Use of molecular probes to study regulation of aromatase cytochrome P-450.
Aromatase, an enzyme complex localized in the endoplasmic reticulum of estrogen-producing cells, is composed of NADPH-cytochrome P-450 reductase, and aromatase cytochrome P-450 (cytochrome P-450AROM). To define the molecular mechanisms involved in the multifactorial regulation of cytochrome P-450AROM in estrogen-producing cells, we have isolated a cDNA specific for human cytochrome P-450AROM and have used this cDNA to isolate the human cytochrome P-450AROM gene. The cDNA sequence encodes a polypeptide of 503 amino acids and contains--near the carboxy-terminus, a region of high homology with the putative heme-binding regions of other P-450 cytochromes. COS1 cells transfected with an expression plasmid containing the cytochrome P-450AROM cDNA had the capacity to aromatize testosterone, androstenedione and 16 alpha-hydroxyandrostenedione, suggesting that a single polypeptide catalyzes all steps of the aromatization reaction using either of the three major C19-substrates. The human cytochrome P-450AROM gene is greater than 52 kb in size and consists of 10 exons and 9 introns. Hormonally induced changes in aromatase activity of human ovarian granulosa and adipose stromal cells are associated with comparable changes in cytochrome P-450AROM gene expression and synthesis, whereas the reductase component is only modestly affected. Studies are in progress to define the molecular mechanisms involved in the regulation of cytochrome P-450AROM gene expression in estrogen-producing cells.


Hydroxamate production by Aquaspirillum magnetotacticum.
Spent culture fluids from Aquaspirillum magnetotacticum MS-1 grown at high (20 microM) but not low (5 microM) iron concentration contained material yielding a positive hydroxamate test. Cells possessed six major outer membrane proteins. Three outer membrane proteins ranging from 72,000 to 85,000 daltons were coordinately produced at iron concentrations conducive to hydroxamate production. A 55,000-dalton iron-repressible outer membrane protein was also present in strain MS-1 cultured at low but not high ferric quinate concentration. Culture fluids from strain MS-1 which were hydroxamate positive augmented growth of a Salmonella typhimurium siderophore-deficient (enb-7) mutant in low-iron medium, suggesting a role of hydroxamate in uptake of iron by the cell.


The International Diabetes Closed-Loop Study: Testing Artificial Pancreas Component Interoperability.
Use of artificial pancreas (AP) requires seamless interaction of device components, such as continuous glucose monitor (CGM), insulin pump, and control algorithm. Mobile AP configurations also include a smartphone as computational hub and gateway to cloud applications (e.g., remote monitoring and data review and analysis). This International Diabetes Closed-Loop study was designed to demonstrate and evaluate the operation of the inControl AP using different CGMs and pump modalities without changes to the user interface, user experience, and underlying controller. Forty-three patients with type 1 diabetes (T1D) were enrolled at 10 clinical centers (7 United States, 3 Europe) and 41 were included in the analyses (39% female, >95% non-Hispanic white, median T1D duration 16 years, median HbA1c 7.4%). Two CGMs and two insulin pumps were tested by different study participants/sites using the same system hub (a smartphone) during 2 weeks of in-home use. The major difference between the system components was the stability of their wireless connections with the smartphone. The two sensors achieved similar rates of connectivity as measured by percentage time in closed loop (75% and 75%); however, the two pumps had markedly different closed-loop adherence (66% vs. 87%). When connected, all system configurations achieved similar glycemic outcomes on AP control (73% [mean] time in range: 70-180 mg/dL, and 1.7% [median] time <70 mg/dL). CGMs and insulin pumps can be interchangeable in the same Mobile AP system, as long as these devices achieve certain levels of reliability and wireless connection stability.


Burdensome Research Procedures in Trials: Why Less Is More.
A large volume of trials involve invasive, nontherapeutic research procedures, like organ biopsy or sham surgeries, that can pose risks comparable with the experimental treatment itself but that have no direct benefit for volunteers. Though such procedures can enhance the value of clinical investigations, recent studies suggest that many studies involving invasive, nontherapeutic research procedures are not well planned and reported; some studies suggest that their results are often not utilized in the planning of new investigations. This commentary offers recommendations for how investigators, sponsors, and ethics committees might improve evaluation and implementation of studies involving invasive nontherapeutic procedures. We conclude by urging more demanding scientific standards for the rationale, design, and reporting of burdensome, nontherapeutic research procedures-particularly where they involve risk of serious complications.


Changes of the quality-of-life under the treatment of severe senile osteoporosis with teriparatide.
Despite being treated with antiresorptive drugs, the severe osteoporosis (SO) is being considered as a condition in which patients are still subject to one or more vertebral or femoral fractures, or non-vertebral or non-femoral fractures, i.e., of other parts of the body such as the wrist, shoulder, tibia, ribs or hip. These patients are defined as non-responders (NRs) to the antiresorptive therapy, and recent research has shown that they represent 10-25% of all SO patients. During the last almost 3 years a new drug has become available in Italy, called teriparatide (rh-PTH-1-34), produced in Escherichia coli using the recombinant-DNA technique. It shows remarkable trophic and anabolic actions on the bones, and proved to be very useful for treating the osteoporosis in general. This study describes our experience in using teriparatide for the treatment of SO in a sample of 141 elderly women of mean age 73.4+/-5.8 years, with a mean number of fractures of 3.0+/-0.85, with a spine deformity index (SDI) of 5.92+/-1.27 and a mean vertebral T-Score (L1-L4) of -3.15+/-0.39, and a mean femoral T-Score of -2.50+/-0.28. All these patients had been treated with antiresorptive drugs for at least 1 year: specifically 70 of them with Alendronate, 42 of them with Risedronate and 29 of them with Raloxifene. For 18 months, all these patients were injected subcutaneously with 20 microg of teriparatide, with the daily addition of 1 g of calcium and 880 IU of vitamin D. The study was continued for 24 months, at the end of which the patients continued to take only calcium and vitamin D. The patients underwent a CBM-DEXA control of vertebral column and femur every 6 months, and they were also administered a Quality-of-Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO). The QUALEFFO (41 items) questionnaire to evaluate the changes in the quality-of-life (QoL) and the consumption of non-steroidal anti-inflammatory drugs (NSAIDs) was also recorded. The results showed that teriparatide protected 96.5% against new fractures (only five new fractures occurred), bone mineral density (BMD) increased approximately by 12% in the vertebral column and by 11% in the femur, consumption of NSAIDs was reduced at the early stage approximately 80%, the QoL improved considerably and remained so during the 18 months of teriparatide treatment, with only a slight decrease during the 6 subsequent months.


Redefining Therapeutic Outcomes of Depression Treatment.
Responses to evidence-based interventions for depression are divergent: Some patients benefit more than others during treatment and some do not benefit at all or even deteriorate. Tailoring interventions to the individual may improve outcomes. However, such personalization of evidence-based treatment in depression requires investigation of individual outcomes and the individual trajectories towards these outcomes. This theoretical paper provides a critical reflection on individual outcomes of depression treatment. First, it is argued that outcomes should be broadened, from a focus on mainly depressive symptomatology to recovery in different domains. It is acknowledged that recovery from depression reflects a personal journey that differs from person to person. Second, outcome measures should be lengthened beyond the acute treatment phase, taking a lifetime perspective on depression. The challenge then is to discover which trajectories of what measures during what interventions result in personalized sustainable recovery and for whom. Routine outcome monitoring systems may be used to inform this quest towards assessment of personalized sustainable therapeutic outcomes. Adaptations to broaden and lengthen measurements in routine outcome monitoring systems are proposed to identify predictors of personalized sustainable recovery. Routine outcome monitoring systems may eventually be used to implement personalized treatments for depression that result in personalized sustainable recovery.


New evidence for brain angiotensin and for its role in hypertension.
Twenty years ago it was demonstrated that angiotensin II (Ang II) acts on the brain, which results in an elevation of blood pressure. Ten years later, reninlike activity was discovered in the brain of the rat and dog, which gave rise to the concept of an endogenous brain renin-angiotensin system. In the periphery, the kidney, liver, and lungs work in unison to produce Ang II. Evidence for brain renin, substrate, converting enzyme, and angiotensins is reviewed. New data indicate that the enzyme system for the synthesis of Ang II within the brain may in fact be contained in the cell. All the components for a renin-angiotensin system have now been found in neuroblastoma/glioma cell lines and Ang II is present in primary cell culture of rat brain neurons. The significance of angiotensin in the brain for hypertension is that it may be a stimulus for vasopressin release and sympathetic activation, which can maintain high blood pressure. In the spontaneously hypertensive rat, there is evidence of increased brain angiotensin. Also, experiments with angiotensin-converting enzyme inhibitors show that blockade of brain angiotensin production leads to a long-lasting lowering of blood pressure. The activity of the inhibitors in part appears to be directly on the brain.


Cannabidiol Μay Prolong Survival in Patients With Glioblastoma Multiforme.
Glioblastoma multiforme (GBM) is a relatively rare type of brain tumour with an incidence rate around 6 per 100,000. Even with the widely practiced combination of radiotherapy with adjuvant temozolomide, the median overall survival remains low with just 13.5 to 16 months after diagnosis. We retrospectively reviewed the survival of a cohort of 15 consecutive, unselected patients with histopathologically confirmed glioblastoma multiforme (GBM) who received CBD (400 to 600 mg orally per day) in addition to standard therapy (maximum resection of the tumour followed by radio-chemotherapy). Of 15 patients, seven (46.7%) are now living for at least 24 months, and four (26.7%) for at least 36 months. This is more than twice as long as has been previously reported in the literature. The mean overall survival is currently 24.2 months (median 21 months). CBD is a well supported co-medication and seems to prolong the survival of patients with glioblastoma multiforme.


