Association of PIK3CA Mutation Status before and after Neoadjuvant Chemotherapy with Response to Chemotherapy in Women with Breast Cancer.
The association between PIK3CA mutations and response to neoadjuvant chemotherapy in women with primary breast cancer is not fully elucidated. PIK3CA mutations in breast cancer tissues that were taken prior to the initiation of neoadjuvant chemotherapy were identified in 729 operable primary breast cancer patients who received neoadjuvant chemotherapy. Among these, the PIK3CA mutations were also reassessed in tumor tissues procured following operation in 102 patients after completion of neoadjuvant chemotherapy. A total of 206 out of 729 (28.3%) patients had PIK3CA mutations, and 19.5% of patients (142/729) in this cohort achieved a pathologic complete response (pCR) after neoadjuvant chemotherapy. Patients with PIK3CA mutations exhibited a lower pCR rate than did those with wild-type (14.6% vs. 21.4%, P = 0.035). No significant differences in disease-free survival (DFS) or distant disease-free survival (DDFS) were observed between PIK3CA mutant and wild-type in the entire study population. Among the 102 patients with PIK3CA mutation statuses available before and after neoadjuvant chemotherapy, 24 patients (23.5%) had PIK3CA mutations before neoadjuvant chemotherapy. Of these 24 patients, 15 patients retained their initial PIK3CA mutations and 9 patients lost their initial mutations after neoadjuvant chemotherapy. Patients who retained the initial mutations after neoadjuvant chemotherapy (n = 15) had a worse DDFS than the remaining patients (n = 87) in this subgroup [unadjusted HR, 2.34; 95% confidence interval (CI), 0.98-5.62; P = 0.050]. Patients with PIK3CA mutations are less likely to respond to neoadjuvant chemotherapy. Patients who retain their initial PIK3CA mutations after neoadjuvant chemotherapy have an unfavorable survival.


Developmental toxicity studies in mice, rats, and rabbits with the anticonvulsant gabapentin.
The developmental toxicity of the anticonvulsant agent gabapentin was evaluated in mice, rats, and rabbits treated by gavage throughout organogenesis. Mice received 500, 1000, or 3000 mg/kg on gestation days (GD) 6-15 and rats and rabbits received 60, 300, or 1500 mg/kg on GD 6-15 (rats) or 6-18 (rabbits). Additional groups received an equivalent volume of the vehicle, 0.8% methylcellulose, or remained untreated. All dams were observed daily for clinical signs of toxicity. In mice, body weights and food consumption were recorded on GD 0, 6, 12, 15, and 18 while in rats and rabbits these parameters were evaluated daily. Near term (mouse, GD 18; rat, GD 20; and rabbit, GD 29) each female was euthanatized, necropsies were performed, and litter and fetal data were collected. Live fetuses were examined for external, visceral, and skeletal variations and malformations. No adverse maternal or fetal effects were observed in mice or rats given doses up to 1500 or 3000 mg/kg, respectively. No treatment-related maternal or fetal effects were apparent in rabbits given 60 or 300 mg/kg. At 1500 mg/kg, one rabbit died, four others aborted, and reduced food consumption and body weight gain were observed. No other reproductive, litter, or fetal parameters were affected, except that the incidence of visceral variations in rat fetuses was slightly but statistically significantly increased at 1500 mg/kg due to a slight increase in the incidence of dilated renal pelvis. This finding was not considered biologically significant because this degree of variability has been seen in this strain of rats.(ABSTRACT TRUNCATED AT 250 WORDS)


