-week outcome after liver resection and prediction of postoperative complications from baseline values before liver resection. METHODS: In 19 patients, the SF-36 was recorded preoperatively (baseline) and on postoperative day (POD) 7. SF-36 z-values (means +/- SD) for the physical component summary (PCS) and mental component summary (MCS) were calculated. QoR-9 (score 0-18) was performed at baseline, POD1, POD3, POD5 and POD7. Descriptive analysis and effect sizes (d) were calculated. RESULTS: From baseline to POD7, PCS decreased from -0.38 +/- 1.30 to -2.10 +/- 0.76 (P = 0.002, d = -1.57) and MCS from -0.71 +/- 1.50 to -1.33 +/- 1.11 (P = 0.061, d = -0.46). QoR-9 was significantly lower at POD1, POD3 and POD5 compared with baseline (P < 0.050, d < -2.0), but not at POD7 (P = 0.060, d = -1.08). Baseline PCS was significantly lower with a high effect size in patients with complications (n = 12) compared with patients without complications (n = 7) (-0.76 +/- 1.46 vs. 0.27 +/- 0.56; P = 0.044, d = -0.84) but not baseline MCS (P = 0.831, d = -0.10) or baseline QoR-9 (P = 0.384, d = -0.44). CONCLUSIONS: The SF-36 indicates that liver resection surgery has a higher impact on physical health than on mental health. QoR-9 determines the feasible time course of recovery with a 1-week return to baseline. Preoperative impaired physical health might predict postoperative complications.

Patients with oral tumors. Part 2: Quality of life after treatment with resection prostheses. Resection prosthetics: evaluation of quality of life

In the present study, the oral health-related quality of life of 18 patients (13 men and 5 women) was evaluated using validated questionnaires as proposed by the European Organization of Research and Treatment of Cancer (EORTC). The patients belonged to a cohort of 48 patients, whose prosthetic treatment was performed during the years 2004-2007. In the course of tumor resection, 12 patients underwent graft surgery and 14 patients radiotherapy. One patient required a nasal epithesis since resection of the nose became necessary. Five patients underwent a full block resection of the mandible, and tumor resection in 3 patients resulted in a large oronasal communication. Prosthetic rehabilitation was performed in all patients, and the follow-up period with regular care covered a minimum of 3 years. Eleven patients received dental implants for better support and retention of the prostheses. In spite of compromised oral conditions, functional restrictions, and some difficulties with the prostheses, the answers to the questionnaire were quite positive. The majority judged their general health as good or even excellent. The subjective perception of the patients may contradict the objective view by the dentist. In fact, the individual patient's history and experience provide a better understanding of the impact of oral tumors on daily life. The overall assessment identified 4 items that were perceived as major problems by all patients: swallowing solid food, dry mouth, limited mouth opening, and appearance. Prosthetic rehabilitation has only a limited influence on such problems.

Evaluation of control and surveillance strategies for classical swine fever using a simulation model

Classical swine fever (CSF) outbreaks can cause enormous losses in naïve pig populations. How to best minimize the economic damage and number of culled animals caused by CSF is therefore an important research area. The baseline CSF control strategy in the European Union and Switzerland consists of culling all animals in infected herds, movement restrictions for animals, material and people within a given distance to the infected herd and epidemiological tracing of transmission contacts. Additional disease control measures such as pre-emptive culling or vaccination have been recommended based on the results from several simulation models; however, these models were parameterized for areas with high animal densities. The objective of this study was to explore whether pre-emptive culling and emergency vaccination should also be recommended in low- to moderate-density areas such as Switzerland. Additionally, we studied the influence of initial outbreak conditions on outbreak severity to improve the efficiency of disease prevention and surveillance. A spatial, stochastic, individual-animal-based simulation model using all registered Swiss pig premises in 2009 (n=9770) was implemented to quantify these relationships. The model simulates within-herd and between-herd transmission (direct and indirect contacts and local area spread). By varying the four parameters (a) control measures, (b) index herd type (breeding, fattening, weaning or mixed herd), (c) detection delay for secondary cases during an outbreak and (d) contact tracing probability, 112 distinct scenarios were simulated. To assess the impact of scenarios on outbreak severity, daily transmission rates were compared between scenarios. Compared with the baseline strategy (stamping out and movement restrictions) vaccination and pre-emptive culling neither reduced outbreak size nor duration. Outbreaks starting in a herd with weaning piglets or fattening pigs caused higher losses regarding to the number of culled premises and were longer lasting than those starting in the two other index herd types. Similarly, larger transmission rates were estimated for these index herd type outbreaks. A longer detection delay resulted in more culled premises and longer duration and better transmission tracing increased the number of short outbreaks. Based on the simulation results, baseline control strategies seem sufficient to control CSF in low-medium animal-dense areas. Early detection of outbreaks is crucial and risk-based surveillance should be focused on weaning piglet and fattening pig premises.