Phase II study of oral ridaforolimus in women with recurrent or metastatic endometrial cancer.
The phosphatidylinositol-3 kinase/serine-threonine kinase PI3K/AKT pathway is postulated to be central to cancer cell development. Activation of this pathway is believed to promote angiogenesis, protein translation and cell cycle progression. A large percentage of endometrial carcinomas have demonstrated mutations within this regulation pathway which result in constitutional activation. The downstream effector protein mammalian target of rapamycin (mTOR) acts as a critical checkpoint in cancer cell cycling and is a logical target for drug development. The efficacy and tolerability of the oral mTOR inhibitor ridaforolimus were evaluated in this study. This phase II study evaluated the single agent tolerability and activity of oral ridaforolimus administered at a dose of 40mg for 5 consecutive days followed by a 2day break, in women with recurrent or metastatic endometrial carcinoma who had received no chemotherapy in the metastatic setting. 31 of 34 patients were evaluable. Three partial responses (8.8%) were observed with response duration ranging between 7.9 and 26.5months. An additional 18 patients showed disease stabilization (52.9%) for a median duration of 6.6months. Response rates were not affected by previous chemotherapy exposure. No correlation was found between response and mutation status. Oral ridaforolimus was reasonably tolerated and demonstrated modest activity in women with recurrent or metastatic endometrial cancers. Potential synergy between mTOR inhibition, angiogenesis and hormonal pathways warrants ongoing evaluation.


Containment Care Units for Managing Patients With Highly Hazardous Infectious Diseases: A Concept Whose Time Has Come.
The concept of containment care for patients with highly hazardous infectious diseases originated in conjunction with the development of sophisticated biosafety level 4 laboratories at the US Army Medical Research Institute of Infectious Diseases in the late 1960s. Over time, the original containment facility served as a model for the development of other facilities in the United States at government and academic centers. The Ebola outbreak of 2014-2015 brought the issue of containment care into the mainstream and led to the development of such capabilities at strategic points around the country. We describe the original concepts behind development of such facilities, how the concept and acceptance has evolved over time, and how the guidelines for managing patients infected with viral hemorrhagic fevers have evolved as new information has been learned about protecting medical care providers from highly hazardous infectious pathogens.


Cavernous carotid aneurysms in the era of flow diversion: a need to revisit treatment paradigms.
Recent techniques of endoluminal reconstruction with flow-diverting stents have not been incorporated into treatment algorithms for cavernous carotid aneurysms. This study examines the authors' institutional experience and a systematic review of the literature for outcomes and complications using the Pipeline Embolization Device in unruptured cavernous carotid aneurysms. A retrospective search for cavernous carotid aneurysms from a prospectively collected data base of aneurysms treated with the Pipeline Embolization Device at our institution was performed. Baseline demographic, clinical, and laboratory values; intrainterventional data; and data at all follow-up visits were collected. A systematic review of the literature for complication data was performed with inquiries sent when clarification of data was needed. Forty-three cavernous carotid aneurysms were included in the study. Our mean radiographic follow-up was 2.05 years. On last follow-up, 88.4% of the aneurysms treated had complete or near-complete occlusion. Aneurysm complete or near-complete occlusion rates at 6 months, 12 months, and 36 months were 81.4%, 89.7%, and 100%, respectively. Of patients with neuro-ophthalmologic deficits on presentation, 84.2% had improvement in their visual symptoms. Overall, we had a 0% mortality rate and a 2.3% major neurologic complication rate. Our systematic review of the literature yielded 227 cavernous carotid aneurysms treated with the Pipeline Embolization Device with mortality and morbidity rates of 0.4% and 3.1%, respectively. Endoluminal reconstruction with flow diversion for large unruptured cavernous carotid aneurysms can yield high efficacy with low complications. Further long-term data will be helpful in assessing the durability of the cure; however, we advocate a revisiting of current management paradigms for cavernous carotid aneurysms.


Self-reported and urinary biomarker-based measures of exposure to glyphosate and mancozeb and sleep problems among smallholder farmers in Uganda.
We aim to showcase the impact of applying eight different self-reported and urinary biomarker-based exposure measures for glyphosate and mancozeb on the association with sleep problems in a study among 253 smallholder farmers in Uganda. The questionnaire-based exposure measures included: (1) the number of application days of any pesticide in the last 7 days (never, 1-2; >2 days) and six glyphosate and mancozeb-specific measures: (2) application status over the last 12 months (yes/no), (3) recent application status (never, last 7 days and last 12 months), (4) the number of application days last 12 months, (5) average exposure-intensity scores (EIS) and (6) EIS-weighted number of application days in last 12 months. Based on 384 repeated urinary biomarker concentrations of ethylene thiourea (ETU) and glyphosate from 84 farmers, we also estimated (7) average biomarker concentrations for all 253 farmers. Also in the 84 farmers the measured pre-work and post-work biomarker concentrations were used (8). Multivariable logistic regression models were used to assess the association between the exposure measures and selected Medical Outcomes Study Sleep Scale (MOS-SS) indices (6-item, sleep inadequacy and snoring). We observed positive associations between (1) any pesticide application in the last 7 days with all three MOS-SS indices. Glyphosate application in the last 7 days (3) and mancozeb application in the last 12 months (3) were associated with the 6-item sleep problem index. The estimated average urinary glyphosate concentrations showed an exposure-response association with the 6-item sleep problem index and sleep inadequacy in the same direction as based on self-reported glyphosate application in the last 7 days. In the analysis with the subset of 84 farmers, both measured and modelled post-work urinary glyphosate concentration showed an association with snoring. Self-reported, estimated average biomarker concentrations and measured urinary biomarker exposure measures of glyphosate and mancozeb showed similar exposure-response associations with sleep outcomes.


[Use of cyclosporine 0.05% in various ocular surface disorders].
It is proved that chronic ocular surface inflammatory disease (including allergic blepharitis, recurrent chalyazia, punctuate keratitis, recurrent herpetic corneal erosions, late stages of adenoviral keratoconjunctivitis, etc.) takes part in the development of secondary dry eye syndrome (DES). However, therapies for inflammation-induced impairment of tear production do not provide long-term control of inflammatory process. Cyclosporine 0.05% eye drops are an option. Their effect is well-studied in foreign practice. Local application experience of cyclosporine 0.05% eye drops was summarized at a meeting of the Russian expert group on DES and conclusions were made on their effectiveness in treatment of dry eye syndrome associated with certain ocular surface inflammatory disorders, such as allergic blepharoconjunctivitis, late stages of adenoviral keratoconjunctivitis, and others.


Behaviour of temperate phage Mu in Salmonella typhi.
We have developed a convenient system for genetic analysis of Salmonella typhi exploiting the properties of the mutator phage Mu. In spite of the fact that wild-type Salmonella typhi strains do not allow Mu to form plaques on them, we have shown that these strains are actually sensitive to the phage. It proved possible to use Mu to induce mutations and to promote intra- and interspecific genetic transfer, without having to introduce the phage into the bacteria by means other than infection. Furthermore, we isolated Salmonella typhi derivatives on which Mu formed plaques, and studied the behaviour of Mu in these and wild-type strains.


Progress in developing polymerized crystalline colloidal array sensors for point-of-care detection of myocardial ischemia.
The difficulty of rapid, definitive diagnosis of myocardial ischemia leads to unnecessary hospital admissions and treatment delays. Previously, decreased metal binding affinity in human serum was investigated as a marker for myocardial ischemia. Polymerized Crystalline Colloidal Array (PCCA) sensors for Ni2+ may be useful in developing a point-of-care test to determine metal binding affinity in plasma and to help rule out myocardial ischemia. PCCA sensors for Ni2+, with 5-amino-8-hydroxyquinoline as a chelating agent, were tested in aqueous solutions and diluted human plasma. The peak wavelength diffracted by the sensors was monitored by reflectance spectrometry and correlated with Ni2+ concentration. The PCCA sensors show a linear response to aqueous Ni2+ concentrations between 0.2 and 1.0 mmol L(-1), and can detect changes in free Ni2+ concentration of <60 micromol L(-1). The sensors respond at physiologic pH and can be reversibly dehydrated. The PCCA sensors developed here can report on free Ni2+ concentration in the presence of human plasma. These sensors can be used to detect a decrease in the Ni2+ affinity of plasma proteins, which may indicate recent myocardial ischemia. PCCA sensors offer a practical approach to rapid, point-of-care detection of a proposed biochemical signature of myocardial ischemia.


Characterization of cerebrospinal fluid (CSF) microbiota from patients with CSF shunt infection and reinfection using high throughput sequencing of 16S ribosomal RNAgenes.
Nearly 20% of patients with cerebrospinal fluid (CSF) shunt infection develop reinfection. It is unclear whether reinfections are caused by an organism previously present or are independent infection events. We used bacterial culture and high throughput sequencing (HTS) of 16S ribosomal RNA (rRNA) genes to identify bacteria present in serial CSF samples obtained from children who failed CSF shunt infection treatment. We hypothesized that organisms that persist in CSF despite treatment would be detected upon reinfection. Serial CSF samples were obtained from 6 patients, 5 with 2 infections and 1 with 3 infections; the study was limited to those for which CSF samples were available from the end of infection and beginning of reinfection. Amplicons of the 16S rRNA gene V4 region were sequenced. Taxonomic assignments of V4 sequences were compared with bacterial species identified in culture. Seven infection dyads averaging 13.5 samples per infection were analyzed. A median of 8 taxa [interquartile range (IQR) 5-10] were observed in the first samples from reinfection using HTS. Conventional culture correlated with high abundance of an organism by HTS in all but 1 infection. In 6 of 7 infection dyads, organisms identified by culture at reinfection were detected by HTS of culture-negative samples at the end of the previous infection. The median Chao-Jaccard abundance-based similarity index for matched infection pairs at end of infection and beginning of reinfection was 0.57 (IQR 0.07-0.87) compared to that for unmatched pairs of 0.40 (IQR 0.10-0.60) [p = 0.46]. HTS results were generally consistent with culture-based methods in CSF shunt infection and reinfection, and may detect organisms missed by culture at the end of infection treatment but detected by culture at reinfection. However, the CSF microbiota did not correlate more closely within patients at the end of infection and beginning of reinfection than between any two unrelated infections. We cannot reject the hypothesis that sequential infections were independent.