Zolpidem Activation of Alpha 1-Containing GABAA Receptors Selectively Inhibits High Frequency Action Potential Firing of Cortical Neurons.
Introduction: High frequency neuronal activity in the cerebral cortex can be induced by noxious stimulation during surgery, brain injury or poisoning. In this scenario, it is essential to block cortical hyperactivity to protect the brain against damage, e.g., by using drugs that act as positive allosteric modulators at GABAA receptors. Yet, cortical neurons express multiple, functionally distinct GABAA receptor subtypes. Currently there is a lack of knowledge which GABAA receptor subtypes would be a good pharmacological target to reduce extensive cortical activity. Methods: Spontaneous action potential activity was monitored by performing extracellular recordings from organotypic neocortical slice cultures of wild type and GABAAR-α1(H101R) mutant mice. Phases of high neuronal activity were characterized using peri-event time histograms. Drug effects on within-up state firing rates were quantified via Hedges' g. Results: We quantified the effects of zolpidem, a positive modulator of GABAA receptors harboring α1-subunits, and the experimental benzodiazepine SH-053-2'F-S-CH3, which preferably acts at α2/3/5- but spares α1-subunits. Both agents decreased spontaneous action potential activity but altered the firing patterns in different ways. Zolpidem reduced action potential firing during highly active network states. This action was abolished by flumazenil, suggesting that it was mediated by benzodiazepine-sensitive GABAA receptors. SH-053-2'F-S-CH3 also attenuated neuronal activity, but unlike zolpidem, failed to reduce high frequency firing. To confirm that zolpidem actions were indeed mediated via α1-dependent actions, it was evaluated in slices from wild type and α(H101R) knock-in mice. Inhibition of high frequency action potential firing was observed in slices from wild type but not mutant mice. Conclusion: Our results suggest that during episodes of scarce and high neuronal activity action potential firing of cortical neurons is controlled by different GABAA receptor subtypes. Exaggerated firing of cortical neurons is reduced by positive modulation of α1-, but not α2/3/5-subunit containing GABAA receptors.


65 YEARS OF THE DOUBLE HELIX: The advancements of gene editing and potential application to hereditary cancer.
Hereditary cancer predisposition syndromes are associated with germline mutations that lead to increased vulnerability for an individual to develop cancers. Such germline mutations in tumour suppressor genes, oncogenes and genes encoding for proteins essential in DNA repair pathways and cell cycle control can cause overall chromosomal instability in the genome and increase risk in developing cancers. Gene correction of these germline mutations to restore normal protein functions is anticipated as a new therapeutic option. This can be achieved through disruption of gain-of-function pathogenic mutation, restoration of loss-of-function mutation, addition of a transgene essential for cell function and single nucleotide changes. Genome editing tools are applicable to precise gene correction. Development of genome editing tools comes in two waves. The first wave focuses on improving targeting specificity and editing efficiency of nucleases, and the second wave of gene editing draws on innovative engineering of fusion proteins combining deactivated nucleases and other enzymes that are able to create limitless functional molecular tools. This gene editing advancement is going to impact medicine, particularly in hereditary cancers. In this review, we discuss the application of gene editing as an early intervention and possible treatment for hereditary cancers, by highlighting a selection of highly penetrant cancer syndromes as examples of how this may be achieved in clinical practice.


Is youth smoking responsive to cigarette prices? Evidence from low- and middle-income countries.
To estimate the price elasticity of cigarette demand among youth in low- and middle-income countries (LMIC). The Global Youth Tobacco Survey was used to obtain data on the smoking behaviour of 315,353 adolescents from 17 LMIC. Two-part model of cigarette demand with country fixed effects. The first part estimates the impact of prices on smoking participation while the second part estimates the impact of prices on the number of cigarettes smoked among current smokers. Besides controlling for individual characteristics such as Age, Gender, Parental Smoking and availability of Pocket Money, the authors control for confounding environmental factors such as anti-smoking sentiment, the prevalence of cigarette advertising and anti-tobacco media messAges, and ease of purchasing cigarettes. All countries in this study are represented with at least two observations over time, which allows us to control for unobserved country characteristics and/or policies that may influence smoking patterns within countries. Cigarette price is an important determinant of smoking. The estimated price elasticity of smoking participation is -0.74, and the estimated price elasticity of conditional cigarette demand is approximately -1.37. The total price elasticity of cigarette demand is -2.11, implying that an increase in price of 10% would reduce youth cigarette consumption by 21.1% at the mean.


In vitro proliferation and lifespan of bovine aorta endothelial cells: response to conditioned media.
The effect of conditioned medium on the growth rate of bovine aorta endothelial cells (CSC311) was examined. Media conditioned by several cell types (both immortal and normal) was found to increase the growth rate of CSC311 cells. The growth rate of CSC311 was increased even when the medium was conditioned by other CSC311 cells. The rate of growth of unstimulated CSC311 cells is 0.43 population doublings (p.d./day. Conditioned medium from several cell types gave a maximum stimulated growth rate of 1.3 p.d./day. In addition, we present evidence for an increase in the degree of stimulation by the growth-promoting activity found in conditioned medium with increasing in vitro age of CSC311 cells.


