Host-produced ethylene is required for marked cell expansion and endoreduplication in dodder search hyphae.
The genus Cuscuta comprises stem holoparasitic plant species with wide geographic distribution. Cuscuta spp. obtain water, nutrients, proteins, and mRNA from their host plants via a parasitic organ called the haustorium. As the haustorium penetrates into the host tissue, search hyphae elongate within the host tissue and finally connect with the host's vascular system. Invasion by Cuscuta spp. evokes various reactions within the host plant's tissues. Here, we show that, when Arabidopsis (Arabidopsis thaliana) is invaded by Cuscuta campestris, ethylene biosynthesis by the host plant promotes elongation of the parasite's search hyphae. The expression of genes encoding 1-aminocylclopropane-1-carboxylic acid (ACC) synthases, ACC SYNTHASE2 (AtACS2) and ACC SYNTHASE6 (AtACS6), was activated in the stem of Arabidopsis plants upon invasion by C. campestris. When the ethylene-deficient Arabidopsis acs octuple mutant was invaded by C. campestris, cell elongation and endoreduplication of the search hyphae were significantly reduced, and the inhibition of search hyphae growth was complemented by exogenous application of ACC. In contrast, in the C. campestris-infected Arabidopsis ethylene-insensitive mutant etr1-3, no growth inhibition of search hyphae was observed, indicating that ETHYLENE RESPONSE1-mediated ethylene signaling in the host plant is not essential for parasitism by C. campestris. Overall, our results suggest that C. campestris recognizes host-produced ethylene as a stimulatory signal for successful invasion.


Interscanner variation in brain MRI lesion load measurements in MS: implications for clinical trials.
We evaluated the effect of interscanner variation on brain MRI-measured lesion volumes and measurement reproducibility in MS. Twenty clinically definite MS patients were each scanned on two or three scanners (a total of 14 scanners were used). In addition, a formalin-fixed MS brain was studied on eight scanners from different manufacturers and with different field strengths. For the formalin-fixed MS brain, on each machine we obtained two scans with slice thicknesses of 5 and 3 mm. Only 5-mm-thick slices were obtained from patients. The lesion volume present on each scan was evaluated three times by a single observer in random order, using a local thresholding technique. In two groups of eight patients scanned on machines with different field strengths, the mean lesion volumes present on scans obtained at 1.5 T were significantly higher than those measured on scans obtained with machines operating at 0.5 and 1.0 T (p < 0.01). When a single observer repeatedly evaluated the same scan, a median introbserver agreement of 98.7% (95% CI, 97.9 to 99.1) was achieved. However, when the observer evaluated the scans from different MRI scanners, the agreement (an interscanner agreement) fell to 91.1% (CI, 90.2 to 94.1). When only scanners operating at 1.5 T were considered, the median interscanner agreement was 96.7% (CI, 95 to 97.5). Also, for the formalin-fixed MS brain, the intraobserver agreements obtained with both slice thicknesses were significantly higher than the corresponding interscanner agreements. The interscanner agreement, but not the intraobserver agreement, obtained with a slice thickness of 3 mm was higher than that obtained with a slice thickness of 5 mm. Our results indicate that lesion volume measurements in MS are influenced significantly by the use of different MR scanners and that a patient included in a serial study should be always scanned with the same MR machine using 3-mm thick slices.


Effects of DksA and ClpP protease on sigma S production and virulence in Salmonella typhimurium.
Salmonella typhimurium responds to a variety of environmental stresses by accumulating the alternative sigma factor sigmaS. The repertoire of sigmaS -dependent genes that are subsequently expressed confers tolerance to a variety of potentially lethal conditions including low pH and stationary phase. The mechanism(s) responsible for triggering sigmaS accumulation are of considerable interest, because they help to ensure survival of the organism during encounters with suboptimal environments. Two genes associated with regulating sigmaS levels in S. typhimurium have been identified. The first is clpP, encoding the protease known to be responsible for degrading sigmaS in Escherichia coli. The second is dksA, encoding a protein of unknown function not previously associated with regulating sigmaS levels. As predicted, clpP mutants accumulated large amounts of sigmaS even in log phase. However, dksA mutants failed to accumulate sigmaS in stationary phase and exhibited lower accumulation during acid shock in log phase. DksA appears to be required for the optimal translation of rpoS based upon dksA mutant effects on rpoS transcriptional and translational lacZ fusions. The region of rpoS mRNA between codons 8 and 73 is required to see the effects of dksA mutations. This distinguishes the role of DksA from that of HF-I (hfq ) in rpoS translation, as the HF-I target area occurs well upstream of the rpoS start codon. DksA appears to be involved in the expression of several genes in addition to rpoS based on two-dimensional SDS-PAGE analysis of whole-cell proteins. As a result of their effects on gene expression, mutations in clpP and dksA decreased the virulence of S. typhimurium in mice, consistent with a role for sigmaS in pathogenesis.


Brain magnetic resonance metabolic and microstructural changes in adult-onset autosomal dominant leukodystrophy.
adult-onset autosomal dominant leukodystrophy (ADLD) is a rare inherited disorder due to a duplication of lamin-B1 (LMNB1) gene. The aim of this study was to investigate brain metabolic and microstructural alterations by using advanced MR techniques. we performed brain MR scans including single-voxel proton-MR Spectroscopy ((1)H-MRS) of the lateral ventricles and parietal white matter and diffusion tensor imaging (DTI) in 4 subjects with LMNB1 gene duplication, 6 non-mutated relatives and 7 unrelated healthy controls. Cervical and thoracic spinal cord MR was performed in three symptomatic subjects with LMNB1 mutation. All participants underwent clinical and neuropsychological evaluation. all subjects with LMNB1 gene duplication presented pathological accumulation of lactate in lateral ventricles CSF and no alterations of brain white matter absolute metabolites concentrations or metabolites/Cr ratios. We found increased white matter intra- and extracellular water transverse relaxation times. Tract-based spatial statistics analysis detected a significantly reduced fractional anisotropy in the genu of the corpus callosum in mutated cases compared to unrelated healthy controls and non-mutated relatives. Moreover, we detected different degrees of the typical white matter signal intensity alterations and brain and spinal atrophy at conventional MRI in symptomatic subjects with LMNB1 mutation. A mild impairment of executive functions was found in subjects with LMNB1 gene mutation. in subjects with LMNB1 gene duplication, we found a pathological increase in CSF lactate, likely due to active demyelination along with glial activation, and microstructural changes in the genu of the corpus callosum possibly underpinning the mild neuropsychological deficits.


PLANETARY SCIENCE: Fountains of Youth.
The search for geologic features indicative of past or present water is central to Mars exploration programs. As Tanaka explains in his Perspective, such features have tended to be associated with very old (> 1 billion years) regions. However, a study by Malin and Edgett indicates that the youngest geologic features on Mars show signs of fluid discharge and runoff. If the results hold up, then some very unusual event must have occurred in the recent past on Mars.


Screening for depression, sleep-related disturbances, and anxiety in patients with adenocarcinoma of the pancreas: a preliminary study.
Screening for depression, sleep-related disturbances, and anxiety in patients with diagnosed adenocarcinoma of the pancreas. Patients were evaluated at initial consultation and subsequent visits at the multidisciplinary pancreatic cancer clinic at our University Cancer Center. Cross-sectional and longitudinal psychosocial distress was assessed utilizing Personal Health Questionnaire 9 (PHQ9) to screen for depression and monitor symptoms, the Penn State Worry Questionnaire (PSWQ) for generalized anxiety, and the University of Michigan Sleep Questionnaire to monitor sleep symptoms. Twenty-two patients diagnosed with pancreatic cancer participated during the 6-month pilot study with longitudinal followup for thirteen patients. In this study, mild-to-moderate depressive symptoms, anxiety, and potential sleep problems were common. The main finding of the study was 23% of the patients who were part of this pilot project screened positive for moderately severe major depressive symptoms, likely anxiety disorder or a potential sleep disorder during the study. One patient screened positive for moderately severe depressive symptoms in longitudinal followup. Depression, anxiety, and sleep problems are evident in patients with pancreatic cancer. Prospective, longitudinal studies, with larger groups of patients, are needed to determine if these comorbid symptoms impact outcome and clinical course.


Synthesis of (6R)- and (6S)-5,10-dideazatetrahydrofolate oligo-gamma-glutamates: kinetics of multiple glutamate ligations catalyzed by folylpoly-gamma-glutamate synthetase.
Folylpoly-gamma-glutamate synthetase (FPGS, EC 220.127.116.11) catalyzes the ATP-dependent ligation of glutamic acid to reduced folates including (6S)-5,6,7,8-tetrahydrofolate (H4PteGlu), as well as to anticancer drugs such as 5,10-dideaza-5,6,7,8-tetrahydrofolate ((6R)-DDAH4PteGlu1, (6R)-DDATHF, Lometrexol). Synthesis of unlabeled mono- and polyglutamates, DDAH4PteGlu(n) (6R, n = 1-6; 6S, n = 1-2), as well as (6R)-DDAH4Pte[14C]Glu1, was effected from (6R)- or (6S)-5,10-dideazatetrahydropteroyl azide and glutamic acid, H-Glu-gamma-Glu(n)-gamma-Glu-OH (n = 0-4), or [14C]glutamic acid, respectively. These compounds were evaluated as FPGS substrates to determine steady-state kinetic constants. Michaelis-Menten kinetics were observed for (6R)-DDAH4PteGlu1, the isomer corresponding to H(4)PteGlu, whereas marked substrate inhibition was observed for (6S)-DDAH4PteGlu(n) (n = 1-2) and (6R)-DDAH4PteGlu(n) (n = 2-5), but not (6R)-DDAH4PteGlu6. Multiple ligation of glutamate renders a quantitative analysis of these data difficult. However, approximate values of K(M) = 0.65-1.6 microM and K(I) = 144-417 microM for DDAH4PteGlu(n) were obtained using a simple kinetic model.


