Factors affecting the levels of tea polyphenols and caffeine in tea leaves.
An isocratic HPLC procedure was developed for the simultaneous determination of caffeine and six catechins in tea samples. When 31 commercial teas extracted by boiling water or 75% ethanol were analyzed by HPLC, the levels of (-)-epigallocatechin 3-gallate (EGCG), and total catechins in teas were in the order green tea (old leaves) > green tea (young leaves) and oolong tea > black tea and pu-erh tea. Tea samples extracted by 75% ethanol could yield higher levels of EGCG and total catechins. The contents of caffeine and catechins also have been measured in fresh tea leaves from the Tea Experiment Station in Wen-Shan or Taitung; the old tea leaves contain less caffeine but more EGCG and total catechins than young ones. To compare caffeine and catechins in the same tea but manufactured by different fermentation processes, the level of caffeine in different manufactured teas was in the order black tea > oolong tea > green tea > fresh tea leaf, but the levels of EGCG and total catechins were in the order green tea > oolong tea > fresh tea leaf > black tea. In addition, six commercial tea extracts were used to test the biological functions including hydroxyl radical scavenging, nitric oxide suppressing, and apoptotic effects. The pu-erh tea extracts protected the plasmid DNA from damage by the Fenton reaction as well as the control at a concentration of 100 microg/mL. The nitric oxide suppressing effect of tea extracts was in the order pu-erh tea >/= black tea > green tea > oolong tea. The induction of apoptosis by tea extract has been demonstrated by DNA fragmentation ladder and flow cytometry. It appeared that the ability of tea extracts to induce HL-60 cells apoptosis was in the order green tea > oolong > black tea > pu-erh tea. All tea extracts extracted by 75% ethanol have stronger biological functions than those extracted by boiling water.


Benefit of living donor liver transplantation in graft survival for extremely high model for end-stage liver disease score ≥35.
Living liver donation with high model for end-stage liver disease (MELD) score was discouraged despite organ shortage. This study aimed to compare graft survival between living donor liver transplantation (LDLT) and deceased donor liver transplantation (DDLT) recipients with extremely high-MELD (score of ≥35). Between 2008 and 2018, 359 patients who underwent liver transplantation with a MELD score ≥35 were enrolled. We compared graft survival between LDLT and DDLT after propensity score matching (PSM) and performed subgroup analysis according to donor type. After PSM, there was no statistical difference in graft survival between the LDLT and DDLT groups (p = .466). Old age, acute on chronic liver failure, re-transplantation, preoperative intensive care unit stay and red blood cell (RBC) transfusion during the operation were risk factors for graft failure (p = .046, .005, .032, .015 and .001, respectively). Biliary complications were more common in the LDLT group (p = .021), while viral infection, postoperative uncontrolled ascites, and postoperative hemodialysis were more common in the DDLT group (p = .002, .018, and .027, respectively). In the LDLT group, acute chronic liver failure, intraoperative RBC transfusion, and early postoperative complications were risk factors for graft failure (p = .007, <.001, and .001, respectively). Our study showed that LDLT is not inferior to DDLT in graft survival if appropriate risk evaluation is performed in cases of extremely high-MELD scores. This result will help overcome organ shortages in high-MELD liver transplantation.


Association of rs9939609 Polymorphism with Metabolic Parameters and FTO Risk Haplotype Among Tunisian Metabolic Syndrome.
Variants in the fat mass and obesity-associated (FTO) gene are associated with obesity and type 2 diabetes mellitus. This study aims to assess the association of the rs9939609 variant and haplotypes in FTO gene with metabolic syndrome (MetS) components in a Tunisian population sample. A total of 685 Tunisian subjects were genotyped for the rs9939609T>A using TaqMan allelic discrimination assay. Two variants rs1421085T>C and rs8057044A>G already genotyped in a previous study were used to test haplotype association of the FTO gene. Genotype distribution of the variant rs9939609 was different between MetS and controls (P = 0.017). Individuals carrying TA genotypes had a significantly increased risk independently of body mass index or age (P = 0.009). The variant rs9939609 was also associated with impaired fasting glucose (IFG) (P = 0.002). Among the eight haplotypes in the population, the haplotype GCA was significantly associated with a higher risk of developing the MetS, higher systolic blood pressure, and higher levels of fasting glucose and triglycerides (TGs) in the total sample and females, separately. Separate analysis by gender revealed a protective haplotype TGT among women (P = 0.023). FTO haplotypes have a strong influence on blood pressures and TG and IFG levels. These findings provide evidence that FTO gene may play a critical role in leading to MetS in Tunisian population.


Effects of chlordiazepoxide, buspirone and cocaine on behavior suppressed by timeout presentation.
Male Wistar rats were exposed to a two-component multiple schedule: a random-interval 30 s schedule of pellet presentation and a conjoint random-interval 30 s schedule of pellet presentation, random-interval 2 s schedule of timeout 10 s presentation. Once responding had stabilized subjects were injected intraperitoneally with vehicle, chlordiazepoxide (1-30 mg/kg), buspirone (0.1-4.2 mg/kg) or cocaine (1-30 mg/kg), 15 min before the start of the experimental session. Before drug administration, punished response rates were less than 30% of unpunished response rates for four of the six subjects, and 60% and 75% for the other two. Low doses of chlordiazepoxide (1 and 3 mg/kg) increased punished responding (range 25-300%), and slightly increased unpunished response rates (by 25% in all but one subject, whose rates increased by 75%). The higher doses of chlordiazepoxide (10-30 mg/kg) dose-dependently decreased response rates in both components. The lower doses of buspirone (0.1 and 0.3 mg/kg) either did not affect, or decreased response rates in both components of the schedule; the higher doses produced dose-dependent decreases. Low doses of cocaine (1, 3 and 5.6 mg/kg) did not affect response rates in either component of the multiple schedule, whereas higher doses produced a dose-dependent decrease in response rates, except for one subject whose punished response rates increased substantially. The behavioral effects of chlordiazepoxide and buspirone observed in the present experiment were similar to those observed in experiments in which response rates were suppressed by shock presentation.


THE CONSTRUCTION AND OPERATION OF EXPERIMENTAL ROOMS FOR THE STUDY OF AIR-BORNE INFECTION.
This communication describes the construction and operation of two identical experimental rooms in which it is possible to produce and maintain a wide range of temperature and humidity with or without exchange of the room air. The ability to maintain a large air mass under constant conditions makes it possible to study the effects of different atmospheric states on air-suspended bacteria and viruses in relation to their survival, particle size, humidification, killing by lethal vapors, and host susceptibility. A brief description of the functioning of the rooms under experimental conditions is given.


A review of neuroimaging findings in repetitive brain trauma.
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease confirmed at postmortem. Those at highest risk are professional athletes who participate in contact sports and military personnel who are exposed to repetitive blast events. All neuropathologically confirmed CTE cases, to date, have had a history of repetitive head impacts. This suggests that repetitive head impacts may be necessary for the initiation of the pathogenetic cascade that, in some cases, leads to CTE. Importantly, while all CTE appears to result from repetitive brain trauma, not all repetitive brain trauma results in CTE. Magnetic resonance imaging has great potential for understanding better the underlying mechanisms of repetitive brain trauma. In this review, we provide an overview of advanced imaging techniques currently used to investigate brain anomalies. We also provide an overview of neuroimaging findings in those exposed to repetitive head impacts in the acute/subacute and chronic phase of injury and in more neurodegenerative phases of injury, as well as in military personnel exposed to repetitive head impacts. Finally, we discuss future directions for research that will likely lead to a better understanding of the underlying mechanisms separating those who recover from repetitive brain trauma vs. those who go on to develop CTE.


A bilateral rehabilitation system for the lower limbs.
Bilateral and unilateral training equipment for the upper limbs facilitates rehabilitation after stroke. In this work, we tested the first device designed for bilateral training of the lower limbs. Characteristics and usage of the novel MedExercise® ST device were evaluated by four healthy volunteers. A pedometer and temperature sensor were attached to the device and used to measure cadence and intensity of training, respectively. The heart rates of participants were recorded with a fingertip pulse oximeter. Thirty elderly patients assessed usability of the device and completed the survey. It was shown that the device could be operated in sitting and recumbent positions. The resistance levels and range of joint motion were individually adjustable for each leg, allowing both bilateral and unilateral training. When pedals were linked together, one leg could help moving the other leg. Recording of training intensities allowed leg fitness testing, personalized exercise prescription and analysis of self-controlled training. A usability survey demonstrated positive perception of elderly patients towards the device. This training system has a range of useful features, which can facilitate rehabilitation of the lower limbs via early leg mobilization and self-controlled training. Implications for Rehabilitation Bilateral and unilateral training devices are widely used to improve the effectiveness of upper limb rehabilitation, but there is no analogous equipment available for the lower limbs. Here, we show that the MedExercise® ST training system allows independent exercise of each leg in bilateral and unilateral modes, and objective recording of training activities. Elderly patients attending the exercise rehabilitation clinic demonstrated a positive perception towards usability of this equipment. The results of this study suggest suitability of the system for optimization of lower limb rehabilitation, including early leg mobilisation and self-controlled training.


Sulphated endothelial ligands for L-selectin in lymphocyte homing and inflammation.
Lymphocytes from the blood home to secondary lymphoid tissues through a process of tethering, rolling, firm adhesion and transmigration. Tethering and rolling of lymphocytes is mediated by the interaction of L-selectin on lymphocytes with sulphated ligands expressed by the specialized endothelial cells of high endothelial venules (HEVs). The sulphate-dependent monoclonal antibody MECA79 stains HEVs in peripheral lymph nodes and recognizes the complex of HEV ligands for L-selectin termed peripheral node addressin. High endothelial cell GlcNAc-6-sulphotransferase/L-selectin ligand sulphotransferase is a HEV-expressed sulphotransferase that contributes to the formation of the MECA79 epitope and L-selectin ligands on lymph node HEVs. MECA79-reactive vessels are also common at sites of chronic inflammation, suggesting mechanistic parallels between lymphocyte homing and inflammatory trafficking.