Structural basis of CD4 downregulation by HIV-1 Nef.
The HIV-1 Nef protein suppresses multiple immune surveillance mechanisms to promote viral pathogenesis and is an attractive target for the development of novel therapeutics. A key function of Nef is to remove the CD4 receptor from the cell surface by hijacking clathrin- and adaptor protein complex 2 (AP2)-dependent endocytosis. However, exactly how Nef does this has been elusive. Here, we describe the underlying mechanism as revealed by a 3.0-Å crystal structure of a fusion protein comprising Nef and the cytoplasmic domain of CD4 bound to the tetrameric AP2 complex. An intricate combination of conformational changes occurs in both Nef and AP2 to enable CD4 binding and downregulation. A pocket on Nef previously identified as crucial for recruiting class I MHC is also responsible for recruiting CD4, revealing a potential approach to inhibit two of Nef's activities and sensitize the virus to immune clearance.


Gastroprotective and Healing Effects of Polygonum cuspidatum Root on Experimentally Induced Gastric Ulcers in Rats.
Polygonum cuspidatum is widely used as food and medicine in Korea, China, and Japan. Its major bioactive components, resveratrol and emodin, reportedly protect against gastric lesions. We therefore aimed to investigate: (1) the gastroprotective effects of P. cuspidatum roots in hydrochloric acid/ethanol (HCl/EtOH)- and indomethacin-induced acute gastric ulcer rat models; (2) the healing effects in an acetic acid-induced ulcer model; and (3) potential mechanisms by measuring gastric acid secretion-related parameters in a pyloric ligation-induced ulcer model, and by measuring antioxidant enzyme and prostaglandin E2 levels in the gastric tissue of HCl/EtOH-treated rats. Oral administration of P. cuspidatum extract (PCE) at doses of 100 and 300 mg/kg significantly decreased HCl/EtOH- and indomethacin-induced gastric lesions. PCE at 300 mg/kg significantly reduced gastric lesions in acetic acid-induced ulcers. PCE increased superoxide dismutase (SOD)activity and glutathione(GSH) and prostaglandin E2 levels in gastric tissue, whereas it did not alter gastric acid secretion-related parameters. Our findings indicate that PCE has gastroprotective effects against HCl/EtOH and non-steroidal anti-inflammatory drugs(NSAIDs) and promotes healing of acetic acid-induced ulcers. These gastric mucosal protection and ulcer healing effects are associated with antioxidant effects and the augmentation of prostaglandin E2 and suggest that P. cuspidatum might be a promising preventive and therapeutic agent for treating gastric ulcers.


Multidrug-resistant tuberculosis: Treatment and outcomes of 93 patients.
Tuberculosis (TB) remains a leading cause of death worldwide and the emergence of multidrug-resistant TB (MDR TB) poses a threat to its control. There is scanty evidence regarding optimal management of MDR TB. The majority of Canadian cases of MDR TB are diagnosed in Ontario; most are managed by the Tuberculosis Service at West Park Healthcare Centre in Toronto. The authors reviewed 93 cases of MDR TB admitted from January 1, 2000 to December 31, 2011. Eighty-nine patients were foreign born. Fifty-six percent had a previous diagnosis of TB and most (70%) had only pulmonary involvement. Symptoms included productive cough, weight loss, fever and malaise. The average length of inpatient stay was 126 days. All patients had a peripherally inserted central catheter for the intensive treatment phase because medications were given intravenously. Treatment lasted for 24 months after bacteriologic conversion, and included a mean (± SD) of 5 ± 1 drugs. A successful outcome at the end of treatment was observed in 84% of patients. Bacteriological conversion was achieved in 98% of patients with initial positive sputum cultures; conversion occurred by four months in 91%. MDR TB can be controlled with the available anti-TB drugs.


Determinants of olympic fencing performance and implications for strength and conditioning training.
Fencing is one of only a few sports that have featured at every modern Olympic games. Despite this, there is still much the sport science team does not know regarding competition demands and athlete physical characteristics. This review aims to undertake an analysis of the current literature to identify what is known, and questions that must be answered to optimize athlete support in this context. In summary, fencing is an explosive sport requiring energy production predominately from anaerobic sources. Lunging and change-of-direction speed seem vital to performance, and strength and power qualities underpin this. In the elimination rounds, fencers are likely to accumulate high levels of blood lactate, and so high-intensity interval training is recommended to reduce the intolerance to and the accumulation of hydrogen ions. Injury data report the hamstrings as a muscle group that should be strengthened and address imbalances caused by continuous fencing in an asymmetrical stance.