Genetic variations in GJA3, GJA8, LIM2, and age-related cataract in the Chinese population: a mutation screening study.
To investigate the role of genetic variations in three known cataract-associated genes, gap junction protein α3 (GJA3), gap junction protein α8 (GJA8), lens intrinsic membrane protein 2 (LIM2), encoding lens fiber cell membrane proteins in the development of age-related cataracts. One hundred and forty-five sporadic age-related cataract patients and one hundred and fifty-six unrelated random healthy controls participated in this study. Genomic DNA was extracted from peripheral blood leukocytes. All exons of GJA3, GJA8, and LIM2 were sequenced after being amplified by polymerase chain reaction (PCR). The functional consequences of the mutations were analyzed using PolyPhen. We found five novel variations in 145 patients and none of them presented in the 156 controls. There are two variations in GJA3 (c.-39C>G, c. 415G>A); one in GJA8 (c. 823G>A), and two in LIM2 (c.57G>A, c.67A>C). PolyPhen predicted that the LIM2 c.67A>C mutation may have potential pathogenicity. The genetic mutation in GJA3, GJA8, and LIM2 may slightly contribute to the development of age-related cataracts. This study showed a potential relationship between lens fiber cell membrane protein genes and the development of age-related cataracts in the Chinese population.


Nonsteroidal anti-inflammatory drugs and risk of Parkinson's disease.
Inflammation and oxidative stress have been implicated as pathogenic mechanisms in Parkinson's disease (PD). Evidence from in vitro and animal studies suggests a possible protective role of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin. We investigated the risk of PD associated with use of aspirin and nonaspirin NSAIDs in a population-based case-control study among enrollees of Group Health Cooperative, a health maintenance organization in the Seattle area. Subjects included 206 cases between ages 35 and 89 with a new diagnosis of idiopathic PD between 1992 and 2002, and 383 randomly selected controls frequency-matched by age, sex, duration of enrollment, and clinic. We obtained information on participants' age, smoking, and medical history from interview. Exposure to NSAIDs was ascertained from an automated pharmacy database. Medications filled within 5 years of the interview were excluded. After adjusting for age, sex, smoking, duration of enrollment, and clinic, the risk of PD among individuals who received nonaspirin NSAIDs between 1977 and 1992 was 0.90 (95% CI: 0.59-1.35) and 1.67 (95% CI: 0.60-4.60) between 1993 and 2002. Use of ibuprofen was not associated with PD (OR: 0.89; 95% CI: 0.60-1.32). The risk of PD associated with aspirin or aspirin-containing medications was 0.74 (95% CI: 0.49-1.12). We observed no trend in risk according to number of fills for these drugs. Our results provide only limited support for the hypothesis that use of aspirin may reduce the risk of this disease, and no indication of protection from other NSAIDs.


Structural evolution and phase transition mechanism of [Formula: see text] under high pressure.
[Formula: see text] is a layered transition-metal dichalcogenide (TMD) with outstanding electronic and optical properties, which is widely used in field-effect transistor (FET). Here the structural evolution and phase transition of [Formula: see text] under high pressure are systematically studied by CALYPSO structural search method and first-principles calculations. The structural evolutions of [Formula: see text] show that the ground state structure under ambient pressure is the experimentally observed P6[Formula: see text]/mmc phase, which transfers to R3m phase at 1.9 GPa. The trigonal R3m phase of [Formula: see text] is stable up to 72.1 GPa, then, it transforms into a new P6[Formula: see text]/mmc phase with different atomic coordinates of Se atoms. This phase is extremely robust under ultrahigh pressure and finally changes to another trigonal R-3m phase under 491.1 GPa. The elastic constants and phonon dispersion curves indicate that the ambient pressure phase and three new high-pressure phases are all stable. The electronic band structure and projected density of states analyses reveal a pressure induced semiconducting to metallic transition under 72.1 GPa. These results offer a detailed structural evolution and phase diagram of [Formula: see text] under high pressure, which may also provide insights for exploration other TMDs under ultrahigh pressure.


The relationship between time spent on social media and adolescent alcohol use: a longitudinal analysis of the UK Millennium Cohort Study.
To estimate the effect of social media use in 14 year olds on risk of and inequalities in alcohol use and binge drinking at 17 years. Using the UK-representative Millennium Cohort Study, the relationship between time spent on social media (assessed using questionnaires [n = 8987] and time-use-diaries [n = 2520]) with frequency of alcohol use in the past month and binge drinking was estimated using adjusted odds ratios (AORs) or adjusted relative risk ratios (ARRRs). Associations within low and high parental education groups were compared to examine effect modification. Analyses accounted for pre-specified confounders, baseline outcome measures (to address reverse causality), sample design, attrition and item-missingness (through multiple imputation). Questionnaire-reported time spent on social media was associated with increased risk of alcohol use and binge drinking in a dose-response manner. Compared to 1-< 30 min/day social media users, 30 min-<1 h/day users were more likely to report alcohol use ≥6 times/month (ARRR 1.62 [95% confidence interval 1.20 to 2.20]) and binge drinking (AOR 1.51 [1.22 to 1.87]), as were 1-<2 h/day users (ARRR 2.61 [1.90 to 3.58]; AOR 2.06 [1.69 to 2.52]) and ≥2 h/day users (ARRR 4.80 [3.65 to 6.32]; AOR 3.07 [2.54 to 3.70]). Social media measured by time-use-diary was associated with higher risks, although not always demonstrating a dose-response relationship. The effect of social media use (vs no-use) on binge drinking was larger in the higher (vs lower) parental education groups. Analyses repeated in complete case samples, and with adjustment for baseline outcome measures revealed consistent findings. Findings suggest social media use may increase risk of alcohol use and binge drinking. Regulatory action protecting adolescents from harmful alcohol-related social media content is necessary.


[Morphogenesis of human placenta in the first trimester of gestation].
On the basis of morphometric and immunohistochemical study of placental villi obtained from 45 cases of medicinal and medical abortions in healthy women, the new data on placentation are presented with the discrimination of three stages of placental morphogenesis. The first stage (weeks 4 and 5 after fertilization) included a differentiation of villous chorion (chorion frondosum). It was characterized by high mitotic activity of villous cytotrophoblast and intensive vasculogenesis in the villous stroma. The second stage (weeks 6 and 7) included capillary development (angiogenesis) and formation of vascular communications within a "placenta-embryo" subsystem functioning in low-oxygen level environment. The third stage (weeks 8 and 9-10) was characterized by vascular bed formation in "mother-placenta" subsystem and by the beginning of more effective hemochorial embryo and fetal metabolism. As a result of placentation, hemodynamics formation in "mother-placenta-embryo" system was completed, which is a necessary condition for further fetal development.


A phogrin-aequorin chimaera to image free Ca2+ in the vicinity of secretory granules.
Microdomains of high Ca2+ concentration ([Ca2+]) may be critical to the control of intracellular processes such as secretion and metabolism without compromising other cell functions. To explore changes in [Ca2+] in the outer mantle (< 30 nm deep) that surrounds the surface of dense-core secretory granules, we have designed a recombinant chimaera between the granule protein phogrin and aequorin. When expressed in populations of insulin-secreting MIN6 or phaeochromocytoma PC12 cells, the chimaera was targeted to secretory granules as expected. The recombinant protein reported a similar [Ca2+] at the granule surface to that in the bulk cytosol, measured with untargeted aequorin. This was the case both at rest (-Ca2+- = 80-120 nM) and after stimulation with agents that provoke Ca2+ entry or Ca2+ mobilization from intracellular pools, and during activated secretion. Thus depolarization of MIN6 cell populations with high K+ increased [Ca2+] both in the bulk cytosol and close to the granules to approx. 4 microM, with near-identical kinetics of increase and recovery. Similarly, stimulation of PC12 cells with ATP provoked an increase in -Ca2+- in either domain to 1.3 microM. These data argue that, in MIN6 and PC12 neuroendocrine cells (i) significant mobilization of Ca2+ from most secretory granules probably does not occur during activated Ca2+ influx or mobilization of internal Ca2+ stores, and (ii) agonist-stimulated Ca2+-dependent secretion can occur without development of a large gradient of [Ca2+] between the surface of most secretory vesicles and the rest of the cytosol.


Imaging features of intraosseous ganglia: a report of 45 cases.
The aim of this study is to report the spectrum of imaging findings of intraosseous ganglia (IG) with particular emphasis on the radiographic and magnetic resonance (MR) features. Forty-five patients with a final diagnosis of IG were referred to a specialist orthopaedic oncology service with the presumptive diagnosis of either a primary or secondary bone tumour. The diagnosis was established by histology in 25 cases. In the remainder, the imaging features were considered characteristic and the lesion was stable on follow-up radiographic examination. Radiographs were available for retrospective review in all cases and MR imaging in 29. There was a minor male preponderance with a wide adult age range. Three quarters were found in relation to the weight-bearing long bones of the lower limb, particularly round the knee. On radiographs all were juxta-articular and osteolytic; 74% were eccentric in location, 80% had a sclerotic endosteal margin and 60% of cases showed a degree of trabeculation. Periosteal new bone formation and matrix mineralization were not present. Of the 29 cases that underwent MR imaging, 66% were multiloculated. On T1-weighted images the IG contents were isointense or mildly hypointense in 90% cases. Forty-one per cent of the cases showed a slightly hyperintense rim lining that enhanced with a gadolinium chelate. Thirty-eight per cent were associated with soft tissue extension and 17% with a defect of the adjacent articular cortex. Fifty-five per cent showed surrounding marrow oedema on T2-weighted or STIR images and two cases (7%) a fluid-fluid level prior to any surgical intervention. The authors contend that it is semantics to differentiate between an IG and a degenerate subchondral cyst as, while the initial pathogenesis may vary, the histological endpoint is identical, as are the imaging features apart from the degree of associated degenerative joint disease. IGs, particularly when large, may be mistaken for a bone tumour. Correlation of the typical radiographic and MR imaging features will indicate the correct diagnosis and obviate the need for biopsy.


Should the dentist independently assess and treat sleep-disordered breathing?
Sleep-disordered breathing is a chronic problem of the inappropriate mechanical collapse of the upper airway. Symptoms range from mild occasional snoring to severe obstructive sleep apnea. The standard of care for the diagnosis and treatment of sleep-disordered breathing by sleep medicine has been the use of the polysomnogram and continuous positive airway pressure. This approach is burdensome, costly, and ineffective due to lack of compliance with or rejection of treatment. Oral appliances are highly effective in managing the mild snorer to the moderate sleep apneic and are approaching the efficacy of continuous positive airway pressure with the severe apneic. The dentist can and should manage these patients. However, the dental practitioner must acquire sufficient training and knowledge to appropriately treat these patients.