Geochemical Modeling of Celestite (SrSO4) Precipitation and Reactive Transport in Shales.
Celestite (SrSO4) precipitation is a prevalent example of secondary sulfate mineral scaling issues in hydraulic fracturing systems, particularly in basins where large concentrations of naturally occurring strontium are present. Here, we present a validated and flexible geochemical model capable of predicting celestite formation under such unconventional environments. Simulations were built using CrunchFlow and guided by experimental data derived from batch reactors. These data allowed the constraint of key kinetic and thermodynamic parameters for celestite precipitation under relevant synthetic hydraulic fracturing fluid conditions. Effects of ionic strength, saturation index, and the presence of additives were considered in the combined experimental and modeling construction. This geochemical model was then expanded into a more complex system where interactions between hydraulic fracturing fluids and shale rocks were allowed to occur subject to diffusive transport. We find that the carbonate content of a given shale and the presence of persulfate breaker in the system strongly impact the location and extent of celestite formation. The results of this study provide a novel multicomponent reactive transport model that may be used to guide future experimental design in the pursuit of celestite and other sulfate mineral scale mitigation under extreme conditions typical of hydraulic fracturing in shale formations.


Harnessing Environmental Ca2+ for Extracellular Protein Thermostabilization.
Ca2+ is the third-most prevalent metal ion in the environment. EF hands are common Ca2+-binding motifs found in both extracellular and intracellular proteins of eukaryotes and prokaryotes. Cytoplasmic EF hand proteins often mediate allosteric control of signal transduction pathway components in response to intracellular Ca2+ concentration fluctuations by coupling Ca2+ binding to changes in protein structure. We show that an extracellular structural Ca2+-binding site mediates protein thermostabilization by such conformational coupling as well. Binding Ca2+ to the EF hand of the extracellular (periplasmic) Escherichia coli glucose-galactose binding protein thermostabilizes this protein by ∼17 K relative to its Ca2+-free form. Using statistical thermodynamic analysis of a fluorescent conjugate of ecGGBP that reports simultaneously on ligand binding and multiple conformational states, we found that its Ca2+-mediated stabilization is determined by conformational coupling mechanisms in two independent conformational exchange reactions. Binding to folded and unfolded states determines the maximum Ca2+-mediated stability. A disorder → order transition accompanies the formation of the Ca2+ complex in the folded state and dictates the minimum Ca2+ concentration at which the Ca2+-bound state becomes dominant. Similar transitions also encode the structural changes necessary for Ca2+-mediated control elements in signal transduction pathways. Ca2+-mediated thermostabilization and allosteric control, therefore, share a fundamental conformational coupling mechanism, which may have implications for the evolution of EF hands.


Plant Omics Data Center: an integrated web repository for interspecies gene expression networks with NLP-based curation.
Comprehensive integration of large-scale omics resources such as genomes, transcriptomes and metabolomes will provide deeper insights into broader aspects of molecular biology. For better understanding of plant biology, we aim to construct a next-generation sequencing (NGS)-derived gene expression network (GEN) repository for a broad range of plant species. So far we have incorporated information about 745 high-quality mRNA sequencing (mRNA-Seq) samples from eight plant species (Arabidopsis thaliana, Oryza sativa, Solanum lycopersicum, Sorghum bicolor, Vitis vinifera, Solanum tuberosum, Medicago truncatula and Glycine max) from the public short read archive, digitally profiled the entire set of gene expression profiles, and drawn GENs by using correspondence analysis (CA) to take advantage of gene expression similarities. In order to understand the evolutionary significance of the GENs from multiple species, they were linked according to the orthology of each node (gene) among species. In addition to other gene expression information, functional annotation of the genes will facilitate biological comprehension. Currently we are improving the given gene annotations with natural language processing (NLP) techniques and manual curation. Here we introduce the current status of our analyses and the web database, PODC (Plant Omics Data Center; http://bioinf.mind.meiji.ac.jp/podc/), now open to the public, providing GENs, functional annotations and additional comprehensive omics resources.


Birthplace and yield of nipple aspirate fluid in Chinese women.
The different rates of breast cancer found between Chinese women in Asia compared with Chinese-born women in the United States suggest that dietary and environmental factors may be of etiological significance. We evaluated the proportion of 480 premenopausal Chinese women who yielded nipple aspirate fluid (NAF) by birthplace in Asia versus the United States and by reproductive and other risk factors. Birthplace was used as a surrogate for presumed differences in exposures during gestation, childhood, and adolescence that might influence yield of NAF in premenopausal women. In United States-born Chinese women compared with Asia-born Chinese women, the proportion yielding NAF was 44 of 95 (46.3%) versus 120 of 385 (31.2%), respectively. The relative risk of yield of NAF in United States-born women compared with Asia-born women was odds ratio = 2.37 (95% confidence interval, 1.26-4.47). Independent positive associations of NAF yield were also found with history of parity and breast feeding, cerumen phenotype, and a negative association with ever use of oral contraceptives. These findings support the hypothesis that early environmental exposures may have long-lasting physiological effects discernible in the breast glands of adult women.


Dose escalation can maximize therapeutic potential of sunitinib in patients with metastatic renal cell carcinoma.
In patients with metastatic renal cell cancer, based on limited evidence, increased sunitinib exposure is associated with better outcome. The survival and toxicity data of patients receiving individualized dose escalated sunitinib therapy as compared to standard management were analyzed in this study. From July 2013, the data of metastatic renal cell cancer patients with slight progression but still a stable disease according to RECIST 1.1 criteria treated with an escalated dose of sunitinib (first level: 62.5 mg/day in 4/2 or 2 × 2/1 scheme, second level: 75 mg/day in 4/2 or 2 × 2/1 scheme) were collected prospectively. Regarding characteristics, outcome, and toxicity data, an explorative retrospective analysis of the register was carried out, comparing treatments after and before July 1, 2013 in the study (selected patients for escalated dose) and control (standard dose) groups, respectively. The study involved 103 patients receiving sunitinib therapy with a median overall and progression free survival of 25.36 ± 2.62 and 14.2 ± 3.22 months, respectively. Slight progression was detected in 48.5% of them. First and second-level dose escalation were indicated in 18.2% and 4.1% of patients, respectively. The dosing scheme was modified in 22.2%. The median progression free survival (39.7 ± 5.1 vs 14.2 ± 1.3 months (p = 0.037)) and the overall survival (57.5 ± 10.7 vs 27.9 ± 2.5 months (p = 0.044)) were significantly better in the study group (with dose escalation) than in the control group. Patients with nephrectomy and lower Memorial Sloan Kettering Cancer Center (MSKCC) scores showed more favorable outcomes. After dose escalation, the most common adverse events were worsening or development of fatigue, hypertension, stomatitis, and weight loss of over 10%. Escalation of sunitinib dosing in selected patients with metastatic renal cell cancer, especially in case of slight progression, based on tolerable toxicity is safe and improves outcome. Dose escalation in 12.5 mg steps may be recommended for properly educated patients.


A unifying framework for bivalent multilocus linkage analysis of allotetraploids.
An allotetraploid has four paired sets of chromosomes derived from different diploid species, whose meiotic behavior is qualitatively different from the underlying diploids. According to a traditional view, meiotic pairing occurs only between homologous chromosomes, but new evidence indicates that homoeologous chromosomes may also pair to a lesser extent compared with homolog pairing. Here, we describe and assess a unifying analytical framework that incorporates differential chromosomal pairing into a multilocus linkage model. The preferential pairing factor is used to quantify the probability difference of pairing occurring between homologous chromosomes and homoeologous chromosomes. The unifying framework allows simultaneous estimation of the linkage, genetic interference and preferential pairing factor using commonly existing multiplex markers. We compared the unifying approach and traditional approaches assuming random chromosomal pairing by analyzing marker data collected in a full-sib family of tetraploid switchgrass, a bioenergy species whose diploid origins are undefined, but with subgenomes that are genetically well differentiated. The unifying framework provides a better tool for estimating the meiotic linkage and constructing a genetic map for allotetraploids.


Effects of repeated dosing with mechanistically distinct antinociceptive ligands in a rat model of neuropathic spinal cord injury pain.
A lack of efficacy of some analgesic drugs has been previously described in rats with neuropathic spinal cord injury (SCI) pain. It has been suggested that repeated dosing in these animals over time may eventually lead to efficacy. However, it is also possible that efficacy may diminish over time with repeated dosing. This study evaluated the efficacy of various drugs upon repeated dosing over time in a rat model of SCI pain. Four weeks following an acute spinal cord compression at the mid-thoracic level, rats developed decreased hind paw withdrawal threshold, suggestive of below level neuropathic hypersensitivity. Either cannabinoid (CB) receptor agonist CP 55,940, the anticonvulsant carbamazepine or gabapentin, the antidepressant amitriptyline or vehicle was administered over a period of 7 days. Neither carbamazepine nor amitriptyline demonstrated efficacy either after a single or repeated dosing. Beginning with a 50% efficacious dose of gabapentin, the effect of gabapentin in SCI rats neither increased nor decreased over the treatment period. The antinociceptive effect of CP 55,940 was maintained for the entire treatment period, which was mediated by CB1 but not CB2 receptors. The current data suggest that sustained antinociception can be obtained with some drugs in rats with neuropathic SCI pain. Furthermore, the current data do not substantiate the notion that repeated treatment with initially ineffective drugs will eventually lead to efficacy; treatments that are not acutely effective are unlikely to demonstrate clinical efficacy.


Magnetic resonance imaging in multiple sclerosis.
multiple sclerosis (MS) is an inflammatory disease of unknown origin affecting the central nervous system. Magnetic resonance imaging (MRI) plays an increasingly important role in its diagnosis and further monitoring of disease progress. the typical MRI appearance of MS on conventional MRI sequences and current diagnostic criteria for MS are discussed. Advanced imaging techniques are reviewed with respect to application in MS. Finally, the atypical variants of MS are briefly reviewed. although MRI is not intended and will not replace clinical assessment in MS, the recognized MRI criteria may aid in establishing an earlier and more accurate diagnosis of MS in the context of a clinical suspicion or clinically isolated syndrome. In addition, MRI might contribute to rule out differential diagnoses for MS. Moreover, MRI may be used to monitor the evolution of MS and in pharmaceutical trials. Advanced imaging techniques might, in the future, further characterize MS lesion subtypes and potentially guide tailored therapy.