Obesity-Associated Alterations in Glucose Metabolism Are Reversed by Chronic Bilateral Stimulation of the Abdominal Vagus Nerve.
Acute vagal stimulation modifies glucose and insulin metabolism, but the effect of chronic bilateral vagal stimulation is not known. Our aim was to quantify the changes in whole-body and organ-specific insulin sensitivities 12 weeks after permanent, bilateral, vagal stimulation performed at the abdominal level in adult mini-pigs. In 15 adult mini-pigs, stimulating electrodes were placed around the dorsal and ventral vagi using laparoscopy and connected to a dual-channel stimulator placed subcutaneously. Animals were divided into three groups based on stimulation and body weight (i.e., lean nonstimulated, obese nonstimulated, and obese stimulated). Twelve weeks after surgery, glucose uptake and insulin sensitivity were measured using positron emission tomography during an isoglycemic clamp. Mean whole-body insulin sensitivity was lower by 34% (P < 0.01) and the hepatic glucose uptake rate was lower by 33% (P < 0.01) in obese-nonstimulated mini-pigs but was no different in obese-stimulated compared with lean mini-pigs. An improvement in skeletal glucose uptake rate was also observed in obese-stimulated compared with obese-nonstimulated groups (P < 0.01). Vagal stimulation was associated with increased glucose metabolism in the cingulate and prefrontal brain areas. We conclude that chronic vagal stimulation improves insulin sensitivity substantially in diet-induced obesity by both peripheral and central mechanisms.


Relationships of local lithium concentrations in drinking water to regional suicide rates in Italy.
Higher natural concentrations of lithium in drinking water may be associated with lower local rates of suicide. Lithium concentrations in drinking water were assayed by mass spectrometry at 145 sites in Italy, and compared with reported local suicide rates for men and women between 1980 and 2011. Lithium concentrations in drinking water averaged 5.28 [CI: 4.08-6.48] μg/L (0.761 [0.588-0.934] μEq/L) and ranged from 0.110 to 60.8 μg/L (1.58 to 8.76 μEq/L). Lithium concentrations and local suicide rates were not significantly inversely related, except in 1980-1989, particularly among women. A proposed association between trace lithium concentrations in drinking water and risk of suicide was only partially supported, and mechanisms for potential clinical effects of trace levels of lithium are unknown.


TBK1 Is a Synthetic Lethal Target in Cancer with VHL Loss.
TANK binding kinase 1 (TBK1) is an important kinase involved in the innate immune response. Here we discover that TBK1 is hyperactivated by von Hippel-Lindau (VHL) loss or hypoxia in cancer cells. Tumors from patients with kidney cancer with VHL loss display elevated TBK1 phosphorylation. Loss of TBK1 via genetic ablation, pharmacologic inhibition, or a new cereblon-based proteolysis targeting chimera specifically inhibits VHL-deficient kidney cancer cell growth, while leaving VHL wild-type cells intact. TBK1 depletion also significantly blunts kidney tumorigenesis in an orthotopic xenograft model in vivo. Mechanistically, TBK1 hydroxylation on Proline 48 triggers VHL as well as the phosphatase PPM1B binding that leads to decreased TBK1 phosphorylation. We identify that TBK1 phosphorylates p62/SQSTM1 on Ser366, which is essential for p62 stability and kidney cancer cell proliferation. Our results establish that TBK1, distinct from its role in innate immune signaling, is a synthetic lethal target in cancer with VHL loss. SIGNIFICANCE: The mechanisms that lead to TBK1 activation in cancer and whether this activation is connected to its role in innate immunity remain unclear. Here, we discover that TBK1, distinct from its role in innate immunity, is activated by VHL loss or hypoxia in cancer.See related commentary by Bakouny and Barbie, p. 348.This article is highlighted in the In This Issue feature, p. 327.