Development of a novel noninvasive system for measurement and imaging of the arterial phase oxygen density ratio in the retinal microcirculation.
This study was conducted in order to develop a novel noninvasive system for measurement and imaging of the arterial oxygen density ratio (ODR) in the retinal microcirculation. We developed a system composed of two digital cameras with two different filters, which were attached to a fundus camera capable of simultaneously obtaining two images. Actual measurements were performed on healthy volunteer eyes (n = 61). A new algorithm for ODR measurement and pixel-level imaging of erythrocytes was constructed from these data. The algorithm was based on the morphological closing operation and the line convergence index filter. For system calibration, we compared and verified the ODR values in arterioles and venules that were specified in advance for 56 eyes with reproducibility. In 10 additional volunteers, ODR measurements and imaging of the arterial phase in the retinal microcirculation corresponding to changes in oxygen saturation of the peripheral arteries at normal breathing and breath holding were performed. Estimation of incident light to erythrocytes and pixel-level ODR calculation were achieved using the algorithm. The mean ODR values of arterioles and venules were 0.77 ± 0.060 and 1.02 ± 0.067, respectively. It was possible to separate these regions, calibrate at the pixel level, and estimate the arterial phase. In each of the 10 volunteers, changes in the arterial phase ODR corresponding to changes in oxygen saturation of the peripheral arteries were observed before and after breath holding on ODR images. The mean ODR in 10 volunteers was increased by breath holding (p < 0.05). We developed a basic system for arterial phase ODR measurement and imaging of the retinal microcirculation. With further validation and development, this may provide a useful tool for evaluating retinal oxygen metabolism in the retinal microcirculation.


Role of free testosterone levels in patients with metastatic castration-resistant prostate cancer receiving second-line therapy.
A range of new treatment options has recently become available for patients with advanced metastatic castration-resistant prostate cancer (mCRPC). Androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone is continued when performing chemotherapy or androgen deprivation with new second-generation therapeutic agents such as enzalutamide or abiraterone acetate. Despite the fact that free testosterone (FT) is the biologically active form, it is common practice that androgen suppression is monitored via total testosterone levels only. The aim of the present study was to evaluate the role of FT as a prognostic biomarker for cancer-specific survival (CSS) and its feasibility as an ADT monitoring biomarker in patients with mCRPC for the first time. The requirement for continued ADT in mCRPC patients is discussed within the basis of the current literature. A total of 34 patients with continuous measurements of FT levels and mCRPC status underwent therapy with docetaxel, abiraterone acetate, enzalutamide, cabozantinib, carboplatin or cabazitaxel. Data were obtained from the Departments of Urology and Urological Oncology, Hannover Medical School (Hannover, Germany) between March 2009 and April 2014. A cutoff point of 0.5 pg/ml was used to discriminate between patients according to FT levels. Statistical evaluation of CSS was performed by applying Kaplan Meier survival estimates, multivariate Cox regression analyses and log-rank tests. The median age of all 34 patients was 72 years (range, 51-86 years). The mean follow-up interval was 16.1 months (range, 0.7-55.6 months). Despite the fact that all patients were undergoing androgen deprivation, the mean serum FT levels for each patient varied; the mean FT concentration in the cohort was 0.328 pg/ml, ranging from 0.01-9.1 pg/ml. A notable difference with regard to CSS was observed for patients with regard to serum FT concentration; CSS was significantly longer for patients with a serum FT level below the cutoff level (43.6 vs. 17.3 months, respectively, P=0.0063). Upon multivariate Cox regression analysis, the mean FT concentration during treatment remained a significant prognostic factor for CSS (hazard ratio, 1.22; 95% confidence interval, 1.03-1.43; P=0.0182). In conclusion, in patients with mCRPC, the serum FT level is a strong predictor of CSS in patients under therapy with second-line anti-hormonal therapeutic medication and chemotherapy. It may be concluded that FT levels should be included into the routine control of androgen suppression while under treatment with ADT and second-generation hormonal therapy.


Perceived exertion at work in women with fibromyalgia: explanatory factors and comparison with healthy women.
To investigate perceived exertion at work in women with fibromyalgia. A controlled cross-sectional multi-centre study. Seventy-three women with fibromyalgia and 73 healthy women matched by occupation and physical workload were compared in terms of perceived exertion at work (0-14), muscle strength, 6-min walk test, symptoms rated by Fibromyalgia Impact Questionnaire (FIQ), work status (25-100%), fear avoidance work beliefs (0-42), physical activity at work (7-21) and physical workload (1-5). Spearman's correlation coefficient and linear regression analysis were conducted. Perceived exertion at work was significantly higher in the fibromyalgia group than in the reference group (p = 0.002), while physical activity at work did not differ between the groups. Physical capacity was lower and symptom severity higher in fibromyalgia compared with references (p < 0.05). In fibromyalgia, perceived exertion at work showed moderate correlation with physical activity at work, physical workload and fear avoidance work beliefs (rs = 0.53-0.65, p < 0.001) and a fair correlation with anxiety (rs = 0.26, p = 0.027). Regression analysis indicated that the physical activity at work and fear avoidance work beliefs explained 50% of the perceived exertion at work. Women with fibromyalgia perceive an elevated exertion at work, which is associated with physical work-related factors and factors related to fear and anxiety.


The effect of Housing First on adherence to methadone maintenance treatment.
Opioid overdose deaths have become a public health crisis in North America, and those who are homeless are particularly vulnerable. Methadone maintenance treatment (MMT) may prevent overdose and death among homeless people with opioid dependence, but suboptimal medication adherence is a common limitation. Previous research found that Housing First (HF) increases antipsychotic medication adherence among formerly homeless people. However, no experimental trials have examined whether HF has a significant impact on MMT adherence. We examined the intervention effect of HF on MMT adherence in a randomized sample of homeless adults experiencing mental illness and opioid dependence in Vancouver, Canada. Comprehensive administrative and self-reported data from homeless adults living with serious mental illness recruited to the Vancouver At Home study were analyzed. Only methadone recipients were included (n = 97). The medication possession ratio (MPR) was utilized as the measure of adherence, and relevant data were obtained from provincial administrative pharmacy records. Study arms were HF and treatment as usual (TAU). Student t-tests were used to test for differences in MMT MPR between HF and TAU. No significant differences were observed in MMT MPR between participants in HF and TAU (0.52 vs. 0.57, p = 0.559) in the post-randomization period. HF was not associated with significantly different MMT MPR compared to TAU. Additional interventions are indicated as HF alone was insufficient to facilitate improved MMT adherence among formerly homeless adults experiencing concurrent opioid dependence and serious mental illness.


A quantitative ultrastructural comparison of alpha and gamma motoneurons in the thoracic region of the spinal cord of the adult cat.
The cell bodies of motoneurons supplying both the levator costae and external intercostal muscles were identified after retrograde labelling with horseradish peroxidase. A quantitative ultrastructural comparison of cell bodies of large (greater than 40 microns) and small (less than 30 microns) diameter revealed that the intracellular appearance of large and small motoneurons was similar. However, small motoneurons had less than half the synaptic terminal frequency or cover of large motoneurons. Furthermore, only synapses of the S- and F-type were seen on small motoneurons, while S- T- F- and C-type terminals were consistently seen on large motoneurons. The variation between individual small motoneurons for various aspects of their synaptic features was more than twice that found for large motoneurons. No correlation between small motoneuronal ultrastructure and cell body diameter was found, although scatter diagrams of synaptic terminal cover against cell body size indicated the presence of two groups of small motoneurons: one with relatively high values for synaptic cover and the other with relatively low values. On the basis of the similarity of their cell body diameters to those of electrophysiologically identified alpha and gamma motoneurons, it is concluded that the large and small motoneurons examined in the present study are alpha and gamma motoneurons respectively. The synaptic difference found between alpha and gamma motoneurons is discussed in relation to both their different functional properties and the different natures of their respective peripheral targets.


Therapeutic alliance in pediatric primary care: preliminary evidence for a relationship with physician communication style and mothers' satisfaction.
Studies in pediatric primary care suggest that interactions between parents and providers may have therapeutic impact on children's mental health problems. Methods to measure interactions specific to mental health outcomes have been developed in psychotherapy but are only beginning to be applied in primary care. We tested an adaptation of the Vanderbilt Therapeutic Alliance Scale (VTAS) for rating parent-provider interactions in pediatric primary care. Recoding, using the VTAS, of 50 previously collected audiotapes of visits to a pediatric residents' continuity clinic. Concurrent validity of VTAS coding was measured by comparing it to independent coding using the Roter Interaction Analysis System. Predictive validity was tested by comparing VTAS scores to parent ratings of the residents' behavior in the domains of interpersonal sensitivity, partnership, and informativeness. The VTAS demonstrated a factor structure very similar to the structure observed when it has been used to rate mental health visits. VTAS patient and provider subscale scores correlated with corresponding Roter Interaction Analysis System measures of parent and resident participation. Total VTAS scores correlated most strongly with Roter Interaction Analysis System scores indicating emotion and rapport-building statements from the resident. Total VTAS scores predicted parents' ratings of residents' interpersonal sensitivity but not ratings of partnership or informativeness. It appears possible to use therapeutic alliance to rate interactions in primary care. Measuring alliance may bring greater efficiency to primary care mental health studies because of its potential specificity as a marker of mental health-related outcomes.


Genetic basis of methicillin resistance in Staphylococcus aureus.
Methicillin resistance in staphylococci is due to the acquisition of the mecA gene encoding a new penicillin-binding protein (PBP2', PBP2a) that has a lower affinity to methicillin than the endogenous PBPs. PBP2' is involved in the assembly of the cell wall peptidoglycan in the presence of high concentrations of beta-lactams that otherwise inhibit the endogenous PBPs. The production of PBP2' is under dual control by its own mecR1-mecI- and the penicillinase blaR1-blaI-encoded regulatory elements. Resistance to high levels of methicillin depends, in addition to PBP2', on chromosomally encoded factors that are involved in the synthesis and degradation of the peptidoglycan. Any mutations that reduce peptidoglycan precursor formation or change the chemical composition of the muropeptide precursor result in lowered resistance.