The cough and the bedsheet.
Of 33 patients with psychogenic cough tic, 31 were successfully treated using an unusual reinforced suggestion technique. The cough usually follows an incidental upper respiratory tract infection and persists as a loud paroxysmal barking or honking sound for weeks to months. Paroxysms occur all day but cease with sleep. The diagnosis is often delayed for weeks to months while the patient is exposed to an increasing intensity of diagnostic procedures and therapy. Thirty percent of some 20 patients previously reported in the literature had been hospitalized. The reinforced suggestion technique depends upon the physician's convincing the patient that the persistent cough has weakened the chest muscles, which are now unable to contain the cough, and that a bedsheet tightly wrapped around the chest will provide the necessary support to stop the cough within 24 to 48 hours. The typical patient can produce the cough on command, has an ambivalent response to the prospect of care, is unconcerned about his symptoms, submits willingly to the examination and procedures, and is kept out of school for the duration of the cough. Findings on physical examination are normal except for abnormal gag and corneal reflexes. The gag reflex was depressed in six and absent in 20 of the 31 patients. The corneal reflex was depressed in 16 and absent in 5 of the 31 patients. These abnormal responses help to corroborate the psychogenic etiology. Early recognition of the nonorganic nature of this syndrome will reduce parental anxiety, loss of school time, risk of iatrogenic complications, and unnecessary medical and hospital expense.


A National Review of State Laws for Stock Epinephrine in Schools.
Anaphylaxis is a life-threatening allergic reaction with significant risk for children with allergies. Access to potentially life-saving medication is critical for these children. This review aims to describe state laws and policies guiding stock epinephrine in schools for allergic or anaphylactic events and detail recommendations for best practices. This paper is a comprehensive review of the 50 states and the District of Columbia's (DC) laws and policies for stock epinephrine at schools for children in pre-kindergarten through 12th grade. All 50 states and DC allow undesignated epinephrine in schools to use for allergic or anaphylactic reactions. A key difference arises in whether states allow (N = 37) or mandate (N = 14) that schools stock epinephrine. States exhibit differences in the body responsible for developing stock epinephrine policy (N = 48), along with stakeholders responsible for developing procedures (N = 30) and implementing them (N = 19). Differences also exist in state epinephrine procurement, administration, training, and liability. This review of stock epinephrine laws and policies highlights the significant variation in state legislation despite widespread adoption. Only one-quarter of states mandate that schools have stock epinephrine available for emergency use, underscoring need for a more unified approach with consistent guidelines, comprehensive training, and possible funding for implementation.


Genetic deletion of muscle RANK or selective inhibition of RANKL is not as effective as full-length OPG-fc in mitigating muscular dystrophy.
Although there is a strong association between osteoporosis and skeletal muscle atrophy/dysfunction, the functional relevance of a particular biological pathway that regulates synchronously bone and skeletal muscle physiopathology is still elusive. Receptor-activator of nuclear factor κB (RANK), its ligand RANKL and the soluble decoy receptor osteoprotegerin (OPG) are the key regulators of osteoclast differentiation and bone remodelling. We thus hypothesized that RANK/RANKL/OPG, which is a key pathway for bone regulation, is involved in Duchenne muscular dystrophy (DMD) physiopathology. Our results show that muscle-specific RANK deletion (mdx-RANK mko ) in dystrophin deficient mdx mice improves significantly specific force [54% gain in force] of EDL muscles with no protective effect against eccentric contraction-induced muscle dysfunction. In contrast, full-length OPG-Fc injections restore the force of dystrophic EDL muscles [162% gain in force], protect against eccentric contraction-induced muscle dysfunction ex vivo and significantly improve functional performance on downhill treadmill and post-exercise physical activity. Since OPG serves a soluble receptor for RANKL and as a decoy receptor for TRAIL, mdx mice were injected with anti-RANKL and anti-TRAIL antibodies to decipher the dual function of OPG. Injections of anti-RANKL and/or anti-TRAIL increase significantly the force of dystrophic EDL muscle [45% and 17% gains in force, respectively]. In agreement, truncated OPG-Fc that contains only RANKL domains produces similar gains, in terms of force production, than anti-RANKL treatments. To corroborate that full-length OPG-Fc also acts independently of RANK/RANKL pathway, dystrophin/RANK double-deficient mice were treated with full-length OPG-Fc for 10 days. Dystrophic EDL muscles exhibited a significant gain in force relative to untreated dystrophin/RANK double-deficient mice, indicating that the effect of full-length OPG-Fc is in part independent of the RANKL/RANK interaction. The sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) activity is significantly depressed in dysfunctional and dystrophic muscles and full-length OPG-Fc treatment increased SERCA activity and SERCA-2a expression. These findings demonstrate the superiority of full-length OPG-Fc treatment relative to truncated OPG-Fc, anti-RANKL, anti-TRAIL or muscle RANK deletion in improving dystrophic muscle function, integrity and protection against eccentric contractions. In conclusion, full-length OPG-Fc represents an efficient alternative in the development of new treatments for muscular dystrophy in which a single therapeutic approach may be foreseeable to maintain both bone and skeletal muscle functions.


Trauma of the Shared Environment: A Qualitative Analysis of the Experiences of Survivors of College Campus Sexual Assault.
Survivors of campus sexual assault are often tasked with healing while sharing an environment with their perpetrators. However, little is known about the effects of a shared environment on survivor well-being. A qualitative thematic analysis design was employed to address this gap. We conducted semi-structured interviews with nine female survivors who identified their perpetrators as fellow students at a large state university in the southeastern U.S. The five themes that emerged are situated within an ecological framework, which is also used to guide our recommendations for supporting survivors' well-being within higher education.


A data discovery index for the social sciences.
This paper describes a novel search index for social and economic research data, one that enables users to search up-to-date references for data holdings in these disciplines. The index can be used for comparative analysis of publication of datasets in different areas of social science. The core of the index is the da|ra registration agency's database for social and economic data, which contains high-quality searchable metadata from registered data publishers. Research data's metadata records are harvested from data providers around the world and included in the index. In this paper, we describe the currently available indices on social science datasets and their shortcomings. Next, we describe the motivation behind and the purpose for the data discovery index as a dedicated and curated platform for finding social science research data and gesisDataSearch, its user interface. Further, we explain the harvesting, filtering and indexing procedure and give usage instructions for the dataset index. Lastly, we show that the index is currently the most comprehensive and most accessible collection of social science data descriptions available.


Flexible ureteroscopy and laser lithotripsy for stones >2 cm: a systematic review and meta-analysis.
Urinary stones >2 cm are traditionally managed with percutaneous nephrolithotomy (PCNL). Recently, flexible ureteroscopy and laser lithotripsy) (FURSL) has been used to manage them with comparable results. In a comparative study of renal stones between 2 and 3 cm, FURSL was reported to need less second-stage procedures and be just as effective as PCNL. Our purpose was to review the literature for renal stones >2 cm managed by ureteroscopy and holmium lasertripsy. A systematic review and quantitative meta-analysis was performed using studies identified by a literature search from 1990s (the first reported large renal stones treated ureteroscopically) to August 2011. All English language articles reporting on a minimum of 10 patients treated with FURSL for renal stones >2 cm were included. Two reviewers independently extracted the data from each study. The data of studies with comparable results were included into a meta-analysis. In nine studies, 445 patients (460 renal units) were reportedly treated with FURSL. The mean operative time was 82.5 minutes (28-215 min). The mean stone-free rate was 93.7% (77%-96.7%), with an average of 1.6 procedures per patient. The mean stone size was 2.5 cm. An overall complication rate was 10.1%. Major complications developed in 21 (5.3%) patients and minor complications developed in 19 (4.8%) patients. A subgroup analysis shows that FURSL has a 95.7% stone-free rate with stones 2-3 cm and 84.6% in those >3 cm (P=0.01), with a minor complication rate of 14.3% and 15.4%, respectively, and a major complication rate of 0% and 11.5%, respectively. In experienced hands, FURSL can successfully treat patients with stones >2 cm with a high stone-free rate and a low complication rate. Although the studies are from high-volume experienced centers and may not be sufficient to alter everyday routine practice, this review has shown that the efficacy of FURSL allows an alternative to PCNL.


Lymphatic pump treatment mobilizes leukocytes from the gut associated lymphoid tissue into lymph.
Lymphatic pump techniques (LPT) are used clinically by osteopathic practitioners for the treatment of edema and infection; however, the mechanisms by which LPT enhances lymphatic circulation and provides protection during infection are not understood. Rhythmic compressions on the abdomen during LPT compress the abdominal area, including the gut-associated lymphoid tissues (GALT), which may facilitate the release of leukocytes from these tissues into the lymphatic circulation. This study is the first to document LPT-induced mobilization of leukocytes from the GALT into the lymphatic circulation. Catheters were inserted into either the thoracic or mesenteric lymph ducts of dogs. To determine if LPT enhanced the release of leukocytes from the mesenteric lymph nodes (MLN) into lymph, the MLN were fluorescently labeled in situ. Lymph was collected during 4 min pre-LPT, 4 min LPT, and 10 min following cessation of LPT. LPT significantly increased lymph flow and leukocytes in both mesenteric and thoracic duct lymph. LPT had no preferential effect on any specific leukocyte population, since neutrophil, monocyte, CD4+ T cell, CD8+ T cell, IgG+B cell, and IgA+B cell numbers were similarly increased. In addition, LPT significantly increased the mobilization of leukocytes from the MLN into lymph. Lymph flow and leukocyte counts fell following LPT treatment, indicating that the effects of LPT are transient. LPT mobilizes leukocytes from GALT, and these leukocytes are transported by the lymphatic circulation. This enhanced release of leukocytes from GALT may provide scientific rationale for the clinical use of LPT to improve immune function.


Kin selection theory and the design of cooperative crops.
In agriculture and plant breeding, plant traits may be favoured because they benefit neighbouring plants and ultimately increase total crop yield. This idea of promoting cooperation among crop plants has existed almost as long as W.D. Hamilton's inclusive fitness (kin selection) theory, the leading framework for explaining cooperation in biology. However, kin selection thinking has not been adequately applied to the idea of cooperative crops. Here, I give an overview of modern kin selection theory and consider how it explains three key strategies for designing cooperative crops: (1) selection for a less-competitive plant type (a 'communal ideotype'); (2) group-level selection for yield; and (3) exploiting naturally selected cooperation. The first two strategies, using artificial selection, have been successful in the past but suffer from limitations that could hinder future progress. Instead, I propose an alternative strategy and a new 'colonial ideotype' that exploits past natural selection for cooperation among the modules (e.g., branches or stems) of individual plants. More generally, I suggest that Hamiltonian agriculture-a kin selection view of agriculture and plant breeding-transforms our understanding of how to improve crops of the future.