Non-hypoxic preconditioning of myocardium against postoperative atrial fibrillation: mechanism based on enhancement of the antioxidant defense system.
Oxidative stress underlies postoperative atrial fibrillation and electrophysiological remodelling associated with rapid atrial pacing. An increasing body of evidence indicates that the formation of reactive oxygen species (ROS) released following extracorporeal circulation are involved in the structural and functional myocardial impairment derived from the ischemia-reperfusion cycle. ROS behave as intracellular messengers mediating pathological processes, such as inflammation, apoptosis and necrosis, thereby participating in the pathophysiology of atrial fibrillation. Thus, increased superoxide (O(2)(.-)) production has been found in isolated atrial cardiomyocytes from patients with atrial fibrillation. Therefore, it seems reasonable to assume that the reinforcement of the antioxidant defense system should protect the heart against functional alterations in the cardiac rhythm. On this line, antioxidant enzyme induction through in vivo exposure to moderate concentration of ROS is associated with a reduction in the susceptibility of myocytes to ROS-induced injury. This response could be due to a prevailing effect of survival over apoptotic pathway. Previously, tissue preconditioning caused by prior exposure to an ischemia/reperfusion cycle has been successfully applied in experimental models and clinical settings associated with oxidative damage by ROS. However, such hypoxic preconditioning method is harmful to be applied to many clinical conditions associated with oxidative stress. In turn, experimental studies have revealed that non-enzymatic antioxidants produce a significant functional amelioration in cardiomyocytes subjected to an oxidative challenge. Moreover, clinical studies with patients scheduled for primary coronary artery bypass graft surgery had a reduced incidence of postoperative atrial fibrillation. We present the hypothesis of non-hypoxic preconditioning based on the association of pretreatment with n-3 polyunsaturated fatty acids followed by ascorbate plus alpha-tocoferol supplementation diminishes the incidence of postoperative atrial fibrillation in patients subjected to cardiac surgery with extracorporeal circulation.


[An epidemiologic study of brucellosis in the province of Valencia (1943-1989)].
We have carried out an epidemiological study of Brucellosis in Valencia, studying the evolution of morbidity through this disease from 1943 to 1989. On the other hand, and for the period 1985-1988 we have carried out a study researching the distribution of the illness by sex, age-groups, professions, etc., basing ourselves on the epidemiological surveys corresponding to the 516 cases of Brucellosis declared in this period. We highlight the fact that the dominant mechanism of indirect contagion (mainly through consumption of fresh cheese and untreated milk) constrains the epidemiological pattern of this illness in our area. Thus we believe it is important to maintain and increase the sanitary and hygienic controls of the foods involved in the transmission, mainly the production and distribution of unfermented fresh milk and cheese.


Sleep disruption among older men and risk of prostate cancer.
Although positive associations have consistently been reported between sleep disruption and breast cancer, less is known about its potential role in prostate cancer. Within the prospective AGES-Reykjavik cohort study, we followed 2,102 men recruited in 2002-2006 until the end of 2009. Participants answered questions on sleep disruption. Information on the occurrence of prostate cancer was obtained through record linkages across the Icelandic Cancer Registry. We used Cox regression models with 95% confidence intervals (CI) to estimate HRs of prostate cancer by symptoms of sleep disruption. During follow-up, 135 men (6.4%) were diagnosed with prostate cancer. Compared with men without sleep disruption, those with problems falling and staying asleep were at significantly increased risk of prostate cancer [HR, 1.7 (95% CI, 1.0-2.9) and 2.1 (95% CI, 1.2-3.7)], respectively, with increasing sleep disruption severity. When restricted to advanced prostate cancer (≥ stage T3 or lethal disease), these associations became even stronger [HR 2.1 (95% CI, 0.7-6.2) and 3.2 (95% CI, 1.1-9.7)]. The results did not change after excluding from the analyses men who woke up during the night, indicative of nocturia, suggesting limited risk of reverse association. Our data suggest that certain aspects of sleep disruption may confer an increased risk of prostate cancer and call for additional, larger studies with longer follow-up times. Prostate cancer is one of the leading public health concerns in men; if confirmed in future studies, the association between sleep disruption and prostate cancer risk may open new avenues for prevention.