Roundness of grains in cellular microstructures.
Many physical systems are composed of polyhedral cells of varying sizes and shapes. These structures are simple in the sense that no more than three faces meet at an edge and no more than four edges meet at a vertex. This means that individual cells can usually be considered as simple, three-dimensional polyhedra. This paper is concerned with determining the distribution of combinatorial types of such polyhedral cells. We introduce the terms fundamental and vertex-truncated types and apply these concepts to the grain growth microstructure as a testing ground. For these microstructures, we demonstrate that most grains are of particular fundamental types, whereas the frequency of vertex-truncated types decreases exponentially with the number of truncations. This can be explained by the evolutionary process through which grain growth structures are formed and in which energetically unfavorable surfaces are quickly eliminated. Furthermore, we observe that these grain types are "round" in a combinatorial sense: there are no "short" separating cycles that partition the polyhedra into two parts of similar sizes. A particular microstructure derived from the Poisson-Voronoi initial condition is identified as containing an unusually large proportion of round grains. This microstructure has an average of 14.036 faces per grain and is conjectured to be more resistant to topological change than the steady-state grain growth microstructure.


4.5-Gb/s RGB-LED based WDM visible light communication system employing CAP modulation and RLS based adaptive equalization.
Inter-symbol interference (ISI) is one of the key problems that seriously limit transmission data rate in high-speed VLC systems. To eliminate ISI and further improve the system performance, series of equalization schemes have been widely investigated. As an adaptive algorithm commonly used in wireless communication, RLS is also suitable for visible light communication due to its quick convergence and better performance. In this paper, for the first time we experimentally demonstrate a high-speed RGB-LED based WDM VLC system employing carrier-less amplitude and phase (CAP) modulation and recursive least square (RLS) based adaptive equalization. An aggregate data rate of 4.5Gb/s is successfully achieved over 1.5-m indoor free space transmission with the bit error rate (BER) below the 7% forward error correction (FEC) limit of 3.8x10(-3). To the best of our knowledge, this is the highest data rate ever achieved in RGB-LED based VLC systems.


Local radiotherapy with or without transcatheter arterial chemoembolization for patients with unresectable hepatocellular carcinoma.
To evaluate the treatment outcome, patterns of failure, and prognostic factors for patients with unresectable hepatocellular carcinoma (HCC) treated with local radiotherapy alone or as an adjunct to transcatheter arterial chemoembolization (TACE). From March 1994 to December 1997, 25 patients with unresectable HCC underwent local radiotherapy to a portion of the liver. Twenty-three patients were classified as having cirrhosis in Child-Pugh class A and 2 in class B. Mean diameter of the treated hepatic tumor was 10.3 cm. Mean dose of radiation was 46.9 +/- 5.9 Gy in a daily fraction of 1.8-2 Gy. Sixteen patients were also treated with Lipiodol and chemotherapeutic agents mixed with Ivalon or Gelfoam particles for chemoembolization, either before and/or after radiotherapy. Percutaneous ethanol injection therapy (PEIT) was given to one patient. All patients were monitored for treatment-related toxicity and for survival and patterns of failure. In a median follow-up period of 23 months, 11 patients were alive and 14 dead. The median survival duration from treatment was 19.2 months with a 2-year survival of 41%. Only 3 of 25 patients had local progression of the treated hepatic tumor. The recurrences were seen within the liver or extrahepatic. The 2-year local, regional, and extrahepatic progression-free survival rates were 78%, 46%, and 39%, respectively. The local control ranked the highest. Patients with Okuda Stage I disease had significantly longer survival than those with Stage II and III (p = 0.02). Patients with T4 disease (p = 0.02) or treated with radiotherapy alone (p = 0.003) had significantly shorter survival. T4 disease (p = 0.03) and pretreatment alpha-fetoprotein level of more than 200 ng/ml (p = 0. 03) were associated with significantly worse regional progression-free survival. A significant difference was observed in both regional progression-free survival (p = 0.0001) and extrahepatic progression-free survival (p = 0.005) between patients with and without portal vein thrombosis before treatment. The presence of satellite nodules had a significantly worse impact on regional progression-free survival (p = 0.04) and extrahepatic progression-free survival (p = 0.03). Patients with hepatic tumor more than 6 cm in diameter or portal vein thrombosis tended to have shorter survival. Radiation-induced liver disease (RILD) and gastrointestinal bleeding were the most common treatment-related toxicities. Radiotherapy is effective in the treatment of patients with unresectable HCC. Its effect appeared to be more prominent within the site to which radiation was given. The combination of TACE and radiation was associated with better control of HCC than radiation given alone, probably due to the selection of patients with favorable prognosis for the combined treatment. A dose-volume model should be established in the next phase of research in the treatment of unresectable HCC.


3,5-Dimethoxy-(4-methoxyphenyl)benzamide suppresses adipogenesis in 3T3-L1 cells.
In this study, the adipogenesis-suppressing effect of 3,5-dimethoxy(4-methoxyphenyl)benzamide (DMPB), a derivative of the anti-obesity substance resveratrol, was measured in 3T3-L1 cells. The results show that DMPB effectively suppressed the hormone-induced differentiation of 3T3-L1 cells, compared to resveratrol at the same concentration, and reduced the protein expression of fatty acid synthase and acetyl-CoA carboxylase. In addition, DMPB was observed to decrease the PPAR-gamma transcription activity, which was increased by rosiglitazone, in a concentration-dependent manner. From the above results, it is considered that DMPB shows strong potential as an anti-obesity substance.


Providing prostate cancer survivorship care in Japan: Implications from the USA care model.
Despite an increasing number of prostate cancer survivors in Japan, the current delivery of prostate cancer survivorship care is insufficient and lacks a multidisciplinary approach. We carried out a study to characterize prostate cancer survivorship care in Japan, examine the Japanese workforce available to deliver survivorship care, introduce a conceptual framework for survivorship and identify opportunities to improve Japanese survivorship care. We systematically searched PubMed for prostate cancer survivorship care studies, including those from Japan. We also searched the internet for prostate cancer guidelines relevant to survivorship care. We found 392 articles, of which 71 were relevant, read in detail and reported here. In Japan, survivorship care is mostly provided by urologists. Primary care as a specialty does not exist in Japan, and there are no independent nurse practitioners or physician assistants to assist with survivorship care. Japanese quality of life studies characterize the long-term effects of prostate cancer treatment, but routine use of patient-reported outcomes is not common in Japan. In the USA, in light of a growing comprehensive awareness of challenges facing survivors and their providers, the American Cancer Society prostate cancer survivorship care guidelines serve as a tool for optimizing the management of long-term treatment effects and coordination of care. In order to deliver high-quality survivorship care in Japan, urologists need to establish collaborations with other disciplines within the delivery system. A multidisciplinary guideline for prostate cancer survivorship care in Japan appears warranted.


Pyloric trichobezoar in a Canadian lynx (Lynx canadensis).
An adult female Canadian lynx (Lynx canadensis) was presented with a 3-wk history of anorexia and lethargy. Initial examination and diagnostics did not provide a diagnosis. The lynx continued to demonstrate vague clinical signs, including anorexia and an abnormal gait. During follow-up immobilizations 2 wk later, a barium gastrointestinal study revealed a pyloric obstruction. Abdominal exploratory surgery was elected, and a gastrotomy and an enterotomy of the proximal duodenum were performed to remove the pyloric obstruction. The obstruction was determined to be a trichobezoar. Fleas, a likely cause of hair ingestion through grooming, were noted during surgical preparation. The lynx made a full recovery from surgery. Reoccurrence of the trichobezoar was prevented after surgery with the use of monthly flea control and three times a week hairball laxative.


Donor site morbidity of the fasciocutaneous radial forearm flap: what does the patient really bother?
The objective of this study was the evaluation of donor site morbidity in head and neck cancer patients after reconstruction using a free vascularized radial forearm flap with emphasis on subjective complaints. Fifty patients who underwent at least 6 months before a reconstruction using a free vascularized radial forearm flap were asked to fill out two questionnaires regarding cosmetics and sensibility and forearm disabilities. Furthermore, a function test including movement extensions (flexion-extension, ulnar-radial deviation and pronation-supination), strength (pinch and grip) and temperature (digiti I and V) of the donor and non-donor site were measured and compared. Thirty-five percent of the patients reported no complaints regarding cosmetics and sensibility and 75% mentioned no forearm disabilities. There was no difference in movement extensions, temperature and grip strength between donor and non-donor sites. The difference in pinch strength appeared to be significant (p < 0.001). The total score of the questionnaire on forearm disabilities correlated significantly with extension, pronation and grip strength of the donor arm. Donor site morbidity of the radial forearm flap measured by objective functional tests was limited but subjective self-ratings revealed complaints regarding cosmestics and sensibility and to a lesser extent regarding forearm disability. The present data may be used for solid patient counselling.


Real-time opto-electronic verification of patient position in breast cancer radiotherapy.
The clinical application of an opto-electronic system for real-time three-dimensional (3D) control of patient position in breast cancer radiotherapy is described. The specific features of the motion analysis technology (shape recognition of passive markers) are detailed, and the outcomes of its clinical use for quantitative position control and immobility verification of the thoracic irradiation field during breast cancer treatment are reported. The position control system is based on the ELITEtrade mark opto-electronic motion analyzer, which provides in real time the 3D coordinates of a set of passive markers (plastic hemispheres 3 mm in diameter) previously placed on selected landmarks on the patient's skin. The system-dedicated hardware performs marker recognition by means of 2D correlation of shape with a predefined marker modeling mask. This feature ensures a high accuracy, even with small marker dimensions, and successful analysis in a noisy environment (due to room light, reflexes, etc.). The patient repositioning control was based on a comparison between the current positions of the markers and a corresponding reference configuration. The resulting marker displacements were graphically displayed in real time for immediate control. This information was not provided to the operator as a repositioning tool. Instead, the kinematic data was stored for subsequent off-line analysis aimed at quantifying the different factors contributing to patient mis-positioning (initial repositioning errors, patient's breathing, and random movements) when conventional means for patient alignment (laser centering) and immobilization (casting techniques) are used. Clinical application of the system revealed median 3D localization errors for the directly controlled anatomical landmarks of around 4.5 mm. This value is proposed to represent the intrinsic accuracy of conventional laser-centering techniques in breast cancer radiotherapy, including the effects of patient body deformations. When the positional inaccuracies introduced by patients' respiration were also considered, the extent of the resulting 3D mis-positioning of the control points increased to median values of up to 8 mm. The reported clinical trial confirms the significant role that real-time opto-electronic motion analysis based on passive markers can have in augmenting the accuracy of patient repositioning and immobility verification in the radiotherapy of a non-rigid body area while also accounting for physiological movements. Evaluation of the data collected during each irradiation session for five patients provided valuable information concerning the optimization of the efficacy of traditional methods for patient centering and immobilization.