Theoretical Constraints Imposed by Gradient Detection and Dispersal on Microbial Size in Astrobiological Environments.
The capacity to sense gradients efficiently and acquire information about the ambient environment confers many advantages such as facilitating movement toward nutrient sources or away from toxic chemicals. The amplified dispersal evinced by organisms endowed with motility is possibly beneficial in related contexts. Hence, the connections between information acquisition, motility, and microbial size are explored from an explicitly astrobiological standpoint. By using prior theoretical models, the constraints on organism size imposed by gradient detection and motility are elucidated in the form of simple heuristic scaling relations. It is argued that environments such as alkaline hydrothermal vents, which are distinguished by the presence of steep gradients, might be conducive to the existence of "small" microbes (with radii of ≳0.1 μm) in principle, when only the above two factors are considered; other biological functions (e.g., metabolism and genetic exchange) could, however, regulate the lower bound on microbial size and elevate it. The derived expressions are potentially applicable to a diverse array of settings, including those entailing solvents other than water; for example, the lakes and seas of Titan. The article concludes with a brief exposition of how this formalism may be of practical and theoretical value to astrobiology.


Intestinal breast cancer resistance protein (BCRP)/Bcrp1 and multidrug resistance protein 3 (MRP3)/Mrp3 are involved in the pharmacokinetics of resveratrol.
The phytoestrogen resveratrol has putative health-promoting effects and is present in several dietary constituents. Resveratrol is metabolized extensively in the gut epithelium, resulting in the formation of hydrophilic glucuronic acid and sulfate conjugates. These polar resveratrol conjugates need specific transporters to cross the cell membrane. We show here that vectorial transport of some of these metabolites is mediated by multidrug resistance protein 3 (MRP3, ABCC3) and/or breast cancer resistance protein (BCRP, ABCG2) located in the basolateral and apical membranes of enterocytes, respectively. In vitro, MRP3 transports resveratrol-glucuronide (Res-3-G). The absence of Mrp3 in mice results in altered disposition of Res-3-G and its parent compound resveratrol, leading to a reduced percentage of resveratrol being excreted via the urine in Mrp3(-/-) mice. Circumstantial evidence suggests that circulating resveratrol is formed by deglucuronidating Res-3-G in vivo, providing a possible explanation for the health beneficial effects of resveratrol in vivo, despite its rapid and extensive conjugation. BCRP transports Res-3-G and resveratrol sulfates in vitro, and its absence in mice results in high plasma levels of resveratrol-di-sulfate, a resveratrol metabolite hardly detectable in the plasma of wild-type mice and in an increased disposal of resveratrol via the urine. The profound effects of ATP-binding cassette transporters on the disposal of resveratrol may be representative for the handling of several other polyphenols of dietary origin.


Order-disorder transition in the S = ½ kagome antiferromagnets claringbullite and barlowite.
The transition in the quantum magnets barlowite, Cu4(OH)6FBr, and claringbullite, Cu4(OH)6FCl is of an order-disorder type, where at ambient temperature interlayer Cu2+ ions are dynamically disordered over three equivalent positions. The disorder becomes static as the temperature is decreased, resulting in a lowering of symmetry. Ab initio density functional theory calculations explain this structural phase transition and provide insights regarding the differences between these two materials.


IgE-mediated chemotaxis of rat basophilic leukemia cells towards specific antigen.
We evaluated chemotactic properties of four sublines of rat basophilic leukemia cells using blindwell Boyden chamber assays. After sensitization with a mouse monoclonal IgE directed against dinitrophenyl (DNP), cells from sublines 2H3-C and 926a underwent chemotaxis toward DNP-bovine serum albumin (BSA) and sublines RBL-1 and 4A did not. Chemotactic responses required specific IgE and were determined by the IgE antigen specificity used for sensitization. The threshold for chemotaxis was on the order of 10(-10) M DNP-BSA. Release of incorporated [3H]-serotonin did not always parallel chemotactic responses, which suggests that chemotaxis and secretion may be two unlinked processes that occur during basophil activation. Our results predict a possible in vivo mechanism whereby specific chemotactic responses of basophils and other FcR epsilon-bearing cells are mediated via specific IgE bound to membrane FcR epsilon.


Moderate exercise early after influenza virus infection reduces the Th1 inflammatory response in lungs of mice.
We have previously shown that moderate exercise significantly increased survival after influenza virus (A/PR/8/34) infection in mice. We hypothesized that this brief duration of exercise would either increase innate immune defences and/or shift the immune response from a Th1 inflammatory to a Th2 anti-inflammatory response resulting in decreased lung pathology. Adult male BALB/cByJ mice (5-6 months old) were infected with 50 microL of A/PR/8/34 virus (40HAU) intranasally and randomized to either an exercise (EX) or sedentary (SED) group. EX mice performed 20-30 min of moderate exercise (8-12 m/min) on a motorized treadmill 4 hr post-infection and then exercised similarly for 4 consecutive days. SED mice were exposed to similar environmental conditions but did not exercise. Mice from both EX and SED groups were sacrificed 1, 3, or 5 days post-infection (p.i.) and lungs, mediastinal lymph nodes (MLNs) and spleens were harvested. EX significantly reduced total cellular infiltration and IFN-gamma gene expression in lungs at Days 3 and 5 p.i. and there was a qualitative shift in the expression of cytokines in the lung from a Th1 to a Th2 response. There was also a tendency toward a reduction in influenza M1 protein mRNA expression. There was no difference in IFN-beta protein levels between groups. These data suggest that moderate exercise when applied early after infection shifts the immune response away from a Th1 profile in mice infected with influenza virus. This exercise-induced shift in immune response may be responsible for improved survival after influenza virus infection.


A double-blind, placebo-controlled, crossover trial of topiramate in essential tremor.
The antiepileptic drug topiramate has been reported to improve essential tremor, but clinical trials have been small and of unsatisfactory design. We undertook a double-blind, placebo-controlled crossover study of topiramate in essential tremor, using accelerometry, spirography, and an activities of daily living questionnaire. Sixteen subjects were recruited between January and June 2002. Three withdrew consent, 13 commenced the study, and 10 finished it. Subjects were assessed at baseline and after 2, 4, and 6 weeks of treatment (placebo or topiramate doses 25, 50, and 100 mg daily). Following a washout period of 1 week, patients crossed over to the alternate arm of the study. Statistical analysis followed the method described by Altman. There was no period effect or treatment-period interaction. No outcome measure improved significantly in the active treatment period as compared with the placebo control period, although 4 of the 10 patients improved in at least 2 of the 3 outcome measures during the active treatment phase, and none during the control treatment phase. This study provided no evidence of therapeutic benefit of topiramate in essential tremor. A marginally larger study would be required formally to exclude a useful therapeutic effect. To achieve a study with a power of 80% to exclude the null hypothesis, at least 17 patients would be required using accelerometry, 19 using spirography, and 2,00 using an activities of daily living questionnaire.


The Structural Basis of T4 Phage Lysis Control: DNA as the Signal for Lysis Inhibition.
Optimal phage propagation depends on the regulation of the lysis of the infected host cell. In T4 phage infection, lysis occurs when the holin protein (T) forms lesions in the host membrane. However, the lethal function of T can be blocked by an antiholin (RI) during lysis inhibition (LIN). LIN sets if the infected cell undergoes superinfection, then the lysis is delayed until host/phage ratio becomes more favorable for the release of progeny. It has been thought that a signal derived from the superinfection is required to activate RI. Here we report structures that suggest a radically different model in which RI binds to T irrespective of superinfection, causing it to accumulate in a membrane as heterotetrameric 2RI-2T complex. Moreover, we show the complex binds non-specifically to DNA, suggesting that the gDNA from the superinfecting phage serves as the LIN signal and that stabilization of the complex by DNA binding is what defines LIN. Finally, we show that soluble domain of free RI crystallizes in a domain-swapped homotetramer, which likely works as a sink for RI molecules released from the RI-T complex to ensure efficient lysis. These results constitute the first structural basis and a new model not only for the historic LIN phenomenon but also for the temporal regulation of phage lysis in general.


Detection of Pseudomonas pseudomallei by PCR and hybridization.
A molecular method for the detection of Pseudomonas pseudomallei was developed on the basis of the differences in the 23S rRNA sequences of related species of the genus Pseudomonas. An 18-base oligonucleotide probe, designed following partial sequencing of 23s ribosomal DNA (rDNA), was used for the identification and detection of P. pseudomallei either by hybridization or by direct PCR. Optimal detection was obtained by hybridization of the probe with PCR-amplified rDNA rather than with total genomic DNA or colony blots. One nanogram of template DNA amplified in a PCR mixture containing 14% glycerol could be detected in slot blots hybridized with the digoxigenin-labelled probe and the lumigen PPD detection system. Amplified rDNA sequences from 41 P. pseudomallei strains of various origins hybridized with the probe. The probe also hybridized with three Pseudomonas mallei reference strains under conditions of high stringency but failed to hybridize with amplified rDNA sequences from other closely related Pseudomonas spp. PCR with a conserved primer and the 18-base oligonucleotide probe (direct PCR) specifically amplified P. pseudomallei and P. mallei. By using these methods, approximately 10(4) P. pseudomallei cells per ml could be detected in artificially inoculated blood samples and in blood dried on filter paper following Chelex extraction. The detection limit in blood was increased to 10(2) cells per ml by concentration of bacteria from 0.5 ml of blood or by a 24-h blood culture enrichment prior to PCR. Approximately 10(3) cells per ml were detected in seeded sputum samples. The detection times by direct PCR and indirect PCR and then probe hybridization were approximately 5 h and 24 h, respectively. These results indicate that amplification of conserved rDNA sequences by PCR directly or by hybridization with a probe to PCR fragments offers promise for the detection of P. pseudomallei and P. mallei.


Differential diagnosis and treatment of biliary strictures.
Biliary tract strictures present both diagnostic and therapeutic challenges to clinicians. Advances in imaging and endoscopic techniques have improved our ability to differentiate between benign and malignant lesions. Intraductal ultrasonography (IDUS), using an endoscopic approach, has the potential to aid in separating benign and malignant biliary lesions. In a series of 93 patients, a majority of whom had cancer, we found that IDUS had a sensitivity and specificity of 89.7% and 84%, respectively, for diagnosing biliary strictures. However, benign strictures associated with untreated autoimmune pancreatitis and/or the intrapancreatic portion of the distal common bile duct could not be easily distinguished from malignant strictures. Direct visualization of biliary mucosa using a percutaneous transhepatic endoscopic approach also helps separate benign from malignant biliary strictures. Further, the ability to obtain multiple directed biopsies using a percutaneous approach also increases diagnostic accuracy. A final advantage of the percutaneous approach is that once a suitable sized tract has been established, biliary strictures and stents can be placed. IDUS and percutaneous biliary endoscopy are promising new modalities for the diagnosis and treatment of biliary strictures.