Hemophilia Gene Therapy Value Assessment: Methodological Challenges and Recommendations.
Gene therapy for hemophilia is designed to produce health gains for patients over many years. Rewarding that value creation on the basis of a one-time treatment implies a large upfront cost. This cost can only be justified by long-term health benefits and being cost-effective compared with conventional treatments. Yet, uncertainties about the long-term benefits make it challenging to assess clinical and economic value of gene therapies at launch. We identify and discuss key methodological challenges in assessing the value of gene therapy for hemophilia, including the immaturity of evidence on the durability of benefits, lack of definition and valuation of cure for chronic diseases, absence of randomized controlled trials, limitations of traditional quality of life measures in hemophilia, approach for qualifying cost-savings compared with current treatments, and choice of perspective. The Institute for Clinical and Economic Review has developed a framework for assessing single or short-term therapies (ICER-SST) and has applied it in hemophilia. After reviewing this framework and its application, we recommend the following when assessing the value of hemophilia gene therapies: (1) leveraging expert clinical opinion to justify assumptions on the durability of benefits; (2) using external synthetic controls and lead-in, self-controlled trials to assess comparative effectiveness; (3) addressing limitations of traditional quality of life measures through the use of modified utility collection approaches; (4) adjusting cost offsets from gene therapies with caution; (5) considering outcome-based contracting to address uncertainties about prices and long-term outcomes; and (6) presenting societal and healthcare system perspectives in parallel.


Interleukin-17A (IL-17A) and IL-17F Are Critical for Antimicrobial Peptide Production and Clearance of Staphylococcus aureus Nasal Colonization.
Approximately 20% of the population is persistently colonized by Staphylococcus aureus in the nares. Th17-like immune responses mediated by the interleukin-17 (IL-17) family of cytokines and neutrophils are becoming recognized as relevant host defense mechanisms for resolution of S. aureus mucocutaneous infections. Since antimicrobial peptides are regulated by the IL-17 cytokines, we sought to determine the role of IL-17 cytokines in production of antimicrobial peptides in a murine model of S. aureus nasal carriage. We discovered that nasal tissue supernatants have antistaphylococcal activity, and mice deficient in both IL-17A and IL-17F lost the ability to clear S. aureus nasal colonization. IL-17A was found to be sufficient for nasal mBD-3 production ex vivo and was required for CRAMP, mBD-3, and mBD-14 expression in response to S. aureus colonization in vivo These data were confirmed in a clinical study of nasal secretions in which elevated levels of the human forms of these antimicrobial peptides were found in nasal secretions from healthy human subjects when they were colonized with S. aureus but not in secretions from noncolonized subjects. Together, these data provide evidence for the importance of IL-17A regulation of antimicrobial peptides and IL-17F in the clearance of S. aureus nasal carriage.


Glomerulus-on-a-Chip: Current Insights and Future Potential Towards Recapitulating Selectively Permeable Filtration Systems.
Glomerulopathy, characterized by a dysfunctional glomerular capillary wall, results in proteinuria, leading to end-stage renal failure and poor clinical outcomes, including renal death and increased overall mortality. Conventional glomerulopathy research, including drug discovery, has mostly relied on animal experiments because in-vitro glomerulus models, capable of evaluating functional selective permeability, was unavailable in conventional in-vitro cell culture systems. However, animal experiments have limitations, including time- and cost-consuming, multi-organ effects, unstable reproducibility, inter-species reliability, and the social situation in the EU and US, where animal experiments have been discouraged. Glomerulus-on-a-chip, a new in-vitro organ model, has recently been developed in the field of organ-on-a-chip research based on microfluidic device technology. In the glomerulus-on-a-chip, the podocytes and endothelial cells are co-cultured in a microfluidic device with physical stimuli that mimic the physiological environment to enhance cell function to construct a functional filtration barrier, which can be assessed by permeability assays using fluorescently labeled molecules including inulin and albumin. A combination of this glomerulus-on-a chip technology with the culture technology to induce podocytes and endothelial cells from the human pluripotent stem cells could provide an alternative organ model and solve the issue of animal experiments. Additionally, previous experiments have verified the difference in the leakage of albumin using differentiated podocytes derived from patients with Alport syndrome, such that it could be applied to intractable hereditary glomerulopathy models. In this review, we provide an overview of the features of the existing glomerulus-on-a-chip systems, focusing on how they can address selective permeability verification tests, and the challenges they involved. We finally discuss the future approaches that should be developed for solving those challenges and allow further improvement of glomerulus-on-a-chip technologies.