MRI volume of the amygdala: a reliable method allowing separation from the hippocampal formation.
Studies of MRI-derived volume of the amygdala have been mostly performed on coronal sections where its boundaries with the hippocampus and the entorhinal cortex are indistinct. To date, all reports of in vivo amygdala volume have consistently overestimated the size of the structure. We have developed a method for the MRI-based in vivo measurement of the amygdala volume which allows a better separation of the amygdala from the adjoining hippocampal formation. In nine normal volunteers we obtained three-dimensional spoiled gradient recalled acquisition, 1.3-mm thick, T1 weighted sagittal MR images and created electronically linked reformatted images in the coronal and axial planes. On the original sagittal and the reformatted axial planes, where it is more readily apparent, we delineated the boundaries between the amygdala and the hippocampus and the amygdala and the hippocampo-amygdala transition area, respectively. We then projected those markings onto the coronal plane, where the other boundaries of the amygdala are more easily seen. Using these markings as a guide and utilizing extra-amygdalar coronal landmarks for the anterior end, we outlined the whole amygdala on the coronal plane and determined its volume. We observed that 45% of the coronal slices that contained amygdala also contained some hippocampus. The amygdala measurement had high test-retest reliability, with an intra-class correlation coefficient (rICC) of 0.99 for the total volume and an rICC of 0.93 for the measurement at the level of the individual slice. The average amygdala volume was 1.05 +/- 0.17 cm3 on the right and 1.14 +/- 0.15 cm3 on the left. Our amygdala volumes are in agreement with those reported in postmortem studies, which provides the reported method with face validity.


Genetic influence on cognitive development between childhood and adulthood.
Successful cognitive development between childhood and adulthood has important consequences for future mental and physical wellbeing, as well as occupational and financial success. Therefore, delineating the genetic influences underlying changes in cognitive abilities during this developmental period will provide important insights into the biological mechanisms that govern both typical and atypical maturation. Using data from the Philadelphia Neurodevelopmental Cohort (PNC), a large population-based sample of individuals aged 8 to 21 years old (n = 6634), we used an empirical relatedness matrix to establish the heritability of general and specific cognitive functions and determine if genetic factors influence cognitive maturation (i.e., Gene × Age interactions) between childhood and early adulthood. We found that neurocognitive measures across childhood and early adulthood were significantly heritable. Moreover, genetic variance on general cognitive ability, or g, increased significantly between childhood and early adulthood. Finally, we did not find evidence for decay in genetic correlation on neurocognition throughout childhood and adulthood, suggesting that the same genetic factors underlie cognition at different ages throughout this developmental period. Establishing significant Gene × Age interactions in neurocognitive functions across childhood and early adulthood is a necessary first step in identifying genes that influence cognitive development, rather than genes that influence cognition per se. Moreover, since aberrant cognitive development confers risk for several psychiatric disorders, further examination of these Gene × Age interactions may provide important insights into their etiology.


Type II protein secretion and its relationship to bacterial type IV pili and archaeal flagella.
Homologues of the protein constituents of the Klebsiella pneumoniae (Klebsiella oxytoca) type II secreton (T2S), the Pseudomonas aeruginosa type IV pilus/fimbrium biogenesis machinery (T4P) and the Methanococcus voltae flagellum biogenesis machinery (Fla) have been identified. Known constituents of these systems include (1). a major prepilin (preflagellin), (2). several minor prepilins (preflagellins), (3). a prepilin (preflagellin) peptidase/methylase, (4). an ATPase, (5). a multispanning transmembrane (TM) protein, (6). an outer-membrane secretin (lacking in Fla) and (7). several functionally uncharacterized envelope proteins. Sequence and phylogenetic analyses led to the conclusion that, although many of the protein constituents are probably homologous, extensive sequence divergence during evolution clouds this homology so that a common ancestry can be established for all three types of systems for only two constituents, the ATPase and the TM protein. Sequence divergence of the individual T2S constituents has occurred at characteristic rates, apparently without shuffling of constituents between systems. The same is probably also true for the T4P and Fla systems. The family of ATPases is much larger than the family of TM proteins, and many ATPase homologues function in capacities unrelated to those considered here. Many phylogenetic clusters of the ATPases probably exhibit uniform function. Some of these have a corresponding TM protein homologue although others probably function without one. It is further shown that proteins that compose the different phylogenetic clusters in both the ATPase and the TM protein families exhibit unique structural characteristics that are of probable functional significance. The TM proteins are shown to have arisen by at least two dissimilar intragenic duplication events, one in the bacterial kingdom and one in the archaeal kingdom. The archaeal TM proteins are twice as large as the bacterial TM proteins, suggesting an oligomeric structure for the latter.


The origins of insect metamorphosis.
Insect metamorphosis is a fascinating and highly successful biological adaptation, but there is much uncertainty as to how it evolved. Ancestral insect species did not undergo metamorphosis and there are still some existing species that lack metamorphosis or undergo only partial metamorphosis. Based on endocrine studies and morphological comparisons of the development of insect species with and without metamorphosis, a novel hypothesis for the evolution of metamorphosis is proposed. Changes in the endocrinology of development are central to this hypothesis. The three stages of the ancestral insect species-pronymph, nymph and adult-are proposed to be equivalent to the larva, pupa and adult stages of insects with complete metamorphosis. This proposal has general implications for insect developmental biology.


[Validation of half-night polysomnography for sleep apnea/hypoapnea syndrome].
A diagnosis of sleep apnea/hypopnea syndrome (SAHS) is based on clinical signs and nighttime polysomnograms. Brief polysomnography has been proposed as an alternative to all-night recording. The aim of this study was to determine whether a polysomnograms obtained during the first half of the night is sufficient for establishing a diagnosis of SAHS and to determine the correlation between polysomnographic variables recorded during the first four hours (half the study time) with those recorded over the full eight hours (full study time), as well as to determine diagnostic agreement. Thirty-five patients suspected of having SAHS were studied prospectively. Baseline polysomnograms were scored blindly by two independent observers following standard methods. A diagnosis of SAHS was made according to guidelines of the Spanish Society of Pneumology and Chest Surgery. During the first half of the night and up to the end of each recording period we gathered neurophysiological and respiratory variables and diagnostic impressions. The correlation between variables (sleep stage, overall AHI, REM-AHI, non-REM-AHI and sleep efficiency) recorded in the first half of the night and throughout the night was significant (p < 0.05) by both Pearson's correlation coefficient (r) and by the intraclass correlation coefficient (ICC). In 33 of 35 patients (94.3%) diagnostic agreement was achieved (95% CI 80.84-99.30); when SAHS was severe, agreement was 100%. Based on these results, we conclude that for patients with a diagnosis of severe SAHS during the first half of the night, data recorded during the second half can be considered supplementary.


A simple control and high accuracy measurement method of open-cell four-electrode conductivity electrode.
The paper presents a simple control and high-accuracy measurement method for a four-electrode conductivity probe based on the principle of the bi-directional voltage pulse. The two-way differential AC (alternating current) pulse voltage signal for the reference resistance and solution resistance is modulated into the single DC stationary voltage response signal to drop the demand for software and hardware and effectively eliminate the influence of excitation voltage pulse amplitude on measurement accuracy, and then the synchronous rectification DC measurement is proposed without any control timing. Meanwhile, the mathematical expression between the single output DC voltage signal and the solution conductivity is given. The test results in the laboratory and in the field indicate that the relative error of the conductivity measurement is within 2.5% in a conductance range of 10 uS/cm to 200 mS/cm, and the proposed measurement method has a good application prospect in application.


IDO is a nodal pathogenic driver of lung cancer and metastasis development.
Indoleamine 2,3-dioxygenase (IDO) enzyme inhibitors have entered clinical trials for cancer treatment based on preclinical studies, indicating that they can defeat immune escape and broadly enhance other therapeutic modalities. However, clear genetic evidence of the impact of IDO on tumorigenesis in physiologic models of primary or metastatic disease is lacking. Investigating the impact of Ido1 gene disruption in mouse models of oncogenic KRAS-induced lung carcinoma and breast carcinoma-derived pulmonary metastasis, we have found that IDO deficiency resulted in reduced lung tumor burden and improved survival in both models. Micro-computed tomographic (CT) imaging further revealed that the density of the underlying pulmonary blood vessels was significantly reduced in Ido1-nullizygous mice. During lung tumor and metastasis outgrowth, interleukin (IL)-6 induction was greatly attenuated in conjunction with the loss of IDO. Biologically, this resulted in a consequential impairment of protumorigenic myeloid-derived suppressor cells (MDSC), as restoration of IL-6 recovered both MDSC suppressor function and metastasis susceptibility in Ido1-nullizygous mice. Together, our findings define IDO as a prototypical integrative modifier that bridges inflammation, vascularization, and immune escape to license primary and metastatic tumor outgrowth. This study provides preclinical, genetic proof-of-concept that the immunoregulatory enzyme IDO contributes to autochthonous carcinoma progression and to the creation of a metastatic niche. IDO deficiency in vivo negatively impacted both vascularization and IL-6–dependent, MDSC-driven immune escape, establishing IDO as an overarching factor directing the establishment of a protumorigenic environment.


Interferon-alpha for viral hepatitis.
IFN-alpha has emerged as a promising treatment of chronic viral hepatitis. Although therapeutic response to IFN is far from universal, efficacy has been demonstrated; and studies combining IFN-alpha with other agents, as well as trials with new preparations of IFN-alpha, are under way. Children do not represent a large part of the identified population with chronic viral hepatitis. Yet children, by simple virtue of age, are more recently infected. In addition, longer life expectancies can be expected to be associated with greater morbidity from chronic viral hepatitis. Children seem to tolerate therapy with IFN-alpha well. Treatment of children with chronic viral hepatitis should be strongly considered, with protocols designed to ascertain specific pediatric safety and efficacy.