Securing Social Security Solvency Addressing an important social determinant of the health of seniors and the American polity.
Adequate income is a social determinant of health. In the United States, only Social Security beneficiaries receive inflation-protected guaranteed income. Social Security needs another 1983 compromise in which stakeholders accepted "shared pain" to avoid insolvency. We propose indexing the benefit using the chained consumer price index (CPI) for all urban consumers and providing a one-time bonus of 8% to 10% for beneficiaries in their mid-80s, when needs become greater. The chained CPI has little impact when beneficiaries start receiving benefits, but older beneficiaries need protection. The estimated 75-year savings from this restructured benefit amount to 14.2% to 18% of Social Security deficits. Modest increases in payroll taxes and maximum earnings taxed should make up most of the shortfall. Including unearned income with wages and salaries subject to the 6.2% individual tax would produce much more revenue. The discussion explores the proposal's political feasibility, grounding in current policy and political science literature, and the role of income as a social determinant of health.


The limits of marginal economic incentives in the Medicaid program: concerns and cautions.
In January 1985, New York State implemented legislation that allowed for a 30 percent increase in Medicaid fees for physicians providing primary care services. This was intended to increase their levels of participation. Yet the outcome was not as expected. In upstate New York, the number of physicians participating in Medicaid each month actually declined; in New York City, the monthly rate of increase in participating physicians, which was part of the overall sharp rise in all licensed physicians, underwent a decline. Furthermore, utilization measures suggest that "procedural upgrading" might have become a problem in New York City. These results suggest that a marginal increase in New York State's low Medicaid fees will not have a positive effect on physician participation levels.


Food yeasts: occurrence, functions, and stress tolerance in the brewing of fermented foods.
With the rapid development of systems biology technology, there is a deeper understanding of the molecular biological mechanisms and physiological characteristics of microorganisms. Yeasts are widely used in the food industry with their excellent fermentation performances. While due to the complex environments of food production, yeasts have to suffer from various stress factors. Thus, elucidating the stress mechanisms of food yeasts and proposing potential strategies to improve tolerance have been widely concerned. This review summarized the recent signs of progress in the variety, functions, and stress tolerance of food yeasts. Firstly, the main food yeasts occurred in fermented foods, and the taxonomy levels are demonstrated. Then, the main functions of yeasts including aroma enhancer, safety performance enhancer, and fermentation period reducer are discussed. Finally, the stress response mechanisms of yeasts and the strategies to improve the stress tolerance of cells are reviewed. Based on sorting out these related recent researches systematically, we hope that this review can provide help and approaches to further exert the functions of food yeasts and improve food production efficiency.


The significance of site of cut in self-harm in young people.
Self-cutting in young people is associated with high risk of repetition and suicide. It is important, therefore, to identify characteristics of self-cutting that might impact on repetition and aspects of care by staff. This study aimed to explore differences in clinical (e.g., previous self-harm) and psychological characteristics (intent, mental state, precipitants) of self-cutting in young people based on whether site of cut was visible or concealed. Data were from a large prospective self-harm monitoring database that collected data on hospital emergency department presentations for self-harm in the City of Manchester, UK, between 2005 and 2011. Clinical and psychological characteristics, as well as onward referral/clinical management from the emergency department, of 799 young people (totalling 1,196 episodes) age 15-24 who self-cut in visible or concealed areas were compared using logistic regression. During the study period 500 (40%) episodes were in a concealed location. Concealed self-cutting was more likely to be precipitated by specific self-reported precipitants such as abuse and characterised by the following: previous self-harm, current psychiatric treatment, premeditation, and greater risk of repetition within the study period. Receiving a psychosocial assessment and referral to psychiatric services from the emergency department were less likely, however. Repetition and referral to psychiatric treatment were not significantly associated with site of injury when adjusting for other factors. There are meaningful differences in characteristics associated with location of cut. We recommend that all young people who present to hospital following self-harm receive a psychosocial assessment, in line with NICE guidance.


Enforced expression of Lin28b leads to impaired T-cell development, release of inflammatory cytokines, and peripheral T-cell lymphoma.
LIN28A and LIN28B, the mammalian homologs of lin-28, are implicated in malignant transformation in part because of their ability to promote degradation of the let-7 family of miRs. In the present study, we show that overexpression of Lin28b in vivo leads to an aggressive peripheral T-cell lymphoma (PTCL) characterized by widespread infiltration of parenchymal organs with malignant CD4(+) cells. Similar to patients with PTCL, Lin28b-transgenic mice show signs of inflammation such as eosinophilia, increased C-reactive protein, release of inflammatory cytokines, and pleural effusion. The PTCLs that develop in Lin28b mice are derived from activated T cells and show decreased let-7 expression, increased Il6 expression, activation of NF-κB, and infiltration of B cells, all resulting in an inflammatory microenvironment. In addition, LIN28B is overexpressed 7.5-fold in PTCL patient samples compared with activated CD4(+) cells. The results of the present study demonstrate for the first time that Lin28b can transform primary cells in vivo, identify a previously unsuspected link between Lin28b and PTCL, and provide a unique animal model for the study of PTCL biology and therapy.


Granular Nematicides for Control of the Yam Nematode, Scutellonema bradys, and Relevant Residues in Raw Tubers.
Four granular nentaticides were evaluated for control of the yam nematode, Scutellonema bradys (Steiner &LeHew) Andrassy, on Guinea yam, Dioscorea rotundata Poir, under field conditions prevelant in the tropics. A single application of nematicides (sidedressing) at the rate of 2 kg ai/ha as postplanting treatment at the onset of the rainy season depressed numbers of S. bradys attacking yams during the growing season and significantly increased tuber yields over untreated. The efficacy, based on the regression coefficient values of evaluated nematicides, was in the order of miral, carbofuran, aldicarb, and oxamyl (b = -75.9, -75.5, -72.1, and -65.9, respectively). Yam tuber yields increased by 136.9, 90.6, 87.9, and 85.3% over untreated (P = 0.05) in aldicarb, carbofuran, oxamyl, and miral treated plots, respectively. Residues in raw tubers pretreated with aldicarb, carbofuran, or miral were negligible (front less than 0.02 to 0.3 ppm) and far below the established tolerance levels (l.0 and 1.3 ppm for aldicarb and carbofuran, respectively) of a related crop in the United States. This is the first report on residues of systemic pesticides in yams.


ON NORRIS' THEORY FOR THE SHAPE OF THE MAMMALIAN ERYTHROCYTE.
This paper is concerned with an attempt to put Norris' theory for the shape of the mammalian erythrocyte into a quantitative form. The theory supposes that the biconcave form of the cell is brought about by an expansive force enlarging the surface, and is also supposed to apply to the formation of the myelin forms of lecithn. The attempt is not successful, and is published merely because it is suggestive. Various points regarding the shape of the cell, the curvature of its surface, and the kind of system to which Norris' theory might be supposed to apply, are discussed, and an empirical formula is given for the curve which bounds the cross-section of the cell. This empirical formula describes the shape almost to perfection.


Workplace violence in healthcare settings: risk factors and protective strategies.
This article describes the risk factors and protective strategies associated with workplace violence perpetrated by patients and visitors against healthcare workers. Perpetrator risk factors for patients and visitors in healthcare settings include mental health disorders, drug or alcohol use, inability to deal with situational crises, possession of weapons, and being a victim of violence. Worker risk factors are gender, age, years of experience, hours worked, marital status, and previous workplace violence training. Setting and environmental risk factors for experiencing workplace violence include time of day and presence of security cameras. Protective strategies for combating the negative consequences of workplace violence include carrying a telephone, practicing self-defense, instructing perpetrators to stop being violent, self- and social support, and limiting interactions with potential or known perpetrators of violence. Workplace violence is a serious and growing problem that affects all healthcare professionals. Strategies are needed to prevent workplace violence and manage the negative consequences experienced by healthcare workers following violent events.


A probabilistic ribbon model for shape analysis of the cerebral sulci: application to the central sulcus.
An approach for quantifying the shapes of the cerebral sulci is presented, utilizing a probabilistic geometric model, and it is applied to the central sulcus. The geometric structure of the central sulcus is determined from a set of outlines on cross-sectional images and is used by a procedure that automatically labels the major crest lines, i.e., curves of locally maximal curvature, along the sulcus. An automated procedure then determines a parametric representation of the central sulcus that is consistent across individuals, in that it assigns the same parametric coordinates to corresponding regions of the sulcus. The method is applied to the central sulci from 20 subjects. The use of this shape representation in cortical morphometric analysis applications is demonstrated, in particular in obtaining local depth and curvature measurements of a sulcus as well as in determining average shapes and variability. With this method, we were able to build parametric representations of the sulcal ribbons by preserving anatomical homologies.


Long-term outcomes of etiology specific annuloplasty ring repair of ischemic mitral regurgitation.
Reductive annuloplasty repair of ischemic mitral regurgitation (IMR) is associated with high rates of recurrent MR, which may be improved with etiology-specific annuloplasty rings. From October 2005 to May 2015, 128 consecutive patients underwent repair of IMR with the GeoForm ring. Clinical data was extracted from our local Society of Thoracic Surgeons database and electronic medical records. Mortality data was obtained from the Michigan State Social Security Death Index. The average age of patients was 65±11 years with mean pre-op left ventricular ejection fraction (LVEF) of 30%±10% and MR grade of 3.1±0.9 (0-4+). Thirty-day mortality was 4.7%, rate of renal failure 7.9%, rate of atrial fibrillation 27.3%, and no strokes were observed. Of the surviving patients, 89% (109/122) had a follow-up echocardiogram beyond 1 month with a mean echocardiographic follow-up of 59±39 months. LVEF improved from 30%±10% to 38%±14%, P<0.001) while end-diastolic (5.9±0.0 to 5.3±0.9 cm, P<0.001) and end-systolic (5.0±1.0 to 4.4±1.1 cm, P<0.001) left ventricular (LV) diameters decreased, as compared to pre-operative values. Seven patients were found to have recurrent moderate or greater IMR in follow-up to 10 years with three being due to ring dehiscence. One-, 5-, and 10-year freedom from recurrent moderate or severe IMR was 98%, 94%, and 80% respectively. One-, 5-, and 10-year survival was 91%, 77%, and 44%, respectively. Overall, etiology-specific ring repair of IMR was associated with low rates of recurrent MR on long-term follow-up, coupled with significant LV reverse remodeling and improvement in ejection fraction.


