Experimental testing of a prototype cantilevered liquid-nitrogen-cooled silicon mirror.

This report presents testing of a prototype cantilevered liquid-nitrogen-cooled silicon mirror. This mirror was designed to be the first mirror for the new soft X-ray beamlines to be built as part of the Advanced Light Source Upgrade. Test activities focused on fracture, heat transfer, modal response and distortion, and indicated that the mirror functions as intended.

Building global development strategies for cf therapeutics during a transitional cftr modulator era.

As CFTR modulator therapy transforms the landscape of cystic fibrosis (CF) care, its lack of uniform access across the globe combined with the shift towards a new standard of care creates unique challenges for the development of future CF therapies. The advancement of a full and promising CF therapeutics pipeline remains a necessary priority to ensure maximal clinical benefits for all people with CF. It is through collaboration across the global CF community that we can optimize the evaluation and approval process of new therapies. To this end, we must identify areas for which harmonization is lacking and for which efficiencies can be gained to promote ethical, feasible, and credible study designs amidst the changing CF care landscape. This article summarizes the counsel from core advisors across multiple international regions and clinical trial networks, developed during a one-day workshop in October 2019. The goal of the workshop was to identify, in consideration of the highly transitional era of CFTR modulator availability, the drug development areas for which global alignment is currently uncertain, and paths forward that will enable advancement of CF therapeutic development.

Increased birth weight is associated with altered gene expression in neonatal foreskin.

Elevated birth weight is linked to glucose intolerance and obesity health-related complications later in life. No studies have examined if infant birth weight is associated with gene expression markers of obesity and inflammation in a tissue that comes directly from the infant following birth. We evaluated the association between birth weight and gene expression on fetal programming of obesity. Foreskin samples were collected following circumcision, and gene expression analyzed comparing the 15% greatest birth weight infants (n=7) v. the remainder of the cohort (n=40). Multivariate linear regression models were fit to relate expression levels on differentially expressed genes to birth weight group with adjustment for variables selected from a list of maternal and infant characteristics. Glucose transporter type 4 (GLUT4), insulin receptor substrate 2 (IRS2), leptin receptor (LEPR), lipoprotein lipase (LPL), low-density lipoprotein receptor-related protein 1 (LRP1), matrix metalloproteinase 2 (MMP2), plasminogen activator inhibitor-1 (PAI-1) and transcription factor 7-like 2 (TCF7L2) were significantly upregulated and histone deacetylase 1 (HDAC1) and thioredoxin (TXN) downregulated in the larger birth weight neonates v. CONTROLS: Multivariate modeling revealed that the estimated adjusted birth weight group difference exceeded one standard deviation of the expression level for eight of the 10 genes. Between 25 and 50% of variation in expression level was explained by multivariate modeling for eight of the 10 genes. Gene expression related to glycemic control, appetite/energy balance, obesity and inflammation were altered in tissue from babies with elevated birth weight, and these genes may provide important information regarding fetal programming in macrosomic babies.

Associations between socio-economic status and dietary patterns in US black and white adults.

Socio-economic status (SES) has been associated with measures of diet quality; however, such measures have not directly captured overall eating practices in individuals. Based on the factor analysis of fifty-six food groups from FFQ, associations between patterns of food consumption and SES were examined in a nationwide sample of 17,062 black (34·6%) and white participants (age >45 years) from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Logistic regression models adjusted for age, sex, racial group and geographic region were used to examine adherence to five emergent dietary patterns (convenience, plant-based, sweets/fats, southern and alcohol/salads) according to four levels each of individual education, household income and community-level SES. Further models assessed adherence to these dietary patterns by racial group, and an overall model including both racial groups examined whether the relationships between SES and adherence to these dietary patterns differed among black and white participants. For all the three measures of SES, higher SES had been associated with greater adherence to plant-based and alcohol/salads patterns, but lower adherence to sweets/fats and southern patterns. Statistically significant differences between black and white participants were observed in the associations between household income and adherence to alcohol/salads, individual education and adherence to plant-based and sweets/fats, and community SES and adherence to convenience patterns. As adherence to dietary patterns has been shown to be associated with health outcomes in this population (e.g. stroke), the present study offers valuable insight into behavioural and environmental factors that may contribute to health disparities in the diverse US population.