Is there a need for change in cancer survivorship care? A qualitative exploration of survivor experiences and needs at the Sydney Cancer Survivorship Centre Clinic.
Effective cancer survivorship care is contingent on a comprehensive understanding and management of the dynamic needs of cancer survivors. The Sydney Cancer Survivorship Centre (SCSC) clinic established a holistic, multidisciplinary model of survivorship care. We aimed to explore survivors' experiences and perceptions of the clinic, and to identify their unmet needs. Semi-structured focus groups (FGs) involving participants recruited from the SCSC clinic were conducted by an experienced facilitator and observer using a guide covering: survivor perceptions of first SCSC clinic visit, services accessed, ongoing unmet needs, and how needs changed over time. FGs were audio-recorded and transcribed. Interpretive description using a Framework approach was undertaken and participant characteristics summarised descriptively. Eight FGs were conducted involving a total of 26 participants (mean age: 60), most were female (n = 20), born in Australia (n = 14), and with breast cancer diagnoses (n = 16). Four overarching themes were identified: (i) perceptions of the SCSC clinic; (ii) patient-centred care; (iii) adjustment to illness; and (iv) external supports and resources. Participants valued the centralisation of multidisciplinary survivorship care at the SCSC clinic, which helped their recovery. Mitigating ongoing treatment sequelae, reassurance of good-health, normalisation of survivorship experiences, and handling caregiver stress represent some needs identified. The SCSC clinic offers holistic, specialised care and reassurance to cancer survivors. Adjustment to the survivorship journey, inter-survivor shared experiences, and management of physical treatment sequelae were perceived as important in their recovery. Managing survivor needs is integral to improving long-term survivorship care.


Disparity between adjusted and actual opening cerebrospinal fluid pressure in a patient with the Codman Hakim programmable valve: occult form of shunt failure due to head banging. Case report.
Although the Codman Hakim programmable valve (CHPV) system is popular, several problems arising from its design have been described. The authors report an additional cause of shunt failure associated with the use of the CHPV system. A 7-year-old girl who had previously undergone placement of a ventriculoperitoneal shunt with the CHPV system was admitted in a comatose state. Radiography did not demonstrate any breakage or change in the opening pressure of the valve. Manual pumping of the valve resulted in neurological improvement and shrinkage of the girl's ventricles. However, ventriculomegaly was again observed several hours later, and an emergency valve revision was performed. The manufacturer's examination of the extracted valve revealed a crack on the surface of the hard plastic housing covering the valve chamber, which appeared to be suggestive of some type of blunt trauma. In addition, the flat spring that transmitted resistance from the pressure control cam to the valve ball was deformed in such a manner that it caused excessive pressure against the valve ball. Because of this deformity, the actual opening pressure in this patient had reached a maximum level of 226 mm H2O instead of the adjusted pressure of 60 mm H2O. In patients with the CHPV system whose medical history is difficult to ascertain, the possibility of damage to the valve spring and the need for a prompt revision surgery should be considered. The authors conclude that placement of the CHPV system may be contraindicated in patients with a known habit of head banging.


Age differences in infants' attention to patterns of different complexities.
Infants 3 weeks, 8 weeks, and 14 weeks old were presented with checkerboard patterns which differed in the number of squares they contained. The older the infants, the more complex was the checkerboard that they looked at longest. This result does not appear to depend on changes in visual acuity or accommodation related to age.


Social roles among recruits in Switzerland: Do social roles relate to alcohol use and does role change have an impact?
Young men are likely to report high levels of alcohol use. Previous studies found a reduction in alcohol use when adopting adult social roles. This study examines the frequency of parenthood, partnership and stable employment among young men in Switzerland. It tests whether the alcohol use of those with adult social roles differs from those without and whether changes in social roles relate to changes in alcohol use. Data was available from 5025 men (20.0 years) at baseline (August 2010 to November 2011) and 15 months later. Changes in social roles and their impact on alcohol use were examined in multiple regression models. At baseline, 15.8% had a job and 4.9% a stable partner, and 1.5% had a child or were expecting one (30.5%, 6.1% and 2.2% at follow-up). Having a partner was associated with a significant decrease in annual frequency of drinking and weekly risky single-occasion drinking (RSOD) at follow-up. A higher number of social roles at follow-up was associated with a significant decrease in weekly RSOD. Apart from a significant decrease in weekly RSOD among those remaining in a stable partnership, role development was not found to have significant effects on alcohol use between baseline and follow-up. In Switzerland, an early engagement in permanent social roles is uncommon. Nevertheless, holding single or multiple social roles was commonly associated with reduced alcohol use, although not always significantly so. In western European countries, the engagement in adult social roles is postponed to later ages.


Genome evolution and phylogenomic analysis of Candidatus Kinetoplastibacterium, the betaproteobacterial endosymbionts of Strigomonas and Angomonas.
It has been long known that insect-infecting trypanosomatid flagellates from the genera Angomonas and Strigomonas harbor bacterial endosymbionts (Candidatus Kinetoplastibacterium or TPE [trypanosomatid proteobacterial endosymbiont]) that supplement the host metabolism. Based on previous analyses of other bacterial endosymbiont genomes from other lineages, a stereotypical path of genome evolution in such bacteria over the duration of their association with the eukaryotic host has been characterized. In this work, we sequence and analyze the genomes of five TPEs, perform their metabolic reconstruction, do an extensive phylogenomic analyses with all available Betaproteobacteria, and compare the TPEs with their nearest betaproteobacterial relatives. We also identify a number of housekeeping and central metabolism genes that seem to have undergone positive selection. Our genome structure analyses show total synteny among the five TPEs despite millions of years of divergence, and that this lineage follows the common path of genome evolution observed in other endosymbionts of diverse ancestries. As previously suggested by cell biology and biochemistry experiments, Ca. Kinetoplastibacterium spp. preferentially maintain those genes necessary for the biosynthesis of compounds needed by their hosts. We have also shown that metabolic and informational genes related to the cooperation with the host are overrepresented amongst genes shown to be under positive selection. Finally, our phylogenomic analysis shows that, while being in the Alcaligenaceae family of Betaproteobacteria, the closest relatives of these endosymbionts are not in the genus Bordetella as previously reported, but more likely in the Taylorella genus.


Quality assurance of qualitative research: a review of the discourse.
Increasing demand for qualitative research within global health has emerged alongside increasing demand for demonstration of quality of research, in line with the evidence-based model of medicine. In quantitative health sciences research, in particular clinical trials, there exist clear and widely-recognised guidelines for conducting quality assurance of research. However, no comparable guidelines exist for qualitative research and although there are long-standing debates on what constitutes 'quality' in qualitative research, the concept of 'quality assurance' has not been explored widely. In acknowledgement of this gap, we sought to review discourses around quality assurance of qualitative research, as a first step towards developing guidance. A range of databases, journals and grey literature sources were searched, and papers were included if they explicitly addressed quality assurance within a qualitative paradigm. A meta-narrative approach was used to review and synthesise the literature. Among the 37 papers included in the review, two dominant narratives were interpreted from the literature, reflecting contrasting approaches to quality assurance. The first focuses on demonstrating quality within research outputs; the second focuses on principles for quality practice throughout the research process. The second narrative appears to offer an approach to quality assurance that befits the values of qualitative research, emphasising the need to consider quality throughout the research process. The paper identifies the strengths of the approaches represented in each narrative and recommend these are brought together in the development of a flexible framework to help qualitative researchers to define, apply and demonstrate principles of quality in their research.


Assessment of a Mobile Game ("MobileKids Monster Manor") to Promote Physical Activity Among Children.
The majority of children in North America are not meeting current physical activity guidelines. The purpose of this study was to evaluate the impact of a mobile phone game ("MobileKids Monster Manor") as a tool to promote voluntary physical activity among children. The game integrates data from an accelerometer-based activity monitor (Tractivity(®); Kineteks Corp., Vancouver, BC, Canada) wirelessly connected to a phone and was developed with the involvement of a team of young advisors (KidsCan Initiative: Involving Youth as Ambassadors for Research). Fifty-four children 8-13 years old completed a week of baseline data collection by wearing an accelerometer but receiving no feedback about their activity levels. The 54 children were then sequentially assigned to two groups: One group played "MobileKids Monster Manor," and the other received daily activity feedback (steps and active minutes) via an online program. The physical activity (baseline and intervention weeks) was measured using the activity monitor and compared using two-way repeated-measures analysis of variance (intervention×time). Forty-seven children with a body mass index (BMI) z-score of 0.35±1.18 successfully completed the study. Significant (P=0.01) increases in physical activity were observed during the intervention week in both the game and feedback groups (1191 and 796 steps/day, respectively). In the game group, greater physical activity was demonstrated in children with higher BMI z-score, showing 964 steps/day more per BMI z-score unit (P=0.03; 95 percent confidence interval of 98 to 1829). Further investigation is required to confirm that our game design promotes physical activity.


The 42nd Lauriston S. Taylor Lecture: Radiation Dosimetry Research for Medicine and Protection-A European Journey.
The assessment of doses related to exposures to ionizing radiation is an essential part of all applications of ionizing radiation including radiation medicine, radiation protection, radiation biology, radiation epidemiology, and also industrial uses of radiation. Absorbed dose is generally considered to be the fundamental quantity of radiation dosimetry. It is a metrologically sound quantity for which even primary standards exist for some materials, and it is used routinely in practice. However, there is no unique correlation between absorbed dose and the radiation-induced biological effect considered. There are also different objectives of radiation dosimetry for different applications. In radiation protection, quantities are required to set meaningful exposure limits and to implement the principle of optimization. In radiation therapy, the dependence of clinical outcomes on temporal aspects of the irradiations must be accounted for. In radiation diagnostics, quantities are needed to enable and monitor optimization of radiation dose and image quality. In radiation protection and in therapy with high linear-energy-transfer radiations, appropriate methods and parameters are needed to account for differences in radiation quality. These limitations of the quantity absorbed dose have led to the use of a multiplicity of dose quantities and dose modification factors. Radiation dosimetry continues, therefore, to be a field of active research regarding fundamental and conceptual aspects, taking account of advances in technologies, of novel methods in radiation therapy and diagnostics, and of progress in computational dosimetry. Dosimetry of high-energy radiations such as cosmic radiation encountered at flight altitudes and during space missions as well as at high-energy accelerators has become an important issue. In Europe, collaboration and coordination of radiation research in general, and dosimetry research in particular, are playing an important role. Dedicated research programs of the European Commission have been and still are very valuable and include collaborations with institutes in Eastern Europe and non-European countries. Several current and recent research topics in radiation dosimetry are addressed based on research carried out within European research programs, at European research centers including the European Organization for Nuclear Research (known as CERN), in European particle therapy projects, and at national metrological institutes. One focus is the quantification of radiation quality in radiation protection and in high linear-energy-transfer radiation therapy with emphasis on measurements with low-pressure proportional counters. Another focus is dosimetry of high-energy radiations with respect to measurements of cosmic radiation and at CERN's high-energy accelerators.