Prostate cancer chemoprevention by soy isoflavones: role of intestinal bacteria as the "second human genome".
It has been found that the composition of intestinal microbiota can indicate the risk of disease to each individual. The concepts of biodynamics as used by the Benziger Winery in California, which treats every part of an agricultural environment as a living, breathing entity, can be usefully used in the construction of a system for cancer prevention, which seeks to use the relationship of coexistence (symbiosis) shared between people and intestinal symbiosis, that is, microbiota. Changes in the incidence rate of cancer among Japanese emigrants to Hawaii demonstrate the effect of the changes in the living environment. This leads to the hypothesis that an intake of soy-derived food products and the metabolization of the isoflavones they contain by intestinal microbiota is one of the factors for the significant difference in the incidence rate of prostate cancer among Asian and European/North American populations. It is further hypothesized that isoflavones, particularly equol, are a key factor in the difference in incidence rate between Asia and the West. It is suggested that not having equol converting bacteria in the intestine (non-equol producers) can be a risk factor for prostate cancer and that one direction for future research will be to examine the possibility of improving the intestinal environment to enable equol production.


Flaxseed extract exhibits mucosal protective effect in acetic acid induced colitis in mice by modulating cytokines, antioxidant and antiinflammatory mechanisms.
New treatments for inflammatory bowel disease are of interest due to high rate of remission failure. Natural products have been effective in IBD therapeutics as they have multiple constituents. The aim of the present study was to evaluate the effect of Flaxseed extract (Fs.Cr) on ulcerative colitis and identify the possible mechanisms involved. Colitis was induced by intrarectal administration of 6% AA in BALB/c mice. Colonic mucosal damage was assessed after 24h by calculating disease activity index (DAI), macroscopic and histological damage scores, biochemical measurement of myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), and total glutathione activities. Since cytokines are involved in exacerbating inflammatory cascade with emerging role of innate immune cytokines in IBD therapeutics, we hence assessed the effect on the levels of TNF-α, IFN-γ and IL-17, at 6, 12 and 24h by ELISA. Fs.Cr ameliorated the severity of AA colitis as evident by improved DAI, macroscopic damage and the histopathological scores along with restoration of goblet cells. Fs.Cr decreased MDA and MPO activities and enhanced antioxidant activity compared to the AA group. Finally, Fs.Cr in doses (300 and 500mg/kg) decreased TNF-α and IFN-γ levels at all time points with simultaneous increase in IL-17 levels at 24h as compared to the AA group. These results suggest that Fs.Cr ameliorates the severity of AA colitis by reducing goblet cell depletion, scavenging oxygen-derived free radicals, reduce neutrophil infiltration that may be attributed due to decreasing IFN-γ and TNF-α and increasing IL-17 levels.


The immediate effect of unilateral lumbar Z-joint mobilisation on posterior chain neurodynamics: a randomised controlled study.
Hamstring strain (HS) is a common musculoskeletal condition and abnormal neurodynamics has been shown to influence HS and delay recovery. The efficacy of stretching for preventing and treating HS remains uncertain despite extensive research and wide-spread use. The effects of cervical spine mobilisation on peripheral nervous system function, neurodynamics and muscle force in the upper limb have been reported. Very few studies have reported effects of lumbar spine mobilisation on these variables in the lower limb. This study aimed to determine immediate effects of either a unilateral zygopophyseal joint posteroanterior mobilisation or a static posterior chain muscle stretch on the range of passive straight leg raise (SLR) in comparison to a non-treatment control. Using a single-blinded, randomised controlled study design, 36 healthy participants were allocated into one of three groups (control; mobilisation; static posterior chain muscle stretch). Measures of SLR were taken before and after intervention for each group on the day of testing. A General Linear Model (GLM) and a paired sample t-test showed a significant difference between base line and post-intervention for the mobilisation group only (p < 0.001), and suggests that unilateral lumbar spine zygopophyseal joint mobilisation can immediately restore posterior chain neurodynamics.


Identification of human preformed antibody targets in GTKO pigs.
Human preformed antibodies continue to recognize porcine xenografts, despite the advent of α-galactosyltransferase knockout (GTKO) pigs. This study examined the potential reactivity of human preformed IgG and IgM antibodies toward antigens in the GTKO pig liver. Human serum was analyzed for the concentration of IgG, IgM, anti-αgal antibody, anti-non-αgal antibody and cytotoxicity toward domestic and GTKO fibroblasts and liver sinusoidal endothelial cells (LSEC). We detected preformed antibodies in human serum directed toward GTKO pig liver cells and tissue samples using advanced proteomic techniques. The targets of preformed antibodies were identified by MALDI TOF TOF mass spectrometry and validated by confocal microscopy, immunoblot, and immunoprecipitation. Human serum used in this study contained 2.06 μg/ml IgG and 0.013 μg/ml IgM directed toward GTKO fibroblasts. Human IgG and IgM bound to GTKO LSEC in a dose-dependent manner and were cytotoxic. We detected 357 protein spots recognized by human IgG and 233 by human IgM. Two hundred and nineteen proteins were common to both human IgG and IgM. Mass spectrometry identified numerous immunoreactive proteins, of which 19 were membrane proteins on liver cells. The most significant to this study were α-enolase, CFTR, and E-cadherin, which were abundant in GTKO pig tissues and expressed on the surface of GTKO LSEC. Human IgG captured α-enolase, CFTR, and E-cadherin by immunoprecipitation validating the proteomic identification. These experiments indicate that several membrane antigens in GTKO pigs could be recognized directly by human IgG or IgM. Further studies on the contribution of these antigens to antibody-mediated xenograft rejection are necessary.


Mutations and genomic islands can explain the strain dependency of sugar utilization in 21 strains of Propionibacterium freudenreichii.
Propionibacterium freudenreichii (PF) is an actinobacterium used in cheese technology and for its probiotic properties. PF is also extremely adaptable to several ecological niches and can grow on a variety of carbon and nitrogen sources. The aim of this work was to discover the genetic basis for strain-dependent traits related to its ability to use specific carbon sources. High-throughput sequencing technologies were ideal for this purpose as they have the potential to decipher genomic diversity at a moderate cost. 21 strains of PF were sequenced and the genomes were assembled de novo. Scaffolds were ordered by comparison with the complete reference genome CIRM-BIA1, obtained previously using traditional Sanger sequencing. Automatic functional annotation and manual curation were performed. Each gene was attributed to either the core genome or an accessory genome. The ability of the 21 strains to degrade 50 different sugars was evaluated. Thirty-three sugars were degraded by none of the sequenced strains whereas eight sugars were degraded by all of them. The corresponding genes were present in the core genome. Lactose, melibiose and xylitol were only used by some strains. In this case, the presence/absence of genes responsible for carbon uptake and degradation correlated well with the phenotypes, with the exception of xylitol. Furthermore, the simultaneous presence of these genes was in line the metabolic pathways described previously in other species. We also considered the genetic origin (transduction, rearrangement) of the corresponding genomic islands. Ribose and gluconate were degraded to a greater or lesser extent (quantitative phenotype) by some strains. For these sugars, the phenotypes could not be explained by the presence/absence of a gene but correlated with the premature appearance of a stop codon interrupting protein synthesis and preventing the catabolism of corresponding carbon sources. These results illustrate (i) the power of correlation studies to discover the genetic basis of binary strain-dependent traits, and (ii) the plasticity of PF chromosomes, probably resulting from horizontal transfers, duplications, transpositions and an accumulation of mutations. Knowledge of the genetic basis of nitrogen and sugar degradation opens up new strategies for the screening of PF strain collections to enable optimum cheese starter, probiotic and white biotechnology applications.


Health Literacy and Outcomes in Patients With Heart Failure: A Prospective Community Study.
To examine the impact of health literacy on hospitalizations and death in a population of patients with heart failure (HF). Residents from the 11-county region in southeast Minnesota with a first-ever International Classification of Diseases, Ninth Revision code 428 or Tenth Revision code 150 (n=5121) from January 1, 2013, through December 31, 2015, were identified and prospectively surveyed to measure health literacy using established screening questions. A total of 2647 patients returned the survey (response rate, 52%); 2487 patients with complete health literacy data were retained for analysis. Health literacy, measured as a composite score on three 5-point scales, was categorized as adequate (≥8) or low (<8). Cox proportional hazards regression and Andersen-Gill models were used to examine the association of health literacy with mortality and hospitalization. Of 2487 patients (mean age, 73.5 years; 53.6% male [n=1333]), 10.5% (n= 261) had low health literacy. After mean ± SD follow-up of 15.5±7.2 months, 250 deaths and 1584 hospitalizations occurred. Low health literacy was associated with increased mortality and hospitalizations. After adjusting for age, sex, comorbidity, education, and marital status, the hazard ratios for death and hospitalizations in patients with low health literacy were 1.91 (95% CI, 1.38-2.65; P<.001) and 1.30 (95% CI, 1.02-1.66; P=.03), respectively, compared with patients with adequate health literacy. Low health literacy is associated with increased risks of hospitalization and death in patients with HF. The clinical evaluation of health literacy could help design interventions individualized for patients with low health literacy.


Monoclonal antibodies to Bacteroides fragilis lipopolysaccharide.
Monoclonal antibodies (MoAbs) to the lipopolysaccharide (LPS) of Bacteroides fragilis were produced by immunizing mice before hybridization with bacterial outer membranes solubilized with Triton X-100. Nineteen stabile clones were established. They all produced antibodies that reacted more strongly with purified B. fragilis LPS than with crude sonicated antigen in an enzyme immunoassay. Four MoAbs were studied by immunoblotting and enzyme immunoassay inhibition. Immunoblotting confirmed that the target of the MoAbs was LPS. Marked and homogeneous staining occurred in the immunoblotting with both purified LPS and outer membranes in the molecular weight range of 8,000 to 27,000. In enzyme immunoassay inhibition, MoAbs reacted positively with 93 to 96% of B. fragilis strains, including prototype strains ATCC 23745 and NCTC 9343. Within the B. fragilis group, the MoAbs reacted positively with two of five B. ovatus strains and two to six of nine B. thetaiotaomicron strains. No marked cross-reactivity with other bacteria was observed. These results confirm earlier findings that the B. fragilis LPS contains an immunodominant antigenic determinant common to almost all B. fragilis isolates.