Adult offspring of high-fat diet-fed dams can have normal glucose tolerance and body composition.

Maternal high-fat diet consumption and obesity have been shown to program long-term obesity and lead to impaired glucose tolerance in offspring. Many rodent studies, however, use non-purified, cereal-based diets as the control for purified high-fat diets. In this study, primiparous ICR mice were fed purified control diet (10-11 kcal% from fat of lard or butter origin) and lard (45 or 60 kcal% fat) or butter (32 or 60 kcal% fat)-based high-fat diets for 4 weeks before mating, throughout pregnancy, and for 2 weeks of nursing. Before mating, female mice fed the 32 and 60% butter-based high-fat diets exhibited impaired glucose tolerance but those females fed the lard-based diets showed normal glucose disposal following a glucose challenge. High-fat diet consumption by female mice of all groups decreased lean to fat mass ratios during the 4th week of diet treatment compared with those mice consuming the 10-11% fat diets. All females were bred to male mice and pregnancy and offspring outcomes were monitored. The body weight of pups born to 45% lard-fed dams was significantly increased before weaning, but only female offspring born to 32% butter-fed dams exhibited long-term body weight increases. Offspring glucose tolerance and body composition were measured for at least 1 year. Minimal, if any, differences were observed in the offspring parameters. These results suggest that many variables should be considered when designing future high-fat diet feeding and maternal obesity studies in mice.

The effects of high-fat diet, branched-chainamino acids and exercise on female C57BL/6 mouse Achilles tendon biomechanical properties.

OBJECTIVES: The goals of this study were: 1) to determine if high-fat diet (HFD) feeding in female mice would negatively impact biomechanical and histologic consequences on the Achilles tendon and quadriceps muscle; and 2) to investigate whether exercise and branched-chain amino acid (BCAA) supplementation would affect these parameters or attenuate any negative consequences resulting from HFD consumption. METHODS: We examined the effects of 16 weeks of 60% HFD feeding, voluntary exercise (free choice wheel running) and BCAA administration in female C57BL/6 mice. The Achilles tendons and quadriceps muscles were removed at the end of the experiment and assessed histologically and biomechanically. RESULTS: HFD feeding significantly decreased the Achilles tendon modulus without histological alterations. BCAA administration significantly decreased the stiffness of Achilles tendons in the exercised normal diet mice. Exercise partially ameliorated both the weight gain and glucose levels in the HFD-fed mice, led to a significant decrease in the maximum load of the Achilles tendon, and an increase in the average fibril diameter of the quadriceps femoris muscle. There were significant correlations between body weight and several biomechanical properties, demonstrating the importance of controlling obesity for maintaining healthy tendon properties. CONCLUSIONS: In summary, this study showed a significant impact of obesity and body weight on tendon biomechanical properties with limited effects of exercise and BCAAs. Cite this article: Bone Joint Res 2013;2:186-92.

Self-reported outcomes of trans-tibial amputations for non-reconstructable Charcot neuroarthropathy in patients with diabetes: a preliminary report.

AIMS: Lower-extremity amputation in patients with diabetes is associated with premature mortality and impaired ambulatory status. Despite advances in limb salvage techniques, certain patients will require major amputation. The hypothesis of this study is that self-reported outcomes of patients with non-reconstructable Charcot neuroarthropathy and chronic osteomyelitis improve after trans-tibial amputation. METHODS: Self-reported outcome was assessed using the Medical Outcome Study Short Form 36-item health survey (SF-36) and the Foot and Ankle Ability Measure. The study group included 13 patients with diabetes who underwent a trans-tibial amputation and completed both the Medical Outcome Study SF-36 and the Foot and Ankle Measure pre- and post-operatively. RESULTS: Significant improvement after trans-tibial amputation occurred in the SF-36 Physical Component Summary score and both the Foot and Ankle Measure Activity of Daily Living and Sports scores at a mean follow-up of 79 weeks (range 53-122 weeks). Although the SF-36 Mental Component Summary score improved, the improvement did not achieve statistical significance (P = 0.30). Twelve of the 13 patients were satisfied with the amputation and had no reservations. CONCLUSIONS: In a select group of Charcot neuroarthropathy patients with chronic osteomyelitis, trans-tibial amputation resulted in improvement in self-reported outcomes. Although major lower-extremity amputation is a devastating complication in patients with diabetes, the results of this study provides some evidence for optimism in these high-risk patients.