Reviewing the womb.
Throughout most of human history women have been defined by their biological role in reproduction, seen first and foremost as gestators, which has led to the reproductive system being subjected to outside interference. The womb was perceived as dangerous and an object which husbands, doctors and the state had a legitimate interest in controlling. In this article, we consider how notions of conflict surrounding the womb have endured over time. We demonstrate how concerns seemingly generated by the invisibility of reproduction and the inaccessibility of the womb have translated into similar arguments for controlling women, as technology increases the accessibility of the female body and the womb. Developments in reproductive medicine, from in vitro fertilisation (IVF) to surrogacy, have enabled women and men who would otherwise have been childless to become parents. Uterus transplants and 'artificial wombs' could provide additional alternatives to natural gestation. An era of 'womb technology' dawns. Some argue that such technology providing an alternative to 'natural' gestation could be a source of liberation for female persons because reproduction will no longer be something necessarily confined to the female body. 'Womb technology', however, also has the potential to exacerbate the labelling of the female body as a source of danger and an 'imperfect' site of gestation, thus replaying rudimentary and regressive arguments about controlling female behaviour. We argue that pernicious narratives about control, conflict and the womb must be addressed in the face of these technological developments.


National Multi-Institutional Validation of a Surgical Transfusion Risk Prediction Model.
Accurate estimation of surgical transfusion risk is important for many aspects of surgical planning, yet few methods for estimating are available for estimating such risk. There is a need for reliable validated methods for transfusion risk stratification to support effective perioperative planning and resource stewardship. This study was conducted using the American College of Surgeons NSQIP datafile from 2019. S-PATH performance was evaluated at each contributing hospital, with and without hospital-specific model tuning. Linear regression was used to assess the relationship between hospital characteristics and area under the receiver operating characteristic (AUROC) curve. A total of 1,000,927 surgical cases from 414 hospitals were evaluated. Aggregate AUROC was 0.910 (95% CI 0.904 to 0.916) without model tuning and 0.925 (95% CI 0.919 to 0.931) with model tuning. AUROC varied across individual hospitals (median 0.900, interquartile range 0.849 to 0.944), but no statistically significant relationships were found between hospital-level characteristics studied and model AUROC. S-PATH demonstrated excellent discriminative performance, although there was variation across hospitals that was not well-explained by hospital-level characteristics. These results highlight the S-PATH's viability as a generalizable surgical transfusion risk prediction tool.


Teaching Spanish to emergency medicine residents.
To determine the effects of teaching medical Spanish to eight PGY1 emergency medicine residents on their subsequent interactions with Spanish-speaking patients. Eight PGY1 residents completed a 45-hour medical Spanish course administered during their first residency month. Thirty-four subsequent physician-patient interactions by these residents were audiotaped over a six-month period at a suburban teaching ED. The tapes were transcribed and analyzed for errors by a professional medical Spanish interpreter and a native Spanish speaker. Minor errors (e.g., technically incorrect grammar or vocabulary with generally appropriate patient understanding) were found in more than half of the interactions and major errors (e.g., misunderstanding duration of symptoms, misunderstanding of vocabulary) were found in 14% of the interactions. In addition, although the course was designed to supplement, not replace, professional interpreters, the residents called for an interpreter only 46% of the time. Although medical language courses may be a useful adjunct to interpreters, they are not designed to replace them. Significant errors may occur when participants in such courses assume their knowledge is sufficient to obtain a good history, give patient release instructions, and provide medical care in general without an interpreter present.


[I-THOU Eternal relationship in the life of caregivers of children with AIDS: study based on Martin Buber philosophy].
This phenomenological study aimed at understanding, in the light of Martin Buber's philosophy, what is to be a caregiver of children with AIDS. The phenomenological interview guided the meeting with seven caregivers of children with AIDS, selected in a teaching hospital of Porto Alegre-RS, southern of Brazil. The data were interpreted in the light of hermeneutics, emerging the unit of meaning Dialogues 'between' the familiar I and the Eternal THOU. The dialogues take place in the search for answers that allow the understanding of the significance of the impact and challenges they face while living with AIDS. As well, they reveal hope in changes, in the cure and in a vaccine development. We believe that knowing the importance of dialogue in the context of HIV/AIDS epidemic provide the development of a nursing care that brings together the technical-scientific and humanistic aspects.


Galen's use of Aristotle.
The thought of Aristotle has stamped itself on the whole subsequent course of Natural philosophy including the philosophy of healing art since the 4th century B. C. He is known to be the great codifier of ancient Natural philosophy. He developed coherent theories of generation and functional morphology of animals and heredity in his treaties. Aristotle dissected about 70 species of animals and founded the basis of comparative Anatomy.