Image super-resolution using progressive generative adversarial networks for medical image analysis.
Anatomical landmark segmentation and pathology localisation are important steps in automated analysis of medical images. They are particularly challenging when the anatomy or pathology is small, as in retinal images (e.g. vasculature branches or microaneurysm lesions) and cardiac MRI, or when the image is of low quality due to device acquisition parameters as in magnetic resonance (MR) scanners. We propose an image super-resolution method using progressive generative adversarial networks (P-GANs) that can take as input a low-resolution image and generate a high resolution image of desired scaling factor. The super resolved images can be used for more accurate detection of landmarks and pathologies. Our primary contribution is in proposing a multi-stage model where the output image quality of one stage is progressively improved in the next stage by using a triplet loss function. The triplet loss enables stepwise image quality improvement by using the output of the previous stage as the baseline. This facilitates generation of super resolved images of high scaling factor while maintaining good image quality. Experimental results for image super-resolution show that our proposed multi stage P-GAN outperforms competing methods and baseline GANs. The super resolved images when used for landmark and pathology detection result in accuracy levels close to those obtained when using the original high resolution images. We also demonstrate our methods effectiveness on magnetic resonance (MR) images, thus establishing its broader applicability.


Age-related changes in human peripapillary scleral strain.
To test the hypothesis that mechanical strain in the posterior human sclera is altered with age, 20 pairs of normal eyes from human donors aged 20 to 90 years old were inflation tested within 48-h postmortem. The intact posterior scleral shells were pressurized from 5 to 45 mmHg, while the full-field three-dimensional displacements of the scleral surface were measured using laser speckle interferometry. The full strain tensor of the outer scleral surface was calculated directly from the displacement field. Mean maximum principal (tensile) strain was computed for eight circumferential sectors (45° wide) within the peripapillary and mid-peripheral regions surrounding the optic nerve head (ONH). To estimate the age-related changes in scleral strain, results were fit using a functional mixed effects model that accounts for intradonor variability and spatial autocorrelation. Mechanical tensile strain in the peripapillary sclera is significantly higher than the strain in the sclera farther away from the ONH. Overall, strains in the peripapillary sclera decrease significantly with age. Sectorially, peripapillary scleral tensile strains in the nasal sectors are significantly higher than the temporal sectors at younger ages, but the sectorial strain pattern reverses with age, and the temporal sectors exhibited the highest tensile strains in the elderly. Overall, peripapillary scleral structural stiffness increases significantly with age. The sectorial pattern of peripapillary scleral strain reverses with age, which may predispose adjacent regions of the lamina cribrosa to biomechanical insult. The pattern and age-related changes in sectorial peripapillary scleral strain closely match those seen in disk hemorrhages and neuroretinal rim area measurement change rates reported in previous studies of normal human subjects.


Genetic manipulation of francisella tularensis.
Francisella tularensis is a facultative intracellular pathogen that causes the disease tularemia. F. tularensis subsp. tularensis causes the most severe disease in humans and has been classified as a Category A select agent and potential bioweapon. There is currently no vaccine approved for human use, making genetic manipulation of this organism critical to unraveling the genetic basis of pathogenesis and developing countermeasures against tularemia. The development of genetic techniques applicable to F. tularensis have lagged behind those routinely used for other bacteria, primarily due to lack of research and the restricted nature of the biocontainment required for studying this pathogen. However, in recent years, genetic techniques, such as transposon mutagenesis and targeted gene disruption, have been developed, that have had a dramatic impact on our understanding of the genetic basis of F. tularensis virulence. In this review, we describe some of the methods developed for genetic manipulation of F. tularensis.


Quantification of nitrogen in the liquid fraction and in vitro assessment of lysine bioavailability in the solid fraction of soybean meal hydrolysates.
Soybean meal (SBM) is a product generated from the manufacture of soybean oil and has the potential for use as a source of fermentable sugars for ethanol production or as a protein source for animal feeds. Knowing the levels of nitrogen available from ammonium is a necessary element of the ethanolic fermentation process while identifying the levels of essential amino acids such as lysine is important in determining usage as a feed source. As such the purpose of this study was to quantify total nitrogen and ammonium in the liquid fraction of hydrolyzed SBM and to evaluate total and bioavailable lysine in the solid fraction of the hydrolyzed SBM. The effects of acid concentration, cellulase and β-glucosidase on total and ammonium nitrogen were studied with analysis indicating that higher acid concentrations increased nitrogen compounds with ammonium concentrations ranging from 0.20 to 1.24 g L-1 while enzymatic treatments did not significantly increase nitrogen levels. Total and bioavailable lysine was quantified by use of an auxotrophic gfpmut3 E.coli whole-cell bioassay organism incapable of lysine biosynthesis. Acid and enzymatic treatments were applied with lysine bioavailability increasing from a base of 82% for untreated SBM to up to 97%. Our results demonstrated that SBM has the potential to serve in ethanolic fermentation and as an optimal source essential amino acid lysine.


A comparison of the statistical performance of different meta-analysis models for the synthesis of subgroup effects from randomized clinical trials.
When investigating subgroup effects in meta-analysis, it is unclear whether accounting in meta-regression for between-trial variation in treatment effects, but not between-trial variation in treatment interaction effects when such effects are present, leads to biased estimates, coverage problems, or wrong standard errors, and whether the use of aggregate data (AD) or individual-patient-data (IPD) influences this assessment. Seven different models were compared in a simulation study. Models differed regarding the use of AD or IPD, whether they accounted for between-trial variation in interaction effects, and whether they minimized the risk of ecological fallacy. Models that used IPD and that allowed for between-trial variation of the interaction effect had less bias, better coverage, and more accurate standard errors than models that used AD or ignored this variation. The main factor influencing the performance of models was whether they used IPD or AD. The model that used AD had a considerably worse performance than all models that used IPD, especially when a low number of trials was included in the analysis. The results indicate that IPD models that allow for the between-trial variation in interaction effects should be given preference whenever investigating subgroup effects within a meta-analysis.


An Integrated Framework for Process-Driven Model Construction in Disease Ecology and Animal Health.
Process models that focus on explicitly representing biological mechanisms are increasingly important in disease ecology and animal health research. However, the large number of process modelling approaches makes it difficult to decide which is most appropriate for a given disease system and research question. Here, we discuss different motivations for using process models and present an integrated conceptual analysis that can be used to guide the construction of infectious disease process models and comparisons between them. Our presentation complements existing work by clarifying the major differences between modelling approaches and their relationship with the biological characteristics of the epidemiological system. We first discuss distinct motivations for using process models in epidemiological research, identifying the key steps in model design and use associated with each. We then present a conceptual framework for guiding model construction and comparison, organised according to key aspects of epidemiological systems. Specifically, we discuss the number and type of disease states, whether to focus on individual hosts (e.g., cows) or groups of hosts (e.g., herds or farms), how space or host connectivity affect disease transmission, whether demographic and epidemiological processes are periodic or can occur at any time, and the extent to which stochasticity is important. We use foot-and-mouth disease and bovine tuberculosis in cattle to illustrate our discussion and support explanations of cases in which different models are used to address similar problems. The framework should help those constructing models to structure their approach to modelling decisions and facilitate comparisons between models in the literature.


An intraluminal stent facilitates light-activated vascular anastomosis.
Photochemical tissue bonding (PTB) is a sutureless, light-activated technique that produces a watertight, microvascular repair with minimal inflammation compared to standard microsurgery. However, it is practically limited by the need for a clinically viable luminal support system. The aim of this study was to evaluate a hollow biocompatible stent to provide adequate luminal support to facilitate vascular anastomosis using the PTB technique. Forty rats underwent unilateral femoral artery transection. Five rats were used to optimize the stent delivery method, and the remaining 35 rats were randomized into three groups: (1) standard suture repair with 10-0 nylon microsuture (SR), (2) standard suture repair over the stent (SR + S), or (3) PTB repair over stent (PTB + S). For the PTB group, a 2-mm overlapping cuff was painted with 0.1% (wt/vol) Rose Bengal then illuminated for 30 seconds on each side (532 nm, 0.5 W/cm, 30 J/cm). Anastomotic leak and vessel patency (immediate, 1 hour, and 1 week postoperatively) were assessed. Vessels in all three groups were patent immediately and at 1 hour postoperatively. After 1 week, all animals displayed patency in the SR group, while only 5 of 14 and 2 of 8 surviving animals had patent vessels in the PTB + S and SR + S groups, respectively. This study demonstrated successful use of an intraluminal stent for acute microvascular anastomosis using the PTB technique. However, the longer-term presence of the stent at the anastomotic site led to thrombosis in multiple cases. A rapidly dissolvable stent should facilitate a light-activated microvascular anastomosis with excellent long-term patency.


Enzymatic activity profile of a Brazilian culture collection of Candida albicans isolated from diabetics and non-diabetics with oral candidiasis.
The secretion of hydrolytic enzymes is a fundamental virulence factor of Candida albicans to develop disease. The objective of this study was to characterise the virulence of 148 clinical isolates of C. albicans from oral candidiasis by assessing the expression of phospholipase (PL) and secreted aspartyl proteinase (SAP). Isolates were obtained from healthy subjects (HS) and diabetics (DOC) and non-diabetics with oral candidiasis (NDOC). An aliquot (5 μl) of each cell suspension was inoculated on PL and SAP agar plates and incubated. Enzymes secretion was detected by the formation of an opaque halo around the colonies and enzymatic activity (PZ) was determined by the ratio between colony diameter and colony diameter plus the halo zone. Statistical comparisons were made by a one-way anova followed by Tukey's post hoc test (α = 0.05). The clinical sources of C. albicans had significant effect (P < 0.001) on the PZ values of both enzymes. For PL, clinical isolates from NDOC and DOC had highest enzymatic activity than those from HS (P < 0.05), with no significant differences between them (P = 0.506). For SAP, C. albicans from NDOC showed the lower enzymatic activity (P < 0.001). There were no significant differences between isolates from HS and DOC (P = 0.7051). C. albicans isolates from NDOC and DOC patients showed an increased production of PL.