Guided self-help concreteness training as an intervention for major depression in primary care: a Phase II randomized controlled trial.

BACKGROUND: The development of widely accessible, effective psychological interventions for depression is a priority. This randomized trial provides the first controlled data on an innovative cognitive bias modification (CBM) training guided self-help intervention for depression. METHOD: One hundred and twenty-one consecutively recruited participants meeting criteria for current major depression were randomly allocated to treatment as usual (TAU) or to TAU plus concreteness training (CNT) guided self-help or to TAU plus relaxation training (RT) guided self-help. CNT involved repeated practice at mental exercises designed to switch patients from an unhelpful abstract thinking habit to a helpful concrete thinking habit, thereby targeting depressogenic cognitive processes (rumination, overgeneralization). RESULTS: The addition of CNT to TAU significantly improved depressive symptoms at post-treatment [mean difference on the Hamilton Rating Scale for Depression (HAMD) 4.28, 95% confidence interval (CI) 1.29-7.26], 3- and 6-month follow-ups, and for rumination and overgeneralization post-treatment. There was no difference in the reduction of symptoms between CNT and RT (mean difference on the HAMD 1.98, 95% CI -1.14 to 5.11), although CNT significantly reduced rumination and overgeneralization relative to RT post-treatment, suggesting a specific benefit on these cognitive processes. CONCLUSIONS: This study provides preliminary evidence that CNT guided self-help may be a useful addition to TAU in treating major depression in primary care, although the effect was not significantly different from an existing active treatment (RT) matched for structural and common factors. Because of its relative brevity and distinct format, it may have value as an additional innovative approach to increase the accessibility of treatment choices for depression.

Genetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects.

A double-blind crossover study was conducted in four CYP2C19 genotype-defined metabolizer groups to assess whether increase in clopidogrel dosing can overcome reduced pharmacodynamic response in CYP2C19 poor metabolizers (PMs). Ten healthy subjects in each of four metabolizer groups were randomized to a clopidogrel regimen of a 300-mg loading dose (LD) and a 75-mg/day maintenance dose (MD) for 4 days followed by 600-mg LD and 150 mg/day MD, or vice versa. The exposure levels of clopidogrel's active metabolite H4 (clopi-H4) in PMs were 71% lower on the 75-mg/day regimen and 64% lower on the 150-mg/day regimen than the corresponding exposure levels in extensive metabolizers (EMs). In PMs, the maximal platelet aggregation (MPA) induced by adenosine diphosphate (ADP) 5 µmol/l was 10.5% lower on the 75-mg/day regimen and 7.9% lower on the 150-mg/day regimen than the corresponding values in EMs. PMs who were on the clopidogrel regimen of 600-mg LD/150 mg/day MD showed clopi-H4 exposure and MPA levels similar to those in EMs who were on the regimen of 300-mg LD/75 mg/day MD. In a pooled analysis evaluating CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A5, CYP2D6, ABCB1, and P2RY12 polymorphisms (N = 396 healthy subjects), only CYP2C19 had a significant impact on antiplatelet response. In healthy CYP2C19 PMs, a clopidogrel regimen of 600-mg LD/150 mg/day MD largely overcomes diminished clopi-H4 exposure and antiplatelet response, as assessed by MPA levels.

Effectiveness and safety of leflunomide for pulmonary and extrapulmonary sarcoidosis.