Comparison of Whole-Body Cooling Techniques for Athletes and Military Personnel.
The purpose of this study was to evaluate cooling rates of The Polar Life Pod®, a military protocol and cold water immersion. A randomized, repeated measures design was used to compare three treatment options. Participants exercised in an environmental chamber, where they followed a military march protocol on a treadmill, followed by the application of one of three treatments: Cold water immersion tub (5 - 10 °C), Polar Life Pod® (5 - 10 °C), Ice sheets at onset (5 - 10 °C). Mean cooling rate for CWI was 0.072 ºC/min, 0.046ºC/min for ice sheets, and 0.040ºC/min for The Polar Life Pod®. There was a significant difference between conditions (F2,26=13.564, p=0.001, ES=0.511, 1-β=0.969). There was a significant difference in cooling rate among The Polar Life Pod® and CWI (p = 0.006), and no significant difference among The Polar Life Pod® and Ice Sheets (p = 0.103). There was a significant difference of time to cool among the three conditions F2,26 = 13.564, p = 0.001, ES = 0.401, 1-β = 0.950. Our results support multiple organizations that deem CWI as the only acceptable treatment, when compared to the cooling rates of The Polar Life Pod® and ice sheets.


Toxic megacolon associated Clostridium difficile colitis.
Toxic megacolon is a severe complication of Clostridium difficile (C. difficile) colitis. As the prevalence of C. difficile colitis increases and treatments become more refractory, clinicians will encounter more patients with C. difficile associated toxic megacolon in the future. Here, we review a case of toxic megacolon secondary to C. difficile colitis and review the current literature on diagnosis and management. We identify both clinical and radiologic criteria for diagnosis and discuss both medical and surgical options for management. Ultimately, we recommend using the Jalen criteria in conjunction with daily abdominal radiographs to help establish the diagnosis of toxic megacolon and to make appropriate treatment recommendations. Aggressive medical management using supportive measures and antibiotics should remain the mainstay of treatment. Surgical intervention should be considered if the patient does not clinically improve within 2-3 d of initial treatment.


[When must a mastopathy at risk be operated on? The viewpoint of the clinician, the radiologist, the surgeon, and the anatomopathologist].
The mastopathy is said to be truly "at risk" only when an anatomopathological examination has singled out certain criteria. At present, there is no medical treatment, particularly a hormonal one, capable of preventing the evolution towards a breast cancer. The indication for an operation could be based on a real score taking into account the age, the family history, the pregnancies, the fatness, the endogenous hormonal balance and the exogenous hormonal supply. In fact, above all considerations is the local mammary state, "the major mastoses", where a joint analytical study of: the clinical state, the mammography, the thermography and the cytopuncture is essential. The possibility of carrying out micro-biopsies under local anaesthesia is also underlined. Finally, we retain two big types of indication: of necessity. A lesion for which a doubt exists must be operated upon. The radiological location constitutes a considerable progress. Of principle. Namely in women with a heavy family history of breast cancer, a fortiori if the mammographies reveal dense, heterogeneous aspects, difficult to follow. Finally, the women for whom a previous biopsy has revealed lesions with an evolution potential (lobe neoplasia, extensive atypical epitheliosis). In conclusion, the indications are not often easy and is usually the object of a study of each case individually.


Long-term risk of seizures and epilepsy in patients with posterior reversible encephalopathy syndrome.
Seizures are common in patients with posterior reversible encephalopathy syndrome (PRES), which is reported in up to 70% of cases, and antiepileptic drugs (AEDs) are commonly prescribed. There is a paucity of data regarding the risk of subsequent seizures following resolution of PRES, and therefore the optimal duration of treatment with AEDs is currently unknown. The objective of this study was to identify the frequency of recurrent seizures and epilepsy following recovery from PRES. We performed a retrospective review of consecutive adults diagnosed with PRES between 2000 and 2010. One hundred twenty-seven patients, median age 53 years (interquartile range [IQR] 37-64), were included in the analysis. The most common causes of PRES were hypertension (72%) and immunosuppression (20%). Renal failure was present in 47%. Eighty-four patients (66%) had seizures at presentation (39 focal, 45 generalized), and 13 (15%) of them presented with status epilepticus. Median duration of follow-up was 3.2 years (IQR 4 months to 6.9 years). Patients with seizures were treated with AEDs for a median of 3 months (IQR 2-7). Fifteen patients (12%) had provoked seizures during the follow-up period; in eight (53%) patients seizures were caused by recurrent PRES. Only three patients had subsequent unprovoked seizures, one of whom was considered to have developed epilepsy. We conclude that unprovoked seizures and epilepsy are uncommon in patients who have recovered from PRES. Discontinuation of AEDs following resolution of PRES should be considered, provided there is adequate control of risk factors, and absence of factors that could substantially lower the seizure threshold.


Design and Analysis of a Low Latency Deterministic Network MAC for Wireless Sensor Networks.
The IEEE 802.15.4e standard has four different superframe structures for different applications. Use of a low latency deterministic network (LLDN) superframe for the wireless sensor network is one of them, which can operate in a star topology. In this paper, a new channel access mechanism for IEEE 802.15.4e-based LLDN shared slots is proposed, and analytical models are designed based on this channel access mechanism. A prediction model is designed to estimate the possible number of retransmission slots based on the number of failed transmissions. Performance analysis in terms of data transmission reliability, delay, throughput and energy consumption are provided based on our proposed designs. Our designs are validated for simulation and analytical results, and it is observed that the simulation results well match with the analytical ones. Besides, our designs are compared with the IEEE 802.15.4 MAC mechanism, and it is shown that ours outperforms in terms of throughput, energy consumption, delay and reliability.


Parathyroid hormone concentration and risk of cardiovascular diseases: the Atherosclerosis Risk in Communities (ARIC) study.
According to a recent meta-analysis, parathyroid hormone (PTH) excess is associated with increased cardiovascular disease (CVD) risk, but existing studies are limited. We examined in a prospective study the association of PTH with the incidence of CVD, taking into account vitamin D and other confounding variables. The ARIC study measured PTH using a second-generation assay (Roche, Indianapolis, IN) in stored serum samples from 1990 to 1992 and related levels in 10,392 adults to incident cardiovascular outcomes (coronary heart disease [n = 808], heart failure [n = 1,294], stroke [n = 586], peripheral artery disease [n = 873], atrial fibrillation [n = 1,190], and CVD mortality [n = 647]) through 2010 (median follow-up 19 years). Contrary to the hypothesis, PTH level was not associated positively with any CVD outcome. The associations of incident heart failure, peripheral artery disease, and CVD mortality with PTH actually were weakly inverse (P trend = .02-.04) in the most fully adjusted models. For example, the hazard ratios across PTH quartiles were 1.00, 1.07, 1.07, and 0.96 (P trend = .74) for coronary heart disease incidence and were 1.00, 0.69, 0.74, and 0.74 (P trend = .02) for CVD mortality. Patterns were similar when restricted to participants with normal baseline kidney function. This large prospective study failed to support the hypothesis that elevated PTH is an independent risk marker for incident CVD. When our data were added to the previous meta-analysis, the pooled hazard ratio remained statistically significant but weakened.


Stimulation of glucose transport in Clone 9 cells by insulin and thyroid hormone: role of GLUT-1 activation.
Thyroid hormone (T3) and insulin are both shown to stimulate glucose transport in Clone 9 cells, a rat liver cell line in which the utilization of glucose is limited by transport rate and in which only the GLUT-1 transporter isoform is expressed. Pre-treatment of these cells with T3 moreover substantially enhances the stimulatory effect of insulin such that at maximally effective hormone concentrations the effects of T3 and insulin on glucose transport are more than additive and indeed nearly multiplicative, suggesting that the mechanisms mediating the enhancement of glucose transport differ between the two hormones. Cell surface biotinylation followed by Western-blot analysis of plasma membrane fractions showed that the stimulatory effects of T3 and insulin on glucose transport, whether acting singly or in combination, exceed the attendant increases in the abundance of GLUT-1 in the plasma membrane. It is suggested that activation of GLUT-1 molecules pre-existing in the plasma membrane plays a major role in mediating the stimulatory effects of T3 and insulin on glucose transport in this cell line.


One pot synthesis of opposing 'rose petal' and 'lotus leaf' superhydrophobic materials with zinc oxide nanorods.
The synthesis in one pot(1) of opposing 'rose petal' and 'lotus leaf' superhydrophobic materials from commercially available superhydrophilic cloth substrates of varying texture is described for the first time. Surfaces of 'rough' textured cloth and 'smooth' textured cloth were simultaneously rendered superhydrophobic by growing zinc oxide (ZnO) nanorods by a hydrothermal process in the same chemical bath. Contact angle hysteresis and water pendant drop tests revealed strong water adhesion to ZnO microrod-treated rough cloth. The combination of water contact angle >150° and strong adhesion is indicative of the 'rose petal effect' with potential for water pinning. Smooth cloth with ZnO nanorods exhibited no adhesion to water droplets with facilitative roll-off. The combination of water contact angle >150° and weak to no adhesion with water is indicative of the 'lotus leaf effect' with potential for self-cleaning. Pendant water drop tests indicated cohesive failure of water on rough cloth coated with ZnO nanorods. Natural rose petals demonstrated adhesive failure between the petal surface and water droplet. A parsimonious explanation is presented. We also describe the development of superhydrophobic clothes without the need for special conditions or further chemical modification.