High Mobility Group Protein B1 Decreases Surface Localization of PD-1 to Augment T-cell Activation.
High-mobility group protein B1 (HMGB1) is a danger signaling molecule that has been found to trigger an effective antitumor immune response. However, the mechanisms underlying its antitumor effects are not fully understood. Here, we found that HMGB1 release induced by chemotherapy in patients with non-small cell lung cancer was negatively correlated with PD-1 expression on CD8+ T cells. In vitro analysis indicated that treatment with HMGB1 led to a significant decrease in the level of expression of PD-1 on CD8+ T cells. Further analysis demonstrated that HMGB1 reduced PD-1 expression by inducing dynamin-mediated internalization of the protein, leading to early endocytosis in the cytoplasm, and subsequently degradation in the lysosomes. In a xenograft model, HER2-targeted chimeric antigen receptor (CAR) T cells had enhanced function in the presence of HMGB1. These data identify a role for HMGB1 as a negative regulator of PD-1 signaling in lung cancer and the observed antitumor effect of HMGB1 on CAR T cells may provide a theoretical foundation for a new immunotherapy combination.


Is There Evidence That Stimulus Parameters and Electrode Placement Affect the Cognitive Side Effects of Electroconvulsive Therapy in Patients With Schizophrenia and Schizoaffective Disorder?: A Systematic Review.
Seventy percent of patients with treatment-resistant schizophrenia do not respond to clozapine. Electroconvulsive therapy (ECT) can potentially offer significant benefit in clozapine-resistant patients. However, cognitive side effects can occur with ECT and are a function of stimulus parameters and electrode placements. Thus, the objective of this article is to systematically review published clinical trials related to the effect of ECT stimulus parameters and electrode placements on cognitive side effects. We performed a systematic review of the literature up to July of 2020 for clinical studies published in English or German examining the effect of ECT stimulus parameters and/or electrode placement on cognitive side effects in patients with schizophrenia or schizoaffective disorder. The literature search generated 3 randomized, double-blind, clinical trials, 1 randomized, nonblinded trial, and 1 retrospective study. There are mixed findings regarding whether pulse width and stimulus dose impact on cognitive side effects. One study showed less cognitive side effect for right unilateral (RUL) than bitemporal (BT) electrode placement, and 2 studies showed a cognitive advantage for bifrontal (BF) compared with BT ECT. Only 1 retrospective study measured global cognition and showed post-ECT cognitive improvement with all treatment modalities using Montreal Cognitive Assessment in comparison to pre-ECT Montreal Cognitive Assessment scores. Current data are limited, but evolving. The evidence suggests that RUL or BF ECT have more favorable cognitive outcomes than BT ECT. Definitive larger clinical trials are needed to optimize parameter and electrode placement selection to minimize adverse cognitive effects.


Multiple Friends with Benefits: An Optimal Mutualist Management Strategy?
Most mutualisms in nature involve interactions between multispecies mutualist guilds and multiple partner species. While mechanisms such as niche partitioning can explain part of this diversity, the presence of low-quality partners, which produce relatively low returns on investment compared with other guild members, is not well understood. Here, we consider a novel explanation for this persistence: that low-quality partners are actively maintained by their hosts as part of a growth-maximizing strategy, even in the presence of higher-quality alternatives. We use a model inspired by the interaction between host trees and ectomycorrhizal fungi to demonstrate that when the environment is variable, trees maintain low-quality fungal partners that they would not otherwise maintain in constant environments. This active investment, which emerges as a response to saturating returns on investment in higher-quality partners, could contribute to the maintenance of diversity in multispecies mutualisms.


[The clinico-allergic indices of yersiniosis patients].
Eighty patients with yersiniosis (40 with intestinal yersiniosis, 40 with pseudotuberculosis) were examined for clinical and allergic characteristics (collection of allergological histories, identification of the most common allergic symptoms of the disease and determination of the index of mast cell degranulation). According to the data obtained, the patients with yersiniosis are admitted to the hospital with an aggravated premorbid condition in the form of body allergization, in whose origin both hereditary and acquired factors are of importance. The allergic manifestations of the disease are more pronounced in patients with pseudotuberculosis. In the acute disease period, noticeable allergization of the sick body develops whatever the gravity of the disease in both infections whereas during convalescence, only in patients with the recurrent infectious process.


Urban-rural factors affecting cancer mortality in Kentucky, 1950-1969.
Urban-rural factors associated with cancer mortality were studied in Kentucky to develop likely hypotheses on cancer prevention. Factor analysis was performed on county data for 25 variables which selected 17 variables for use in a multiple regression analysis. Age-adjusted cancer mortality rates used as outcome variables in this analysis included total and colorectal cancer (male, female, and both sexes combined) and female breast cancer. Each of these cancer sites was regressed against the 17 independent variables. Best predictive models for cancer outcome were selected on the basis of maximum total variance explained. Subsistence farming, where most of the farm produce is kept for home use rather than sold, was the single best predictor of low overall cancer rates for males, females, and both sexes combined in rural and Appalachian Kentucky. The subsistence farming diet is one based largely on milk and whole grains, rich in the following suspected anticarcinogens: selenium, magnesium, calcium, protease inhibitors, fiber, phenolics, and allelopaths. The diet lacks variety in fruits and vegetables and is low in vitamins A and C.


Resistance of naive mice to murine hepatitis virus strain 3 requires development of a Th1, but not a Th2, response, whereas pre-existing antibody partially protects against primary infection.
Murine hepatitis virus strain 3 (MHV-3) produces a strain-dependent spectrum of disease. The development of liver necrosis has been shown to be related to production of a unique macrophage procoagulant activity (PCA), encoded by the gene fgl-2, in susceptible mice. These studies were designed to examine the influence of Th1/Th2 cells on resistance/susceptibility and production of macrophage PCA in resistant (A/J) and susceptible (BALB/cJ) strains of mice following infection with MHV-3. Immunization of A/J mice with MHV-3 induced a Th1 cellular immune response, and one Th1 cell line (3E9.1) protected susceptible mice and inhibited PCA production by macrophages both in vitro and in vivo. In contrast, immunization of BALB/cJ mice with an attenuated variant of MHV-3 derived from passaging MHV-3 in YAC-1 cells resulted in a Th2 response. Transfer of spleen cells and T cell lines from immunized BALB/cJ mice failed to protect naive susceptible syngeneic mice from infection with MHV-3 and augmented macrophage PCA production to MHV-3 in vitro. However, serum from immunized BALB/cJ mice contained high titrated neutralizing Ab that protected naive BALB/cJ animals from lethal primary MHV-3 infection. These results demonstrate that susceptible BALB/cJ mice generate a Th2 response following MHV-3 infection and that these Th2 cells neither inhibit MHV-3-induced macrophage PCA production nor protect naive mice from MHV-3 infection. The results suggest that Ab protects against primary infection but cannot eradicate ongoing infection. Thus, these data define the differential role of Th1/Th2 lymphocytes in primary and secondary MHV-3 infection and emphasize the importance of PCA in the pathogenesis of MHV-3 infection.


Neuropathological diagnostic accuracy.
This study investigated variations in neuropathological diagnosis when histopathological slides are evaluated with access to all information pertinent to a case, compared with evaluation of H & E stained slides with only limited clinical information. The aim of the study is to evaluate the role of 'local' factors in reaching a definitive, neuropathological diagnosis. Each of 227 cases was reviewed by the local neuropathologist at one of three European centres with access to all clinical, radiological and histopathological data. Each case was also reviewed by a second, independent neuropathologist at another European unit, who was blinded to the local pathologist's diagnosis, and only had access to the age and sex of the patient and the location of the lesion. For the histopathological evaluation, initially he had access to H & E and GFAP stains only. Diagnoses were made using the WHO 2000 classification system and the two evaluations were classified into one of the following four categories: complete agreement; minor disagreement (not affecting treatment); minor disagreement (affecting treatment); complete disagreement. In 175 (77.1%) cases there was complete agreement between the two neuropathologists and in 18 (7.9%) cases there were non-treatment altering discrepancies in the diagnoses. Overall, there was disagreement which might potentially affect treatment in 34 (15%) of the cases. Histopathological diagnosis of the majority (85%) of brain tumours is accurate and uniform. However, histopathology is subject to a degree of interpretation. The availability of full, 'local', clinical information may be of considerable importance to the diagnostic process.


Pelvic floor disorders 5-10 years after vaginal or cesarean childbirth.
To estimate differences in pelvic floor disorders by mode of delivery. We recruited 1,011 women for a longitudinal cohort study 5-10 years after first delivery. Using hospital records, we classified each birth as: cesarean without labor, cesarean during active labor, cesarean after complete cervical dilation, spontaneous vaginal birth, or operative vaginal birth. At enrollment, stress incontinence, overactive bladder, anal incontinence, and prolapse symptoms were assessed with a validated questionnaire. Pelvic organ support was assessed using the Pelvic Organ Prolapse Quantification system. Logistic regression analysis was used to estimate the relative odds of each pelvic floor disorder by obstetric history, adjusting for relevant confounders. Compared with cesarean without labor, spontaneous vaginal birth was associated with a significantly greater odds of stress incontinence (odds ratio [OR] 2.9, 95% confidence interval [CI] 1.5-5.5) and prolapse to or beyond the hymen (OR 5.6, 95% CI 2.2-14.7). Operative vaginal birth significantly increased the odds for all pelvic floor disorders, especially prolapse (OR 7.5, 95% CI 2.7-20.9). These results suggest that 6.8 additional operative births or 8.9 spontaneous vaginal births, relative to cesarean births, would lead to one additional case of prolapse. Among women delivering exclusively by cesarean, neither active labor nor complete cervical dilation increased the odds for any pelvic floor disorder considered, although the study had less than 80% power to detect a doubling of the odds with these exposures. Although spontaneous vaginal delivery was significantly associated with stress incontinence and prolapse, the most dramatic risk was associated with operative vaginal birth. II.