Leflunomide has been reported as an alternative therapy in sarcoidosis. However, the published data are limited. We performed a retrospective chart review of the tolerance and effects of leflunomide therapy in patients with sarcoidosis. 76 patients were included. The most common reasons for initiation were progression of disease or failure of other immunomodulator therapy. Side-effects attributable to leflunomide were noted in 34% of subjects, prompting discontinuation in 17%. The lungs were a target of therapy in 33 (44%) and extrapulmonary organs were a target in 45 (59%). The mean ± sd change in forced vital capacity in the 6 months prior to leflunomide was -0.1 ± 0.3 L, and it was +0.09 ± 0.3 L in the following 6 months (p=0.01). For extrapulmonary target organ response, 51% had a good response and 32% a partial response. The median corticosteroid dose at initiation was 10 mg (interquartile range 5-20) mg at baseline, and 0 (0-10) mg at the 6-month follow-up (p<0.001). Leflunomide is a viable alternative agent for pulmonary and extrapulmonary sarcoidosis. Leflunomide appears to facilitate reduction of steroid dose and can be considered as monotherapy or as add-on therapy in cases of progressive disease.

Frequency of abdominal wall hernias: is classical teaching out of date?

OBJECTIVES: Abdominal wall hernias are common. Various authors all quote the following order (in decreasing frequency): inguinal, femoral, umbilical followed by rarer forms. But are these figures outdated? We investigated the epidemiology of hernia repair (retrospective review) over 30 years to determine whether the relative frequencies of hernias are evolving. DESIGN: All hernia repairs undertaken in consecutive adult patients were assessed. Data included: patient demographics; hernia type; and operation details. Data were analysed using Microsoft Excel 2007 and SPSS. SETTING: A SINGLE UNITED KINGDOM HOSPITAL TRUST DURING THREE PERIODS: 1985-1988; 1995-1998; and 2005-2008. MAIN OUTCOME MEASURES: Frequency data of different hernia types during three time periods, patient demographic data. RESULTS: Over the three time periods, 2389 patients underwent 2510 hernia repairs (i.e. including bilateral and multiple hernias in a single patient). Inguinal hernia repair was universally the commonest hernia repair, followed by umbilical, epigastric, para-umbilical, incisional and femoral, respectively. Whereas femoral hernia repair was the second commonest in the 1980s, it had become the fifth most common by 2005-2008. While the proportion of groin hernia repairs has decreased over time, the proportion of midline abdominal wall hernias has increased. CONCLUSION: THE CURRENT RELATIVE FREQUENCY OF DIFFERENT HERNIA REPAIR TYPE IS: inguinal; umbilical; epigastric; incisional; para-umbilical; femoral; and finally other types e.g. spigelian. This contrasts with hernia incidence figures quoted in common reference books.

Buttock cellulitis as a presentation of psoas abscess: a clinical reminder.

Cellulitis is a common condition that is frequently managed by the general physicians on an acute medical take. This case report describes buttock cellulitis as a presentation of an iliopsoas abscess and illustrates the importance of considering a deep abscess when there are atypical features, when the cellulitis is in an unusual location or when the patient fails to improve with standard anti-microbial therapy.

Comparison of the MMSE and RUDAS cognitive screening tools in an elderly inpatient population in everyday clinical use.

We compared test score and performance times of Folstein's Mini Mental State Examination (MMSE) and the Rowland Universal Dementia Assessment Scale (RUDAS). Forty-six patients were recruited. The mean score was 20.6 for the MMSE and 20.5 for the RUDAS. Linear regression analysis revealed an r value of 0.83 (P < 0.05). The mean performance time was 9.4 min for both the MMSE and the RUDAS. Patient satisfaction was similar for both tests. Surveyed clinicians preferred the MMSE because of greater familiarity. We concluded that the RUDAS correlates well with the MMSE and is no more time-consuming to perform. It has good clinical utility as a cognitive screening tool.

Force regulation of ankle extensor muscle activity in freely walking cats.