Caregiving Preparedness and Caregiver Burden in Omani Family Caregivers for Patients with Acquired Brain Injury.
This study aimed to explore the caregiving preparedness and caregiver burden among Omani family caregivers (FCs) of patients with acquired brain injury (ABI). This prospective observational study was conducted at the neurology clinic at Khoula Hospital, Muscat, Oman, from April 2019 to December 2021. Data were collected from 119 FCs and their patients at the time of discharge from the hospital and 16 weeks post-discharge during follow-up care. The questionnaire comprised the Zarit Burden Index, the Preparedness for Caregiving Scale, the Short-Form-12 Health Survey, and a patient symptom scale. The FCs were predominantly female (53.8%), and the mean age was 38.27 ± 9.11 years. Most patients had moderate to severe ABI (95.8%) due to stroke (56.3%) and trauma (30.3%). The most common patient symptoms were loss of muscle strength, speech problems, mood problems, memory loss, and change in behaviour. Most FCs were found to have low caregiving preparedness (58%) at discharge, and 19.1% were found to have a high level of caregiver burden at 16 weeks post-discharge. The length of time post-injury (P <0.01), symptom severity (P <0.01) and the FCs' physical and mental health status (P <0.01 each) were found to be significant predictors of caregiving preparedness, whereas caregiver preparedness (P <0.01), symptom severity (P <0.01), and caregivers' mental health (P = 0.028) were seen as the predictors of caregiver burden. Omani FCs of patients with ABI tend to commence the caregiver role with inadequate preparation, and shortly after, a significant number suffer high caregiver burden. Interventions focusing on the caregiver's health and training in symptom management may improve the outcomes of FCs and patients.


Merotelic attachments and non-homologous end joining are the basis of chromosomal instability.
Although the large majority of solid tumors show a combination of mitotic spindle defects and chromosomal instability, little is known about the mechanisms that govern the initial steps in tumorigenesis. The recent report of spindle-induced DNA damage provides evidence for a single mechanism responsible for the most prominent genetic defects in chromosomal instability. Spindle-induced DNA damage is brought about by uncorrected merotelic attachments, which cause kinetochore distortion, chromosome breakage at the centromere, and possible activation of DNA damage repair pathways. Although merotelic attachments are common early in mitosis, some escape detection by the kinetochore pathway. As a consequence, a proportion of merotelic attachments gives rise to chromosome breakage in normal cells and in carcinomas. An intrinsic chromosome segregation defect might thus form the basis of tumor initiation. We propose a hypothesis in which merotelic attachments and chromosome breakage establish a feedback loop that results in relaxation of the spindle checkpoint and suppression of anti-proliferative pathways, thereby promoting carcinogenesis.


Protective effect of chelerythrine on gentamicin-induced nephrotoxicity.
Despite their beneficial effects, aminoglycosides including gentamicin (GEN) have considerable nephrotoxic side-effects. The toxicity of GEN at the level of the kidney seems to relate to the generation of reactive oxygen species (ROS). ROS have been reported to be involved in the activation of protein kinase C (PKC). The unique structural aspects of PKC cause it to function as a sensor for oxidative stress. It seems likely that the increased NAD(P)H oxidase-derived superoxide (O2) production is at least in part mediated by PKC. We investigated the effects of chelerythrine, a commonly used PKC inhibitor, on GEN-induced changes of renal malondialdehyde (MDA), nitric oxide (NO) generation, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities, glutathione (GSH) content, and serum creatinine (Cr), blood urea nitrogen (BUN) levels. Morphological changes in the kidney were also examined. GEN administration to control rats increased MDA and NO generation but decreased CAT, SOD and GSH-Px activities, and GSH content. Chelerythrine administration with GEN caused significantly decreased MDA, NO generation and increased CAT, SOD and GSH-Px activities, and GSH content when compared with GEN alone. Chelerythrine also significantly decreased serum Cr and BUN levels. Morphological changes in the kidney including tubular necrosis were evaluated qualitatively. Both biochemical findings and histopathological evidence showed that administration of chelerythrine reduced the GEN-induced kidney damage. We propose that chelerythrine acts in the kidney as a potent scavenger of free radicals to prevent the toxic effects of GEN via the inhibition of a PKC pathway.


Wear of ten dental restorative materials in five wear simulators--results of a round robin test.
The purpose of the present study was to prove the hypothesis that different wear measurement methods generate different material rankings. Ten restorative materials, eight composites (BelleGlass, Chromasit, Estenia, Heliomolar RO, SureFil, Targis cured at 95 and 130 degrees C, Tetric Ceram) an amalgam (Amalcap) and a ceramic (Empress) have been evaluated with regard to the wear with five different wear methods (IVOCLAR, ZURICH, MUNICH, OHSU, ACTA). Every center received specimens, which Ivoclar Vivadent had made using the same batch. The test centers did not know which brand they were testing. After completion of the wear test, the raw data were sent to IVOCLAR for further analysis. The statistical analysis of the data included logarithmic transformation of the data, the calculation of relative ranks of each material within each test center, measures of agreement between methods, the discrimination power and coefficient of variation of each method as well as measures of the consistency and global performance for each material. Relative ranks of the materials varied tremendously between the test centers. When all materials were taken into account and the test methods compared with each other, only ACTA agreed reasonably well with two other methods, i.e. OHSU and ZURICH. On the other hand, MUNICH did not agree with the other methods at all. The ZURICH method showed the lowest discrimination power, ACTA and IVOCLAR the highest. Materialwise, the best global performance was achieved by Empress, which was clearly ahead of BelleGlass, SureFil and Estenia. In contrast, Heliomolar RO, Tetric Ceram and especially Chromasit demonstrated a poor global performance. The best consistency was achieved by BelleGlass and SureFil, whereas the consistency of Amalcap and Heliomolar RO was poor. As the different wear simulator settings measure different wear mechanisms, it seems reasonable to combine at least two different wear settings to assess the wear resistance of a new material.


[Pneumonia in patients from a tuberculosis dispensary].
In their everyday practice phthisiologists have to make a differential diagnosis and to treat patients with pneumonia who account for 2.7% of the patients treated at tuberculosis hospital. The main reason of diagnostic errors in patients with pneumonia in general hospitals is that the compulsory diagnostic minimum is not observed and the patients' sputum is not tested for acid-resistant Mycobacteria. The paper analyzes the results of treatment in 20 patients with pneumonia in the contagious isolation wards of the tuberculosis hospital, who were in-effectively treated in the outpatient setting. Multimodality treatment with broad-spectrum antibiotics, including rifampicin and streptomycin, aerosols, and physiotherapy may completely resolve infiltration and eliminate the clinical manifestations of the disease in 19 patients.


Sensing a wave front by use of a diffraction grating.
A method is presented to sense the wave front at the exit of an optical surface. This method uses a set of diffracted rays generated when a He-Ne laser impinges on a rectangular diffraction grating. The grating was placed near the curvature center of the surface to be tested. After they are reflected in the test surface, the diffracted rays have the information of the slopes of the wave front, like in the Hartmann test. The Hartmann pattern was registered near the curvature center and captured with a CCD camera. The slopes for each ray are measured from the experimental pattern, and they are compared with the ideal ones simulated in a computer. The evaluation was carried out by use of Seidel polynomials to obtain the information of the aberrations of a mirror 53 cm in diameter.


6q- is an early and persistent chromosomal aberration in CD3-CD4+ T-cell clones associated with the lymphocytic variant of hypereosinophilic syndrome.
The lymphocytic variant of hypereosinophilic syndrome (LV-HES) is an underrated disease defined by the monoclonal proliferation of interleukin-5 secreting T-cells. This disease is distinguished by a period of chronic lymphoproliferation without clinical transformation, which is frequently a precursor to T-cell lymphoma. In this study, LV-HES was used as a model of pre-malignancy to identify specific marker(s) predictive of the potential for malignant transformation. The karyotypic abnormalities detected in the abnormal CD3-CD4+ T cells were further characterized by fluorescent in situ hybridization. A multi-step retrospective analysis was performed on successive blood samples during a six-year follow up to correlate the evolution of cytogenetic changes with clinical progression. Expression array analysis was used to investigate the effect of these chromosomal aberrations on gene expression. A 6q deletion was detected in the two LV-HES patients during their chronic disease phase. An additional 10p deletion was found alone or in association with the 6q defect in one patient prior to the development of a CD3-CD4+ T-cell lymphoma six years after diagnosis. We show that the 6q but not the 10p deletion is both stable and persistent throughout the chronic disease, finally emerging as the predominant aberration in the lymphoma cells. Six genes mapped to the 6q-deleted region displayed altered gene expression profiles both in the chronic and malignant disease phases. Our data suggest that the 6q deletion represents an early cytogenetic marker for T-cell transformation.


[Historical Transition of Sexuality Education in Japan and Outline of Reproductive Health/Rights].
In this paper, we describe the historical transition of sexuality education in Japan and the direction of sexuality education taken by the Ministry of Education, Culture, Sports, Science and Technology (MEXT). Reproductive health/rights, a key concept in sex education, is also discussed. In Japanese society, discussion on sexuality has long been considered taboo. After the Second World War, sexuality education in Japan began as "purity education." From 1960 until the early 1970s, physical aspects such as genital organs, function, secondary sexual characteristics, and gender differences were emphasized. Comprehensive education as a human being, including physiological, psychological, and social aspects, began to be adopted in the late 1970s. In 2002, it was criticized that teaching genital terms at primary schools and teaching about sexual intercourse and contraceptive methods at junior high schools were "overdue guidance" and "extreme contents." Sexuality education in schools has become a problem and has stagnated for about 10 years. Currently, schools teach sexuality education that does not deviate from the MEXT course guidelines. The direction of MEXT regarding sexuality education should be examined from the basic position that sexual activity by children is inappropriate. Reproductive health/rights apply the concept of human rights to sexuality and reproduction. Reproductive health/rights are key concepts that support sex education and women's health.


Genetic influence on immune phenotype revealed strain-specific variations in peripheral blood lineages.
Inbred mouse strains are routinely used as genetically defined animal models for studying a wide assortment of biological and pathological processes, including immune system function. However, no studies have presented large-scale data on the immune cell populations among the inbred strains in physiological conditions. Here we present a systematic, quantitative analysis of peripheral blood cell phenotypes of 30 mouse strains assessed by flow cytometry. This cohort of mice represents a wide range of genetic origins and includes most of the strains used in genetic, physiological, and immunological studies. We evaluated the relative percentages of peripheral blood leukocyte subtypes (lymphocytes, granulocytes, and monocytes) and lymphocyte subpopulations (CD4+ T, CD8+ T, B220+ B, and natural killer cells) of mature (6-mo-old) mice. Our comprehensive study demonstrated: 1) marked differences in the relative proportions of blood cell populations among the strains at this age, 2) considerable variation of each immune trait with more than twofold difference between strains with the highest and the lowest trait values, and 3) haplotype analysis revealed a strong correlation between eosinophil percentage and a single region on chromosome 14 containing two candidate genes. The strain differences described here provide important information for researchers applying immunophenotyping of peripheral blood in immunological and genetic studies. The data from this study are available as part of the Mouse Phenome Database at http://www.jax.org/phenome.