Changes in volatile flavor components of guava juice with high-pressure treatment and heat processing and during storage.
The changes in volatile flavor components of guava juice during pressure processing (25 degrees C, 600 MPa, 15 min), heat processing (95 degrees C, 5 min), and storage at 4 and 25 degrees C were evaluated by purge and trap/gas chromatography/mass spectrometry. Esters were the major volatile fraction in guava juice, and alcohols were the second. Pressure processing could maintain the original flavor distribution of the juice. Heat processing (95 degrees C, 5 min) caused decreases in the majority of flavor components in the juice when compared with freshly extracted juice. High-pressure treatment at 600 MPa for 15 min can effectively sterilize microbes but partially inactivate enzymes of guava juice; therefore, volatile components in pressure-treated juice gradually changed during storage periods. Pressure-treated guava juice showed increases in methanol, ethanol, and 2-ethylfuran with decreases in the other components during storage period. Nevertheless, the volatile distribution of 600 MPa treated guava juice was similar to that of freshly extracted juice when stored at 4 degrees C for 30 days.


Characterization of a serine proteinase mediating encystation of Acanthamoeba.
Members of the genus Acanthamoeba, amphizoic protozoan parasites, are causative agents of granulomatous amoebic encephalitis and amoebic keratitis. Proteinases play a role in various biologic actions in Acanthamoeba, including host tissue destruction, pathogenesis, and digestion of phagocytosed food. Interestingly, we found that encystation of Acanthamoeba was inhibited by the serine proteinase inhibitor phenylmethanesulfonyl fluoride. In this study, we characterize a serine proteinase that is involved in mediating the encystation of Acanthamoeba. This encystation-mediating serine proteinase (EMSP) is shown to be highly expressed during encystation by real-time PCR and Western blot analysis. Chemically synthesized small interfering RNA against EMSP inhibited the expression of EMSP mRNA and significantly reduced the encystation efficiency of Acanthamoeba. An EMSP-enhanced green fluorescent protein fusion protein localized to vesicle-like structures within the amoeba. Using LysoTracker analysis, these vesicular structures were confirmed to be lysosomes. After incubation of the transfected amoeba in encystment media, small fluorescent vesicle-like structures gathered and formed ball-like structures, which were identified as colocalizing with the autophagosome. Taken together, these results indicate that EMSP plays an important role in the differentiation of Acanthamoeba by promoting autolysis.


Discovering the binding modes of natural products with histone deacetylase 1.
Histone deacetylases (HDACs) belong to a superfamily of enzymes responsible for deacetylating the Nterminal tails of histones. Overproduction of HDACs has a significant role in tumorigenesis. Accordingly, inhibition of HDACs has been widely applied for cancer therapy. It is encouraging that some natural products showed promising potency and selectivity against HDACs. In order to uncover their keys of good performance, the binding patterns of several natural HDAC1 inhibitors in the active site of HDAC1 were navigated by homology modeling, docking and molecular dynamic simulations. Evaluation of the binding poses allowed us to recognize the roles of different residues around the active site, and to understand the core features in the structure of the inhibitor molecule. Hydrophobic and H-bond interactions formed between the ligand and residues were discovered to make significant contributions to the ligand-receptor binding. Finally, the structural requirement of inhibitors for binding to HDAC1 was well proposed. Our results are beneficial to the design of potent HDAC1 inhibitors.


Population-Based Analysis and Projections of Liver Supply Under Redistricting.
To reduce the geographic heterogeneity in liver transplant allocation, the United Network of Organ Sharing has proposed redistricting, which is impacted by both donor supply and liver transplantation demand. We aimed to determine the impact of demographic changes on the redistricting proposal and characterize causes behind geographic heterogeneity in donor supply. We analyzed adult donors from 2002 to 2014 from the United Network of Organ Sharing database and calculated regional liver donation and utilization stratified by age, race, and body mass index. We used US population data to make regional projections of available donors from 2016 to 2025, incorporating the proposed 8-region redistricting plan. We used donors/100 000 population age 18 to 84 years (D/100K) as a measure of equity. We calculated a coefficient of variation (standard deviation/mean) for each regional model. We performed an exploratory analysis where we used national rates of donation, utilization and both for each regional model. The overall projected D/100K will decrease from 2.53 to 2.49 from 2016 to 2025. The coefficient of variation in 2016 is expected to be 20.3% in the 11-region model and 13.2% in the 8-region model. We found that standardizing regional donation and utilization rates would reduce geographic heterogeneity to 4.9% in the 8-region model and 4.6% in the 11-region model. The 8-region allocation model will reduce geographic variation in donor supply to a significant extent; however, we project that geographic disparity will marginally increase over time. Though challenging, interventions to better standardize donation and utilization rates would be impactful in reducing geographic heterogeneity in organ supply.


Antimycobacterial activity of selected medicinal plants traditionally used in Sudan to treat infectious diseases.
The emergence of multidrug-resistant strains of Mycobacterium tuberculosis underscores the need for continuous development of new and efficient methods to determine the susceptibility of isolates of Mycobacterium tuberculosis in the search for novel antimycobacterial agents. Natural products constitute an important source of new drugs, and design and implementation of antimycobacterial susceptibility testing methods are necessary to evaluate the different extracts and compounds. In this study we have explored the antimycobacterial properties of 50 ethanolic extracts from different parts of 46 selected medicinal plants traditionally used in Sudan to treat infectious diseases. Plants were harvested and ethanolic extracts were prepared. For selected extracts, fractionation with hydrophilic and hydrophobic solvents was undertaken. A luminometry-based assay was used for determination of mycobacterial growth in broth cultures and inside primary human macrophages in the presence or absence of plant extracts and fractions of extracts. Cytotoxicity was also assessed for active fractions of plant extracts. Of the tested extracts, three exhibited a significant inhibitory effect on an avirulent strain of Mycobacterium tubercluosis (H37Ra) at the initial screening doses (125 and 6.25µg/ml). These were bark and leaf extracts of Khaya senegalensis and the leaf extract of Rosmarinus officinalis L. Further fractions of these plant extracts were prepared with n-hexane, chloroform, ethyl acetate, n-butanol, ethanol and water, and the activity of these extracts was retained in hydrophobic fractions. Cytotoxicity assays revealed that the chloroform fraction of Khaya senegalensis bark was non-toxic to human monocyte-derived macrophages and other cell types at the concentrations used and hence, further analysis, including assessment of IC50 and intracellular activity was done with this fraction. These results encourage further investigations to identify the active compound(s) within the chloroform fraction of Khaya senegalensis bark.


Immigrant employment and earnings growth in Canada and the USA: evidence from longitudinal data.
We study the short-term trajectories of employment, hours worked, and real wages of immigrants in Canada and the U.S. using nationally representative longitudinal datasets covering 1996-2008. Models with person fixed effects show that on average immigrant men in Canada do not experience any relative growth in these three outcomes compared to men born in Canada. Immigrant men in the U.S., on the other hand, experience positive annual growth in all three domains relative to U.S. born men. This difference is largely on account of low-educated immigrant men, who experience faster or longer periods of relative growth in employment and wages in the U.S. than in Canada. We further compare longitudinal and cross-sectional trajectories and find that the latter over-estimate wage growth of earlier arrivals, presumably reflecting selective return migration.


[Felix Mendelssohn Bartholdy (1809 - 1847): the mystery of his early death].
Composer and director of music at Leipzig's Gewandhaus Felix Mendelssohn Bartholdy died remarkably young, on 4 November 1847, at the age of 38. The cause of his early death has been a mystery ever since. Three contemporary doctors diagnosed Nervenschlag ("nervous stroke"). Starting with a short outline of Mendelssohn's pathography, this paper includes and quotes for the first time all the contemporary accounts of his death. After considering the older medical interpretations, the paper considers these reports from the point of view of present-day neurological and psychiatric expertise. It reveals that all the accounts had been filed by medical laymen, so their personal impressions had played a major role in their reports. However, it is indisputable that it was pathologic brain alterations that lead to Mendelssohn's death. Weighing up and carefully considering the sources, the authors regard subarachnoidal hemorrhage (SAH) as a likely cause of death. There may even have been some kind of genetic predisposition, since what is reported in this paper regarding Mendelssohn's death also applies to the very similar symptoms and circumstances surrounding his sister Fanny's death.


Successful treatment of middle aged and elderly patients with end stage renal disease.
Many patients over the age of 55 with end stage renal disease in the United Kingdom are denied dialysis or transplantation. Although the reasons are complex, anticipation of a poor prognosis for these patients might explain why most British renal units impose an arbitrary age limit on the acceptance of patients for treatment. A study was therefore conducted to examine the prognosis and quality of life of 84 patients (mean age 59.6 years, range 55-72) accepted into our renal replacement programme from the beginning of 1975. The five year survival of the patients was 62.0% with 78.1% of the survivors either having successful transplants or caring for themselves using home haemodialysis or continuous ambulatory peritoneal dialysis. The results show that in terms of survival, economics, and rehabilitation it is both feasible and reasonable to treat middle aged and elderly patients with end stage renal disease. These patients should therefore not be denied dialysis or transplantation on the basis of age alone, and the lack of resources and other factors that allow this state to persist in Britain should be rapidly redressed.


Trans-generational immune priming in the mealworm beetle protects eggs through pathogen-dependent mechanisms imposing no immediate fitness cost for the offspring.
Immune-challenged mothers can improve their offspring immunity through trans-generational immune priming (TGIP). In insects, TGIP endows the offspring with lifetime immunity, including the eggs, which are likely exposed soon after maternal infection. Egg protection may rely on the transfer of maternal immune effectors to the egg or/and the induction of egg immune genes. These respective mechanisms are assumed to have early-life fitness costs of different magnitude for the offspring. We provide evidence in the mealworm beetle Tenebrio molitor that enhanced egg immunity following a maternal immune challenge is achieved by both of these mechanisms but in a pathogen-dependent manner. While previously found having late-life fitness costs for the offspring, TGIP here improved egg hatching success and early larval survival, in addition of improving offspring immunity. These results suggest that early-life of primed offspring is critical in the optimization of life history trajectory of this insect under trans-generational pathogenic threats.