To gain insight into the relative importance of force feedback to ongoing ankle extensor activity during walking in the conscious cat, we isolated the medial gastrocnemius muscle (MG) by denervating the other ankle extensors and measured the magnitude of its activity at different muscle lengths, velocities, and forces accomplished by having the animals walk up and down a sloped pegway. Mathematical models of proprioceptor dynamics predicted afferent activity and revealed that the changes in muscle activity under our experimental conditions were strongly correlated with Ib activity and not consistently associated with changes in Ia or group II activity. This allowed us to determine the gains within the force feedback pathway using a simple model of the neuromuscular system and the measured relationship between MG activity and force. Loop gain increased with muscle length due to the intrinsic force-length property of muscle. The gain of the pathway that converts muscle force to motoneuron depolarization was independent of length. To better test for a causal relationship between modulation of force feedback and changes in muscle activity, a second set of experiments was performed in which the MG muscle was perturbed during ground contact of the hind foot by dropping or lifting the peg underfoot. Collectively, these investigations support a causal role for force feedback and indicate that about 30% of the total muscle activity is due to force feedback during level walking. Force feedback's role increases during upslope walking and decreases during downslope walking, providing a simple mechanism for compensating for changes in terrain.

The population-based prevalence of achondroplasia and thanatophoric dysplasia in selected regions of the US.

There have been no large population-based studies of the prevalence of achondroplasia and thanatophroic dysplasia in the United States. This study compared data from seven population-based birth defects monitoring programs in the United States. We also present data on the association between older paternal age and these birth defects, which has been described in earlier studies. The prevalence of achondroplasia ranged from 0.36 to 0.60 per 10,000 livebirths (1/27,780-1/16,670 livebirths). The prevalence of thanatophoric dysplasia ranged from 0.21 to 0.30 per 10,000 livebirths (1/33,330-1/47,620 livebirths). In Texas, fathers that were 25-29, 30-34, 35-39, and > or =40 years of age had significantly increased rates of de novo achondroplasia among their offspring compared with younger fathers. The adjusted prevalence odds ratios were 2.8 (95% CI; 1.2, 6.7), 2.8 (95% CI; 1.0, 7.6), 4.9 (95% CI; 1.7, 14.3), and 5.0 (95% CI; 1.5, 16.1), respectively. Using the same age categories, the crude prevalence odds ratios for de novo cases of thanatophoric dysplasia in Texas were 5.8 (95% CI; 1.7, 9.8), 3.9 (95% CI; 1.1, 6.7), 6.1 (95% CI; 1.6, 10.6), and 10.2 (95% CI; 2.6, 17.8), respectively. These data suggest that thanatophoric dysplasia is one-third to one-half as frequent as achondroplasia. The differences in the prevalence of these conditions across monitoring programs were consistent with random fluctuation. Birth defects monitoring programs may be a good source of ascertainment for population-based studies of achondroplasia and thanatophoric dysplasia, provided that diagnoses are confirmed by review of medical records.

Role of sensory feedback in the control of stance duration in walking cats.

The rate of stepping in the hind legs of chronic spinal and decerebrate cats adapts to the speed of the treadmill on which the animals walk. This adaptive behavior depends on sensory signals generated near the end of stance phase controlling the transition from stance to swing. Two sensory signals have been identified to have this role: one from afferents activated by hip extension, most likely arising from muscle spindles in hip flexor muscles, and the other from group Ib afferents from Golgi tendon organs in the ankle extensor muscles. The relative importance of these two signals in controlling the stance to swing transition differs in chronic spinal cats and in decerebrate cats. Activation of hip afferents is necessary for controlling the transition in chronic spinal cats but not in decerebrate cats, while reduction in activity in group Ib afferents from GTOs is the primary factor controlling the transition in decerebrate cats. Possible mechanisms for this difference are discussed. The extent to which these two sensory signals control the stance to swing transition in normal walking cats is unknown, but it is likely that both could play an important role when animals are walking in a variable environment.