Cybrd1 (duodenal cytochrome b) is not necessary for dietary iron absorption in mice.
Mammalian nonheme iron absorption requires reduction of dietary iron for uptake by the divalent metal ion transport system in the intestine. This was thought to be mediated by duodenal cytochrome b (Cybrd1), a ferric reductase enzyme resident on the luminal surface of intestinal absorptive cells. To test its importance in vivo, we inactivated the murine Cybrd1 gene and assessed tissue iron stores in Cybrd1-null mice. We found that loss of Cybrd1 had little or no impact on body iron stores, even in the setting of iron deficiency. We conclude that other mechanisms must be available for the reduction of dietary iron.


Production of interleukin 6 by hepatoma cells.
Five rat hepatoma cell lines were shown to secrete hepatocyte-stimulating factors (HSFs) capable of inducing a characteristic spectrum of acute phase genes. Three of these lines, but not normal rat livers or livers from rats with an experimentally induced acute inflammation, produced interleukin 6 (IL6) mRNA. An anti-rat IL6 serum was prepared against synthetic peptides derived from the rat IL6 cDNA sequence. This antiserum cleared authentic rat IL6 and a fraction of the HSF activities secreted by the hepatoma cell lines. After concentration of culture supernatants from FTO2B hepatoma cells, IL6 was detected with the anti-IL6 serum by immuno-blot analysis. Biosynthesis of IL6 in the HTC line was demonstrated by metabolic labeling and immunoprecipitation. Secretion of HSF activities by hepatoma cells was increased by serum factors. These data suggest that different rat hepatoma lines each secrete different characteristic sets of HSF activities and establish unambiguously that IL6 is secreted by at least some of these lines.


Association of platelet function with depression and its treatment with sertraline in patients with chronic kidney disease: analysis of a randomized trial.
Major Depressive Disorder (MDD) can lead to adverse cardiovascular outcomes in patients with chronic kidney disease (CKD). Although one of the proposed mechanisms is heightened platelet activation, effects of MDD and its treatment with a selective serotonin reuptake inhibitor (SSRI) on platelet function in patients with CKD remain unclear. In a pre-specified analysis, changes from baseline to 12 weeks in whole blood platelet aggregation (WBPA) and plasma levels of E-selectin and P-selectin on treatment with sertraline vs. placebo were investigated in 175 patients with CKD (estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73m2) and MDD (MDD+/CKD+) in a randomized, double-blind trial. Correlations between severity of depressive symptoms and platelet function were also analyzed. In order to investigate whether differences in platelet function were due to presence of CKD or MDD, we compared a subgroup of 49 MDD+/CKD+ patients with eGFR < 30 ml/min/1.73m2 to 43 non-depressed CKD controls (28 CKD with eGFR < 30 ml/min/1.73m2 [MDD-/CKD+] and 15 individuals with eGFR ≥90 ml/min/1.73m2 [MDD-/CKD-]. In MDD+/CKD+ individuals, there were no significant correlations between severity of depressive symptoms and platelet function, and no significant changes in platelet function after 12 weeks of treatment with sertraline vs. placebo. There were no significant differences in platelet function among MDD+/CKD+ patients and controls without MDD except in WBPA to 10 μM ADP (P = 0.03). WBPA to ADP was lower in the MDD-/CKD- group (8.0 Ω [5.0 Ω, 11.0 Ω]) as compared to the MDD-/CKD+ group (12.5 Ω [8.0 Ω, 14.5 Ω]), P = 0.01, and the MDD+/CKD+ group (11.0 Ω [8.0 Ω, 15.0 Ω]), P < 0.01. Heightened ADP-induced platelet aggregability was observed in CKD patients compared to controls with normal kidney function, regardless of presence of comorbid MDD, and treatment with sertraline did not affect platelet function. These findings suggest that increased platelet activation may not be a major contributory underlying mechanism by which depression may lead to worse cardiovascular outcomes in patients with CKD. Future studies should include positive MDD controls without CKD to confirm our findings. ClinicalTrials.gov identifier numbers: CAST Study: NCT00946998 (Recruitment Status: Completed. First Posted: July 27, 2009. Results First Posted: January 30, 2018). WiCKDonASA Study: NCT01768637 (Recruitment Status: Completed. First Posted: January 15, 2013. Results First Posted: April 19, 2019).


Terahertz Bessel-Gauss beams of radial and azimuthal polarization from microstructured photoconductive antennas.
We report on emission and detection of pulsed terahertz radiation of radial and azimuthal polarization by microstructured photoconductive antennas. To this end the electrode geometry of the emitter is inverse to the desired THz field pattern and a second periodic structure prevents destructive interference effects. Beam profiles of freely propagating THz waves are studied for divergent and refocused beams. They can be well described as the lowest order Bessel-Gauss modes with a divergence comparable to linearly polarized Gaussian beams. Additionally, mode sensitive detection is demonstrated for radially polarized radiation.


Phenotypic changes in mouse pancreatic stellate cell Ca2+ signaling events following activation in culture and in a disease model of pancreatitis.
The specific characteristics of intracellular Ca 2+ signaling and the downstream consequences of these events were investigated in mouse pancreatic stellate cells (PSC) in culture and in situ using multiphoton microscopy in pancreatic lobules. PSC undergo a phenotypic transformation from a quiescent state to a myofibroblast-like phenotype in culture. This is believed to parallel the induction of an activated state observed in pancreatic disease such as chronic pancreatitis and pancreatic cancer. By day 7 in culture, the complement of cell surface receptors coupled to intracellular Ca 2+ signaling was shown to be markedly altered. Specifically, protease-activated receptors (PAR) 1 and 2, responsive to thrombin and trypsin, respectively, and platelet-derived growth factor (PDGF) receptors were expressed only in activated PSC (aPSC). PAR-1, ATP, and PDGF receptor activation resulted in prominent nuclear Ca 2+ signals. Nuclear Ca 2+ signals and aPSC proliferation were abolished by expression of parvalbumin targeted to the nucleus. In pancreatic lobules, PSC responded to agonists consistent with the presence of only quiescent PSC. aPSC were observed following induction of experimental pancreatitis. In contrast, in a mouse model of pancreatic disease harboring elevated K-Ras activity in acinar cells, aPSC were present under control conditions and their number greatly increased following induction of pancreatitis. These data are consistent with nuclear Ca 2+ signaling generated by agents such as trypsin and thrombin, likely present in the pancreas in disease states, resulting in proliferation of "primed" aPSC to contribute to the severity of pancreatic disease.


Effects of hatching time on behavior and weight development of chickens.
The length of the embryonic period varies both among and within species and can affect the individual phenotype in many ways, both physiologically and behaviorally. In chickens, the hatch window may last 24-48 hours (up to 10% of the incubation time), and studies have shown that incubation length may affect post-hatch growth and physiology. However, little is known about effects on behavior. We therefore investigated how behavior variation correlates with hatching time in the early life of chickens. We also measured egg weight and egg weight loss in relation to hatching time, as well as post-hatch growth. For females, there was a negative correlation between hatch time and body weight from day 4 and throughout the experiment. For males, such a correlation was only observed when testing all hatched males up until day 10. The birds were exposed to a number of behavioral tests, and a principal components analysis was performed on the variables, resulting in four components. For the largest component, termed "Passivity", a tendency of a difference was found between early and middle male hatchers. Furthermore, a significant difference between early and middle male hatchers was found in the second component, termed "Response to novelty". In a spatial learning test, late hatchers tended to learn slower. The behavior of females was not significantly affected by hatching time in any of these tests. This study is among the first to demonstrate a link between time of hatching and early behavior in a precocial species like the chicken, and may help shedding light on the evolutionary trade-offs between incubation length and post-hatch traits. The results may also be relevant from a perspective of stress coping and therefore also for animal welfare and productivity in the chicken industry. The mechanisms linking hatching time with post-hatch phenotype remain to be investigated.


Phase I and II clinical and pharmacological study of 4-demethoxydaunorubicin (idarubicin) in adult patients with acute leukemia.
Fifty-two adults treated previously with either acute leukemia (43 patients) or blastic-phase chronic myelogenous leukemia (nine patients) received 4-demethoxydaunorubicin (20 to 45 mg/sq m) i.v. over 2 to 3 days. Three of the ten patients with acute lymphocytic leukemia achieved a complete remission (CR) lasting 5 to 7 weeks. Five of the 28 patients with acute nonlymphocytic leukemia achieved a CR lasting 5 to 80 weeks. All remissions were induced with one course of treatment with a median time to CR of 28 days (range, 22 to 40 days). None of the patients with blastic chronic myelogenous leukemia or secondary leukemia achieved a CR. The drug was well tolerated; mucositis (36%), nausea and vomiting (35%), and hepatic dysfunction (26%) were the most common side effects. Pharmacokinetic observations on five patients demonstrated multiphasic clearance of 4-demethoxydaunorubicin and extensive formation and prolonged retention of 4-demethoxy-13-hydroxydaunorubicin; that metabolite accumulated in plasma on repeated daily dosing. 4-Demethoxydaunorubicin has sufficient antileukemic activity in both acute lymphocytic leukemia and acute nonlymphocytic leukemia to warrant a prospective comparison, in combination regimens, against the conventional anthracyclines, daunorubicin and/or doxorubicin.