In vivo manipulation (depletion versus activation) of testicular macrophages: central and local effects.
Testicular macrophages are a relevant cell type for the regulation of Leydig cell steroidogenesis. The availability of liposome technology allows in vivo manipulation of macrophages in order to analyze their role in the regulation of the hypothalamic-pituitary-testicular axis. In this study, adult (70 days of age) and prepubertal (22 days of age) rats were injected intratesticularly with liposomes containing either dichloromethylene diphosphonate (C12MDP) to deplete testicular macrophages or muramyl tripeptide (MTP-PE) to activate them. Control rats were injected with the corresponding volumes of 0.9% NaCl. Animals were killed 10 days after treatment. Adult rats injected bilaterally or unilaterally with C12MDP liposomes showed increased serum LH and testosterone concentrations, as well as increased testosterone concentrations in the testicular interstitial fluid. In unilaterally injected rats, testosterone concentrations in the interstitial fluid were higher in the macrophage-containing testes than in the contralateral, macrophage-depleted testes. Adult rats treated bilaterally with MTP-PE liposomes showed increased numbers of testicular macrophages, whereas the number of Leydig cells was unchanged. Serum LH concentrations were decreased, but no changes were found in testosterone concentrations. Prepubertal rats treated bilaterally with C12MDP liposomes showed decreased numbers of Leydig cells. However, serum LH and testosterone concentrations were increased. Otherwise, prepubertal rats treated bilaterally with MTP-PE liposomes showed increased numbers of macrophages and Leydig cells, as well as increased serum testosterone concentrations. These data suggest that testicular macrophage-derived factors act at two different levels in the pituitary-testicular axis: first, at a central level by inhibiting LH secretion, and secondly, at a local level by stimulating Leydig cell steroidogenesis.


Effect of Ta2O5 content on the osseointegration and cytotoxicity behaviors in hydroxyapatite-Ta2O5 coatings applied by EPD on superelastic NiTi alloys.
In the present study, the different contents of tantalum pentoxide (Ta2O5: 10, 15, 20 and 30 wt%) nanoparticles were introduced into the natural hydroxyapatite (nHA) coating structure on NiTi substrate through electrophoretic deposition (EPD) method. The phase compositions of coatings were perused before and after the sintering at 800 °C for 1 h by XRD. The incorporation of 30wt%Ta2O5 into nHA matrix induced the formation of undesirable soluble Ca3(PO4)2 phase in composite coating. The FESEM images showed that the density of continuous nHA coating increased by compositing with Ta2O5. The maximum adhesion strength of 28.3 ± 0.7 MPa accomplished from the nHA-20 wt%Ta2O5 composite coating. The Ni ions concentration measurement results from the passivated-NiTi with nHA and nHA-(10, 15 and 20)wt%Ta2O5 coatings during 30 days of immersion in PBS clarified the positive role of Ta2O5 in decreasing the Ni leaching due to the lowering the open porosities of nHA structure. The biological response of the coating surfaces was assessed in vitro by cell culturing and MTS assay. By considering the morphology and density of adsorbed cells on each coating, the improved biocompatibility of nHA coating in the presence of Ta2O5 was justified by scrutinizing the surface roughness, wettability and charge. The highest cell attachment and proliferation on nHA-20 wt%Ta2O5 coating was related to owning the lowest roughness, wetting angle of 34o ± 0.5 and the highest negative surface charge density. Also, the concentration of the highest negative charge density on nHA-20 wt%Ta2O5 coating surface in the SBF solution caused to the enhancement of the amount of the apatite nuclei through providing more sites to calcium absorption.


Therapeutic Drug Monitoring of Olanzapine and Cytochrome P450 Genotyping in Nonsmoking Subjects.
The relationship between a daily dose of olanzapine, its serum concentration, and the genotype of young nonsmoking men treated for schizophrenia or schizophreniform disorder was investigated in day-to-day clinical practice. Pharmacogenetics was also examined for the selected patients. A total of 49 participants were recruited as in-patients at the Mental Health Research Center (Moscow, Russia). Inclusion criteria were patients who had been diagnosed with schizophrenia or schizoaffective disorder (following DSM-IV guidelines) and were being treated with OLZ. A prospective, observational, open-study design was implemented. In line with the literature, patients were only included if they attained steady-state OLZ concentrations lasting for at least 8 days. A liquid chromatographic-tandem mass spectrometric method was developed for analyzing OLZ in human serum. The single cytochrome P450 polymorphisms were genotyped using an amplifier real-time polymerase chain reaction system following standard protocols. Evidence indicating that CYP2D6 polymorphism has a significant (P = 0.046) effect on the pharmacokinetics of olanzapine was obtained, confirming the beneficial effects of therapeutic drug monitoring (TDM) for olanzapine. TDM should therefore be used as a standard care during olanzapine therapy. TDM is also useful in assessing adherence and may have a role in limiting olanzapine dosage geared at minimizing the risk of long-term toxicity.


How changes in the serial distribution of bronchoconstriction affect lung mechanics.
It is generally accepted that methacholine (MCh) acts predominantly on the central airways and histamine (H) acts on the lung periphery. We hypothesized therefore that lung mechanics would be affected differently by H and MCh aerosols. In 12 anesthetized paralyzed open-chest mongrel dogs, we obtained MCh (0.1-30 mg/ml, n = 6) and H (0.1-30 mg/ml, n = 6) concentration-response curves. The alveolar capsule technique was used to partition lung resistance (RL) into airway (Raw) and tissue (Rti) components. The degree of mechanical heterogeneity across the lung was assessed by computing the coefficient of variation for five alveolar pressures during relaxed expirations. RL increased 823 +/- 202% after H and 992 +/- 219% after MCh. Rti increased 784 +/- 192% after H and 1,014 +/- 279% after MCh. Raw increased 1,098 +/- 297% after H and 1,275 +/- 332% after MCh. Elastance increased 342 +/- 53% after H and 423 +/- 88% after MCh. The coefficient of variation increased 279 +/- 65% after H and 252 +/- 55% after MCh. The patterns of change were similar throughout the H and MCh concentration-response curves. We conclude that H and MCh have comparable effects on lung mechanics and that the degree and pattern of heterogeneity inside the lung after constriction are the same regardless of the agent used. These data support the hypothesis that H and MCh have some similar direct effect on the lung parenchyma. Parenchymal deformation after MCh-induced central airway constriction alone would be unlikely to explain increases in Rti of this magnitude or changes in lung mechanics so similar to those induced by H.


Effect of circulating tumor cell aggregate configuration on hemodynamic transport and wall contact.
Selectin-mediated adhesion of circulating tumor cells (CTCs) to the endothelium is a critical step in cancer metastasis, a major factor contributing to the mortality of cancer. The formation of tethers between tumor cells and endothelial selectins initiates cell rolling, which can lead to firm adhesion, extravasation and the formation of secondary metastases. Tumor cells travel through the bloodstream as single cells, or as aggregates known as circulating tumor microemboli (CTM). CTM have increased survivability and metastatic potential relative to CTCs, and the presence of CTM is associated with worse patient prognosis. The motion of cells and cellular aggregates in flow is a function of their size and shape, and these differences influence the frequency and strength of their contact with the endothelium. In this study, a computational model consisting of the hydrodynamic component of the Multiparticle Adhesive Dynamics simulation analyzed the effects of model aggregate conformation and orientation on adhesive binding potential. Model aggregates of the Colo205 colorectal cancer cell line were created, consisting of two, three, and four cells in simple geometrical conformations. Contact time, contact area, and time integral of contact area were measured as a function of fluid shear rate, initial centroid height, and initial orientation for model aggregates that experienced hydrodynamic collisions with the plane wall. It was found that larger CTM conformations with intermediate nonsphericities had the highest adhesion potential. The results of this study shed light on the correlation between environmental conditions and extravasation efficiency, which could inform the development of new anti-metastatic drugs.


Complementary and alternative medicine use in England: results from a national survey.
In many countries, recent data on the use of complementary and alternative medicine (CAM) are available. However, in England, there is a paucity of such data. We sought to determine the prevalence and predictors of CAM use in England. Data were obtained from the Health Survey for England 2005, a national household survey that included questions on CAM use. We used binary logistic regression modelling to explore whether demographic, health and lifestyle factors predict CAM use. Data were available for 7630 respondents (household response rate 71%). Lifetime and 12-month prevalence of CAM use were 44.0% and 26.3% respectively; 12.1% had consulted a practitioner in the preceding 12 months. Massage, aromatherapy and acupuncture were the most commonly used therapies. Twenty-nine percent of respondents taking prescription drugs had used CAM in the last 12 months. Women (OR 0.491, 95% CI: 0.419, 0.577), university educated respondents (OR 1.296, 95% CI: 1.088, 1.544), those suffering from anxiety or depression (OR 1.341, 95% CI: 1.074, 1.674), people with poorer mental health (on GHQ: OR 1.062, 95% CI 1.026, 1.100) and lower levels of perceived social support (1.047, 95% CI: 1.008, 1.088), people consuming ≥ 5 portions of fruit and vegetables a day (OR 1.327, 95% CI: 1.124, 1.567) were significantly more likely to use CAM. Complementary and alternative medicine use in England remains substantial, even amongst those taking prescription drugs. These data serve as a valuable reminder to medical practitioners to ask patients about CAM use and should be routinely collected to facilitate prioritisation of the research agenda in CAM.


Treatment outcomes with adult children of alcoholics: depression.
This article describes an intervention study investigating treatment outcomes for college-age adult children of alcoholics (ACOA) exposed to group treatment. In this quasi-experimental design, ACOA subjects were randomly assigned to a psychotherapy group, a self-help group, or a control group. While group psychotherapy was as good a treatment modality as self-help groups in decreasing levels of depression, it was found that either of these group treatment modalities was effective in decreasing depression compared with the no treatment control. Implications of these findings are discussed in relation to clinical nurse specialists.


Former Latchkey Children: Personality and Academic Correlates.
The purpose of this study was to examine the prevalence and correlates (demographic, personality, and academic) of former latchkey status (children unsupervised by an adult after school during their elementary or middle school years) in a college student sample (N = 188). A clear operational definition of latchkey status was provided. Students were surveyed and administered a personality questionnaire, and their academic aptitude test scores were verified through university records. Twenty-five percent of the male and 14% of the female participants were identified as former latchkey children, resulting in an 18% latchkey prevalence rate. The mean age of onset of latchkey status was 8.7 years for the male and 10.0 years for the female subjects. Having been a latchkey child was positively associated with being male and Caucasian, coming from a one-parent family, and having had a mother who worked outside the home. Multivariate analyses of the personality and academic measures revealed no significant between-group differences.