Monostotic Fibrous Dysplasia of the Lumbar Spine With Secondary Features of Solid Variant Aneurysmal Bone Cyst.
Fibrous dysplasia is a benign, mass-forming disease of bone composed of abnormal fibrous and osseous elements that can be accompanied by endocrine dysfunction, skin pigmentation, and intramuscular myxomas. It is usually encountered as a solitary lesion in the tibia or femur but can develop in any bone and can be unifocal or multifocal. Difficulty arises when a solitary lesion is identified in an uncommon site or when there are prominent secondary changes, such as aneurysmal bone cyst (ABC). Molecular studies are available as an adjunct to histomorphology to aid distinction from other entities. GNAS mutations, present in greater than 70% of fibrous dysplasia cases, help in the distinction from primary ABC and low-grade osteosarcoma, which exhibit different molecular abnormalities. We report a case of monostotic fibrous dysplasia in a lumbar vertebral body with secondary change consisting of the solid variant of ABC.


Effect of intracranial pressure on cavernous sinus flow: a cadaver model.
Through an artificially created carotid-cavernous fistula, the cavernous sinus of four suitable cadavers was perfused at a constant input pressure of 50 cm H20 at various levels of intracranial pressure. The flow rate fell 25% at an intracranial pressure of 50 mm Hg but could not be totally arrested even at the extremes of intracranial hypertension. The authors conclude that the cavernous sinus in man is not collapsible.


Detection of G protein-coupled receptor (GPCR) dimerization by coimmunoprecipitation.
With 356 members in the human genome, G protein-coupled receptors (GPCRs) constitute the largest family of proteins involved in signal transduction across biological membranes. GPCRs are integral membrane proteins featuring a conserved structural topology with seven transmembrane domains. By recognizing a large diversity of hormones and neurotransmitters, GPCRs mediate signal transduction pathways through their interactions with both extracellular small-molecule ligands and intracellular G proteins to initiate appropriate cellular signaling cascades. As there is a clear link between GPCRs and several disorders, GPCRs currently constitute the largest family of proteins targeted by marketed pharmaceuticals. Therefore, a detailed understanding of the biogenesis of these receptors and of GPCR-protein complex assembly can help to answer some important questions. In this chapter, we will discuss several methods to isolate GPCRs and to study, via coimmunoprecipitation, protein-protein interactions. Special attention will be given to GPCR dimerization, which often starts already in the endoplasmic reticulum and influences the maturation of the receptor. Next, we will also explain an elegant tool to study GPCR biogenesis based on the glycosylation pattern of the receptor of interest.


Topical verapamil HCl, topical trifluoperazine, and topical magnesium sulfate for the treatment of Peyronie's disease--a placebo-controlled pilot study.
Transdermal and intralesional verapamil has been reported to be useful in the treatment of Peyronie's Disease. This study evaluates a topically applied calcium channel blocker (verapamil hydrochloride 15% gel), a topically applied calmodulin blocker (trifluoperazine), and a topically applied weak calcium channel blocker (magnesium sulfate), each incorporated in a transdermal vehicle. This pilot study was conducted to assess the efficacy of a 15% verapamil gel applied topically to the penile shaft twice daily for the treatment of Peyronie's Disease. To assess improvement in curvature, plaque size, resolution of painful erections, and improvement in erection quality. Two simultaneous, three armed, double blinded, placebo-controlled studies were conducted. After randomization into one of four groups, patients were treated for 3 months. At the end of 3 months' treatment using blinded drug, each patient was treated with open label topical verapamil for 6 months. The studies were completed after each patient had been treated and evaluated for 9 months after randomization. Fifty-seven patients were randomized. In total, 94.4% of patients treated for 9 months with topical verapamil experienced improvement in curvature with an average percent curvature change of 61.1% compared with 43.6% curvature improvement at 3 months. At 9 months the average percent plaque change was 84.7% compared with 55% at 3 months. Pain resolution at 9 months was 100% compared with 87.5% at 3 months. Patient perception of erection quality also increased at 9 months to 81.8% compared with 72.7% at 3 months. Topical verapamil gel proved effective in eliminating pain on erection, decreasing the size of plaque, decreasing curvature, and improving erection quality in patients with Peyronie's Disease. Treatment results improved significantly after 9 months' treatment as compared with 3 months' treatment.


Prevalence of Amyotrophic Lateral Sclerosis - United States, 2015.
Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is a progressive and fatal neuromuscular disease; the majority of ALS patients die within 2-5 years of receiving a diagnosis (1). Familial ALS, a hereditary form of the disease, accounts for 5%-10% of cases, whereas the remaining cases have no clearly defined etiology (1). ALS affects persons of all races and ethnicities; however, whites, males, non-Hispanics, persons aged ≥60 years, and those with a family history of ALS are more likely to develop the disease (2). No cure for ALS has yet been identified, and the lack of proven and effective therapeutic interventions is an ongoing challenge. Treatments currently available, Edaravone and Riluzole, do not cure ALS, but slow disease progression in certain patients (3,4). This report presents National ALS Registry findings regarding ALS prevalence in the United States for the period January 1-December 31, 2015. In 2015, the estimated prevalence of ALS cases was 5.2 per 100,000 population with a total of 16,583 cases identified. Overall, these findings are similar to the 2014 ALS prevalence and case count (5.0 per 100,000; 15,927 cases) (2). Prevalence rates by patient characteristics (most common in whites, males, and persons aged ≥60 years) and U.S. Census regions are consistent with ALS demographics and have not changed from 2014 to 2015 calendar years. The algorithm used to identify cases from national administrative databases was updated from the International Classification of Diseases, Ninth Revision (ICD-9) to the ICD-10 codes for claims starting on October 1, 2015, with no apparent effect on case ascertainment. Data collected by the National ALS Registry are being used to better describe the epidemiology of ALS in the United States and to facilitate research on the genetics, potential biomarkers, environmental pollutants, and etiology for ALS.


The middle and inner ears of the Palaeogene golden mole Namachloris: A comparison with extant species.
Many living species of golden moles (Chrysochloridae) have greatly enlarged middle ear ossicles, believed to be used in the detection of ground vibrations through inertial bone conduction. Other unusual features of chrysochlorids include internally coupled middle ear cavities and the loss of the tensor tympani muscle. Our understanding of the evolutionary history of these characteristics has been limited by the paucity of fossil evidence. In this article, we describe for the first time the exquisitely preserved middle and inner ears of Namachloris arenatans from the Palaeogene of Namibia, visualised using computed tomography, as well as ossicles attributed to this species. We compare the auditory region of this fossil golden mole, which evidently did not possess a hypertrophied malleus, to those of three extant species with similarly sized ear ossicles, Amblysomus hottentotus, Calcochloris obtusirostris, and Huetia leucorhinus. The auditory region of Namachloris shares many common features with the living species, including a pneumatized, trabeculated basicranium and lateral skull wall, arteries and nerves of the middle ear contained in bony tubes, a highly coiled cochlea, a secondary crus commune, and no identifiable canaliculus cochleae for the perilymphatic duct. However, Namachloris differs from extant golden moles in the apparent absence of a basicranial intercommunication between the right and left ears, the possession of a tensor tympani muscle and aspects of ossicular morphology. One Namachloris skull showed what may be pneumatization of some of the dorsal cranial bones, extending right around the brain. Although the ossicles are small in absolute terms, one of the Huetia leucorhinus specimens had a more prominent malleus head than the other. This potentially represents a previously unrecognised subspecific difference.


Incidence, Epidemiology, and Transformation of Ocular Myasthenia Gravis: A Population-Based Study.
To establish the incidence of ocular myasthenia gravis (OMG) as well as identify determinants of transformation to generalized myasthenia gravis (GMG) using a population-based record-linkage system. Population-based, retrospective cohort study. All adults (≥18 years) diagnosed with myasthenia gravis (MG) from January 1, 1990, through December 31, 2017, were identified using the Rochester Epidemiology Project. Sixty-five patients with MG were identified. Data were collected regarding symptom onset, diagnostic testing results, and conversion from OMG to GMG. Median follow-up time was 91 months (range 17-333 months). The annual incidence of MG was 2.20/100 000 with a mean age at diagnosis of 59 years (SD=17) and 62% male sex. Thirty-three (51%) of the 65 patients presented with OMG, providing an annual incidence of 1.13/100 000. Eighteen (55%) of the 33 patients presenting with OMG converted to GMG at a median time of 13 months (range 2-180 months). Sixteen (67%) of 24 OMG patients who were seropositive for acetylcholine receptor antibody (AchR Ab) converted to GMG at 5 years compared to 11% (1/9) of those who were seronegative (hazard ratio [HR], 8.2, P = .04). Ten (77%) of 13 OMG patients with a positive single-fiber electromyography (sfEMG) at diagnosis converted to GMG at 5 years, compared with 18% (2/11) of patients who had a negative sfEMG (HR, 5.5, P = .01). In our population-based study, 51% (33/65) of patients with MG presented with isolated ocular involvement, with 55% (18/33) of these patients converting to GMG at some point in the course of their disease. Positive sfEMG and AchR Ab seropositivity at the time of diagnosis increased the risk of conversion to GMG.


Pilot evaluation of anterior dynamic ultrasound screening for developmental dysplasia of the hip in an Australian regional hospital.
Developmental Dysplasia of the Hip (DDH) is the most common notifiable musculoskeletal birth defect in South Australia (SA). Despite routine screening by physical examination of the hips in the neonatal period and at 6 weeks of age, the risk of late diagnosis is increased in rural areas. It is assumed this is due to the examining doctors' reduced clinical expertise. Introducing Anterior Dynamic Ultrasound (ADUS) has reduced the late detection rates in Sweden to almost zero, and may benefit Australian infants in rural areas if routine screening was introduced. This study reports on a small implementation pilot in a SA regional hospital where volunteer postnatal mothers consented to their babies having ADUS examinations. The pilot was evaluated by collecting results of physical examination, ADUS, and surveying parental impressions of the screening test. Hips of 86 infants underwent ADUS during the implementation pilot. Parents' perceptions were mainly very positive and indicated ADUS was an accessible and acceptable screening test. Of the hips scanned, three were found to have maximum movement of the femoral head of >3 mm and were deemed to demonstrate increased laxity. Four hips described as loose or mobile on clinical examination were found to be within normal limits of maximum mobility on ADUS. This study has demonstrated that a larger scale implementation project would be feasible in regional Australia, and would enable researchers to better understand how to reduce the late diagnosis rate of DDH in rural areas.