Conceptualizing disability in US national surveys: application of the World Health Organization's (WHO) International Classification of Functioning, Disability, and Health (ICF) framework.
Disability data inform resource allocation and utilization, characterize functioning and changes over time, and provide a mechanism to monitor progress toward promoting and protecting the rights of individuals with disability. Data collection efforts, however, define and measure disability in varied ways. Our objective was to see how the content of disability measures differed in five US national surveys and over time. Using the WHO ICF as a conceptual framework for measuring disability, we assessed the National Health Interview Survey (NHIS), Current Population Survey (CPS), Survey of Income and Program Participation (SIPP), National Survey of SSI Children and Families (NSCF), and American Community Survey (ACS) for their content coverage of disability relative to each of the four ICF components (i.e., body functions, body structures, activities and participation, and environment). We used second-level ICF three-digit codes to classify question content into categories within each ICF component and computed the proportion of categories within each ICF component that was represented in the questions selected from these five surveys. The disability measures varied across surveys and years. The NHIS captured a greater proportion of the ICF body functions and body structures components than did other surveys. The SIPP captured the most content of the ICF activities and participation component, and the NSCF contained the most content of the ICF environmental factors component. This research successfully illustrated demonstrated the utility of the ICF in examining the content of disability measures in five national surveys and over time.


Isolation and characterization of bleomycin-sensitive Chinese hamster ovary cells.
Nineteen bleomycin-sensitive Chinese hamster ovary cell mutants have been isolated using a replica plating and photography approach. As judged by the dose which reduces cell survival to 37% of the untreated control, these mutants are from 2.5- to 32-fold more sensitive to a 16-h bleomycin treatment than the parental cell, while for chronic bleomycin exposure, the increase in sensitivity was 5 to 58 times that of the parental cell. Four bleomycin-sensitive mutants had increased sensitivities to killing by gamma-rays (2- to 3-fold), mitomycin C (2-fold), and ethyl methane sulfonate (4- to 5-fold), while six other mutants were resistant to these agents. Nine other bleomycin-sensitive mutants displayed a variable pattern of cross-sensitivities to these agents. Using the technique of alkaline elution, the relative frequency of single-strand DNA breaks introduced by varying concentrations of bleomycin was examined in one mutant and its parent cell. The elution profiles of both cells were similar, suggesting that the bleomycin sensitivity of this mutant is not due to a greater frequency of single-strand breaks introduced by bleomycin.


Correlation among lip print pattern, finger print pattern and abo blood group.
To study correlation between lip print pattern, finger print pattern and ABO blood group. The study group consisted of 27 males and 27 females who were aged between 20-40 years. Lip prints, finger prints and ABO and Rh blood groups of each individual were recorded. Lip prints were classified, based on Suzuki's and Tsuchihashi's classification and finger prints were classified, based on Michael's and Kucken's classification. The results were statistically analyzed by using Chi-square test. Complete vertical lip print, loop finger print pattern, O+ blood group were predominant among individual groups. O+ blood group-type I lip print combination, loop finger print pattern-type IV lip print pattern combination, O+ blood group-loop finger print pattern combination and both B+ blood group-loop finger print pattern- type IV lip print pattern combination and O+ blood group-loop finger print pattern-type I lip print pattern were predominant. Though lip prints, finger prints and blood groups had their own specificities, correlation of the three parameters did not show any significance.


[New technology in plastic surgery].
A new model of biorhythm of wound process is proposed with due consideration for the neurodynamic features of its stages. The first phase of repair process is denoted as the tonic (trophotropic) and the second as the physical (ergotropic). In an aseptic wound the repair morphogenesis takes about two weeks, with the tonic effects predominating during the first week and ergotropic processes during the second week. This results in complete taking in of the autotransplant with formation of a fine cicatrice which does not deform the transplanted flap. Impairment of the biorhythm of wound process can involve excessive development of both trophotropic and ergotropic tendencies, rendering a pathologic direction to repair processes. Either tonic or physical component of trophic provision is then boosted and fixed, and hence, wound healing is delayed, which leads to formation rough deforming cicatrices.


Young people making sense of pain: cognitive appraisal, function, and pain in 8-16 year old children.
Recurrent pain is a common childhood problem which for some becomes chronic and is associated with severely impaired functioning. Relationships of psychological variables with impaired functioning have rarely been investigated in samples of children reporting pain in non-clinical settings. The aim of this study was to examine the role of cognitive appraisal in the relationship between chronic pain and level of functioning in a normal school-attending population of children who report pain as a common experience. Five hundred and sixty one schoolchildren aged between 8 and 16 years and their parents participated in a cross-sectional interview and questionnaire study. Child functioning was measured in two ways: self-reported quality of life, and self-reported functional disability associated with pain. Results showed a consistent pattern across both specific measures of functioning used. Catastrophic appraisals of pain can explain partially the functional impairment found in a sample of normal schoolchildren with chronic pain. Positive expectations about ability, the responsibility to exert control over the pain, and the belief that medication and doctors will help to control the pain, were found to be protective of normal functioning in chronic pain. Cognitive factors were found to mediate but not moderate the relationship between pain and disability, and quality of life.


Tunable microfluidic device fabricated by femtosecond structured light for particle and cell manipulation.
Smart devices made of stimuli-responsive (SR) hydrogel can realize accurate shape control with high repeatability attributed to their fast swelling and shrinking upon the change of external stimuli. Integrating these devices into microfluidic chips and utilizing their controllable deformation capability are highly promising approaches to enrich the functions of microfluidic devices and reduce their external apparatuses. Herein we propose and demonstrate a tunable microfluidic device (TMFD) by integrating a pH-sensitive hydrogel microring array into a microchannel. Instantaneous and reversible deformation of the microrings can be finished in less than 200 ms. The array gaps of the microrings are reversibly switched to realize the capture or release of microobjects. In addition, a femtosecond laser holographic processing method is firstly used to pattern and integrate the pH-sensitive hydrogel microrings into a microchannel, and the pH-responsive properties of the hydrogel affected by laser processing dosages are theoretically and experimentally investigated. With this method, the height, diameter (6-16 μm), swelling ratio (35-65%), and diameter change (2-5 μm) can be precisely controlled. As a proof of concept, the filtering of polystyrene particles with multiple sizes and complete trapping of PS particles and cells are demonstrated by these TMFDs. The developed TMFD can be easily integrated by the femtosecond laser holographic processing method, and operates robustly without the need for external precision apparatuses, which hold great promise in the applications of microobject manipulation and biomedical analysis.


Berberine acutely activates the glucose transport activity of GLUT1.
Berberine, which has a long history of use in Chinese medicine, has recently been shown to have efficacy in the treatment of diabetes. While the hypoglycemic effect of berberine has been clearly documented in animal and cell line models, such as 3T3-L1 adipocytes and L6 myotube cells, the mechanism of action appears complex with data implicating activation of the insulin signaling pathway as well as activation of the exercise or AMP kinase-mediated pathway. There have been no reports of the acute affects of berberine on the transport activity of the insulin-insensitive glucose transporter, GLUT1. Therefore, we examined the acute effects of berberine on glucose uptake in L929 fibroblast cells, a cell line that express only GLUT1. Berberine- activated glucose uptake reaching maximum stimulation of five-fold at >40 μM. Significant activation (P < 0.05) was measured within 5 min reaching a maximum by 30 min. The berberine effect was not additive to the maximal stimulation by other known stimulants, azide, methylene blue or glucose deprivation, suggesting shared steps between berberine and these stimulants. Berberine significantly reduced the K(m) of glucose uptake from 6.7 ± 1.9 mM to 0.55 ± 0.08 mM, but had no effect on the V(max) of uptake. Compound C, an inhibitor of AMP kinase, did not affect berberine-stimulated glucose uptake, but inhibitors of downstream kinases partially blocked berberine stimulation. SB203580 (inhibitor of p38 MAP kinase) did not affect submaximal berberine activation, but did lower maximal berberine stimulation by 26%, while PD98059 (inhibitor of ERK kinase) completely blocked submaximal berberine activation and decreased the maximal stimulation by 55%. It appears from this study that a portion of the hypoglycemic effects of berberine can be attributed to its acute activation of the transport activity of GLUT1.


Acidosis and hyperkalemia caused by losartan and enalapril in pediatric kidney transplant recipients.
To evaluate the efficacy and safety of losartan and enalapril in pediatric kidney transplant recipients. A retrospective review was performed in 31 pediatric kidney transplant recipients who were treated with losartan (50 mg/d, oral) for 1 to 6 months because of mild hypertension and persistent proteinuria. All patients were treated concurrently with enalapril (5 or 10 mg daily, oral), and 12 patients (39%) also were treated with amlodipine (5 or 10 mg daily, oral). Demographic and clinical characteristics of the patients were reviewed. Losartan use was associated with a significant decrease in mean systolic (before losartan was started, 123 ± 14 mm Hg; before losartan was stopped, 111 ± 10 mm Hg; P ≤ .001) and diastolic blood pressure (before losartan was started, 78 ± 11 mm Hg; before losartan was stopped, 69 ± 10 mm Hg; P ≤ .001) and urinary protein excretion (before losartan was started, 51 ± 45 mg/m2/h; before losartan was stopped, 28 ± 34 mg/m2/h; P ≤ .001). However, losartan therapy was associated with a significant mean increase in serum potassium level (before losartan was started, 4.0 ± 0.4 mmol/L; before losartan was stopped, 5.7 ± 0.5 mmol/L; P ≤ .001) and decrease in pH (before losartan was started, 7.35 ± 0.0; before losartan was stopped, 7.23 ± 0.0; P ≤ .001). Losartan was stopped because of hyperkalemia and acidosis earlier in patients who were on tacrolimus than cyclosporine immunosuppression (tacrolimus, 3 ± 1 mo; cyclosporine, 4.7 ± 0.8 mo; P ≤ .001). Losartan and enalapril may be beneficial in pediatric kidney transplant recipients by decreasing blood pressure and proteinuria, with maintenance of stable graft function, but may be associated with serious adverse events including hyperkalemia and life-threatening acidosis.


[Membrane model of the cupula of the vestibular semicircular canals].
A mathematical model of the time-course variations of the cupula of the semicircular canals of the vestibular apparatus is presented. The model is found to be in good agreement with experimental data which suggests that the cupular matter has viscosity-elasticity properties. Their role in the functioning of the vestibular apparatus is discussed in qualitative terms. The applicability of the membrane model to the description of the time-course variations of the cupula is considered.