Disease characteristics and treatment patterns of Chinese patients with metastatic colorectal cancer: a retrospective study using medical records from China.
Colorectal cancer (CRC) is the third most prevalent cancer in China but few large-scale studies were conducted to understand CRC patients. The current study is aimed to gain a real-world perspectives of CRC patients in China. Using electronic medical records of sampled patients between 2011 and 2016 from 12 hospitals in China, a retrospective cohort study was conducted to describe demographics and disease prognosis of CRC patients, and examine treatment sequences among metastatic CRC (mCRC) patients. Descriptive, comparative and survival analyses were conducted. Among mCRC patients (3878/8136, 48%), the fluorouracil, leucovorin, and oxaliplatin (FOLFOX) and other oxaliplatin-based regimens were the most widely-used first-line treatment (42%). Fluorouracil, leucovorin, irinotecan (FOLFIRI) and other irinotecan-based regimens dominated the second-line (40%). There was no a dominated regimen for the third-line. The proportion of patients receiving chemotherapy with targeted biologics increased from less than 20% for the first- and second- lines to 34% for the third-line (p < 0.001). The most common sequence from first- to second-line was from FOLFOX and other oxaliplatin-based regimens to FOLFIRI and other irinotecan-based regimens (286/1200, 24%). Our findings reflected a lack of consensus on the choice of third-line therapy and limited available options in China. It is evident o continue promoting early CRC diagnosis and to increase the accessibility of treatment options for mCRC patients. As the only nationwide large-scale study among CRC and mCRC patients before more biologics became available in China, our results can also be used as the baseline to assess treatment pattern changes before and after more third-line treatment were approved and covered into the National Health Insurance Plan in China between 2017 and 2018.


Shoulder Injuries in Individuals Who Participate in CrossFit Training.
CrossFit, a sport and fitness program, has become increasingly popular both nationally and internationally. Researchers have recently identified significant improvements in health and wellness due to CrossFit. However, some individuals assert that CrossFit poses an inherent risk of injury, specifically to the shoulder, due to the intensity of training. Currently, there is limited evidence to support this assertion. Exercises performed during CrossFit do not place the shoulder at greater risk for injury. Injury rates are comparable to other sports of similar intensity. Descriptive survey study. Level 5. An electronic survey was developed and dispersed to approximately 980 individuals who trained in CrossFit gyms. The survey identified demographic data, training characteristics, and the prevalence of injury over a 6-month period in individuals who participated in CrossFit training. A total of 187 (19.1%) individuals completed the survey. Forty-four (23.5%) indicated that they had experienced a shoulder injury during CrossFit training over the previous 6 months. Of those who reported injury, 17 (38.6%) stated that this injury was an exacerbation of a previous injury sustained prior to starting CrossFit. There was no significant relationship between several demographic and training variables and shoulder injury. All shoulder injuries occurred at a rate of 1.94 per 1000 hours training, while "new" shoulder injuries occurred at a rate of 1.18 per 1000 hours training. The most commonly attributed causes of injury were improper form (33.3%) and exacerbation of a previous injury (33.3%). Twenty-five (64.1%) of those who experienced injury reported 1 month or less of training reduction due to the injury. Shoulder injury rates during CrossFit training are comparable to other methods of recreational exercise. Clinicians should be aware of training demands of exercises in CrossFit and modifications for these exercises to safely progress their patients back to participation.


Collagen autoimmunity and arthritis.
Collagen-induced arthritis in animals is an example of polyarthritis that sufficiently resembles human rheumatoid arthritis to be used as a model. It is caused by immunizing susceptible animals with type II collagen isolated from articular cartilage. Susceptibility is genetically determined and linked to the major histocompatibility locus. It is important because some human arthritis is also associated with major histocompatibility genes and may be caused or aggravated by the presence of autoimmunity to normal cartilage components. Collagen-induced arthritis is also important because it is an example of immunologically mediated joint destruction, which may share some of the mechanisms present in human disease. Although it is caused by autoimmunity to collagen, susceptibility and responsiveness to type II collagen are not completely correlated, and there are examples of animals with high levels of collagen immunity who do not develop arthritis. The initial lesion appears to be the deposition of an antibody on the surface of articular cartilage, which precedes development of overt arthritis by several days. Disease can be readily transferred with specific antibody. Arthritogenic antibodies appear to have restricted epitope specificity, which may partially explain the disparities between responsiveness to immunization with collagen and susceptibility to arthritis, but precise delineation of the epitopes involved has not yet been accomplished. Complement activation also appears to be intimately involved since the disease correlates with the presence of high levels of complement-binding IgG isotypes, and passive transfer is possible only into complement-sufficient recipients. Inflammation progresses rapidly so that cartilage destruction and marginal erosion develop over a period of a few days. Collagen-induced arthritis offers a unique opportunity to study autoimmune-mediated arthritis in which the inducing antigen is well characterized and readily available. Analysis of the disease has permitted the proposal of a schema for its pathogenesis.


Self-management education among women with pre-existing diabetes in pregnancy: A scoping review.
Education is a cornerstone of self-management for adults with diabetes. Self-management is particularly important during pregnancy for women with type 1 and type 2 diabetes, as perinatal outcomes are affected by maternal glycemic control. To our knowledge, literature describing the provision of diabetes education and support during pregnancy for women with type 1 and type 2 diabetes has not been synthesized, nor examined within its context as a complex intervention. This scoping review aims to synthesize the evidence regarding prenatal diabetes education and support for women with type 1 and type 2 diabetes and to apply the Medical Research Council framework for complex interventions where appropriate. We searched EMBASE, CINAHL, and MEDLINE from inception to February 2019 for primary studies focused on prenatal diabetes education among women with type 1 and type 2 diabetes. Two independent reviewers screened eligible studies against inclusion criteria. A narrative synthesis of the included studies was conducted. Of 511 identified citations, 30 studies were included in the final review. Approximately 44% of the pooled sample were women with type 1 diabetes, 46% had gestational diabetes mellitus, and 10% had type 2 diabetes. Education focused on self-monitoring of blood glucose, attaining glycemic targets, and following a healthy diet. Many studies included educational elements that went beyond traditional didactic teaching and promoted self-management skills and self-management support. The majority of education was delivered via one-on-one outpatient appointments every one to three weeks. About half of the reviewed studies used a multidisciplinary team approach, with most including a combination of physicians, nurses, dietitians, and midwives. Application of the Medical Research Council framework revealed that most studies were limited in methods (i.e., randomization) and few examined process evaluation or intervention cost-effectiveness. We identified a lack of studies centred on educational interventions for women with type 2 diabetes in pregnancy. As pregnancy for women with type 2 diabetes involves significant changes, including the transition from oral hypoglycemics to insulin therapy, often without exposure to diabetes-specific preconception care and counselling, future research may focus on optimizing preconception and prenatal education and support for this high-risk group. This is particularly relevant as the prevalence of type 2 diabetes is increasing worldwide. Future research ought to also design, implement and evaluate interventions in accordance with the Medical Research Council framework for complex interventions.


Epidermal growth factor receptor mutations should be considered as a prognostic factor for survival of patients with pathological fractures or painful bone metastases from non-small cell lung cancer.
This study aims to assess first, whether mutations in the epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma (kRAS) genes are associated with overall survival (OS) in patients who present with symptomatic bone metastases from non-small cell lung cancer (NSCLC) and secondly, whether mutation status should be incorporated into prognostic models that are used when deciding on the appropriate palliative treatment for symptomatic bone metastases. We studied 139 patients with NSCLC treated between 2007 and 2014 for symptomatic bone metastases and whose mutation status was known. The association between mutation status and overall survival was analysed and the results applied to a recently published prognostic model to determine whether including the mutation status would improve its discriminatory power. The median OS was 3.9 months (95% confidence interval (CI) 2.1 to 5.7). Patients with EGFR (15%) or kRAS mutations (34%) had a median OS of 17.3 months (95% CI 12.7 to 22.0) and 1.8 months (95% CI 1.0 to 2.7), respectively. Compared with EGFR-positive patients, EGFR-negative patients had a 2.5 times higher risk of death (95% CI 1.5 to 4.2). Incorporating EGFR mutation status in the prognostic model improved its discriminatory power. Survival prediction models for patients with symptomatic bone metastases are used to determine the most appropriate (surgical) treatment for painful or fractured lesions. This study shows that NSCLC should not be regarded as a single entity in such models. Cite this article: Bone Joint J 2017;99-B:516-21.


[Disorders related to traumatic events. Screening and treatment].
To educate family physicians about screening, diagnosis, and treatment of psychological disorders related to traumatic events. PsycLIT, PsychINFO, PILOTS, and MEDLINE databases were searched from January 1985 to December 2000 using the terms "acute stress disorder," "posttraumatic stress disorder," "traumatic stress," "psychotherapy," "psychosocial treatment," "treatment," and "pharmacotherapy." Recommendations concerning treatment of acute stress disorder (ASD) and posttraumatic stress disorder (PTSD) are based on evidence from trials of the highest quality. Conclusions about assessment and diagnosis are based on the most recent epidemiologic studies, consensus, and expert opinion. Very often, ASD and PTSD are underdiagnosed and undertreated. Family physicians are likely to see patients suffering from these disorders. Early screening in primary care is a function of active listening; warm, safe patient-physician relationships; and careful examination of difficulties related to traumatic events. Ideally, patients with either ASD or PTSD should be referred to a specialist. If a specialist is unavailable, family physicians can offer support and prescribe medication to address patients' symptoms. Family physicians can help identify and treat patients presenting with disorders related to traumatic events.


Dr Syntax's view of Edinburgh medicine: the life and pictures of John Sheriff (1775-1844).
From the 1820s to the 1840s, one of the most recognisable figures in Edinburgh was the eccentric John Sheriff, generally known as Dr Syntax. He was a talented amateur artist, whose work provides a fascinating and strange insight into the mind of a troubled man and, because of his interest in medicine, into the history of medicine in Scotland at the time. This paper seeks to show that Sheriff and his pictures deserve to be remembered, since they offer intriguing insights for anyone interested in the history of medicine and of Edinburgh at the end of its Golden Age.