The Medicare-HMO revolving door--the healthy go in and the sick go out.
Enrollment in Medicare health maintenance organizations (HMOs) is encouraged because of the expectation that HMOs can help slow the growth of Medicare costs. However, Medicare HMOs, which are paid 95 percent of average yearly fee-for-service Medicare expenditures, are increasingly believed to benefit from the selective enrollment of healthier Medicare recipients. Furthermore, whether sicker patients are more likely to disenroll from Medicare HMOs, thus raising average fee-for-service costs, is not clear. We used Medicare enrollment and inpatient billing records for southern Florida from 1990 through 1993 to examine differences in the use of inpatient medical services by 375,406 beneficiaries in the Medicare fee-for-service system, 48,380 HMO enrollees before enrollment, and 23,870 HMO enrollees after disenrollment. We also determined whether these differences were related to demographic characteristics and whether the pattern of use after disenrollment persisted over time. The rate of use of inpatient services in the HMO-enrollment group during the year before enrollment was 66 percent of the rate in the fee-for-service group, whereas the rate in the HMO-disenrollment group after disenrollment was 180 percent of that in the fee-for-service group. Beneficiaries who disenrolled from HMOs re-enrolled at about the time that their level of use dropped to that in the fee-for-service group. These data show marked selection biases with respect to HMO enrollment and disenrollment. These biases undermine the effectiveness of the Medicare managed-care system and highlight the need for longitudinal and population-based studies.


Stomatal penetration by aqueous solutions--an update involving leaf surface particles.
The recent visualization of stomatal nanoparticle uptake ended a 40-yr-old paradigm. Assuming clean, hydrophobic leaf surfaces, the paradigm considered stomatal liquid water transport to be impossible as a result of water surface tension. However, real leaves are not clean, and deposited aerosols may change hydrophobicity and water surface tension. Droplets containing NaCl, NaClO(3), (NH(4))(2) SO(4), glyphosate, an organosilicone surfactant or various combinations thereof were evaporated on stomatous abaxial and astomatous adaxial surfaces of apple (Malus domestica) leaves. The effects on photosynthesis, necrosis and biomass were determined. Observed using an environmental scanning electron microscope, NaCl and NaClO(3) crystals on hydrophobic tomato (Solanum lycopersicum) cuticles underwent several humidity cycles, causing repeated deliquescence and efflorescence of the salts. All physiological parameters were more strongly affected by abaxial than adaxial treatments. Spatial expansion and dendritic crystallization of the salts occurred and cuticular hydrophobicity was decreased more rapidly by NaClO(3) than NaCl. The results confirmed the stomatal uptake of aqueous solutions. Humidity fluctuations promote the spatial expansion of salts into the stomata. The ion-specific effects point to the Hofmeister series: chaotropic ions reduce surface tension, probably contributing to the defoliant action of NaClO(3), whereas the salt spray tolerance of coastal plants is probably linked to the kosmotropic nature of chloride ions.


Single-input polarization-sensitive optical coherence tomography through a catheter.
Intravascular polarimetry with catheter-based polarization-sensitive optical coherence tomography (PS-OCT) complements the high-resolution structural tomograms of OCT with morphological contrast available through polarimetry. Its clinical translation has been complicated by the need for modification of conventional OCT hardware to enable polarimetric measurements. Here, we present a signal processing method to reconstruct the polarization properties of tissue from measurements with a single input polarization state, bypassing the need for modulation or multiplexing of input states. Our method relies on a polarization symmetry intrinsic to round-trip measurements and uses the residual spectral variation of the polarization states incident on the tissue to avoid measurement ambiguities. We demonstrate depth-resolved birefringence and optic axis orientation maps reconstructed from in-vivo data of human coronary arteries. We validate our method through comparison with conventional dual-input state measurements and find a mean cumulative retardance error of 13.2deg without observable bias. The 95% limit of agreement between depth-resolved birefringence is 2.80 · 10-4, which is less than the agreement between two repeat pullbacks of conventional PS-OCT (3.14 · 10-4), indicating that the two methods can be used interchangeably. The hardware simplification arising from using a single input state may be decisive in realizing the potential of polarimetric measurements for assessing coronary atherosclerosis in clinical practice.


Outcome of older critically ill patients: a matched cohort study.
Admission of older patients to intensive care units is a controversial issue. To estimate age-associated mortality of critically ill patients. A prospective matched cohort study in the Medical-Surgical Intensive Care Unit of a tertiary hospital was conducted. We included 100 consecutive patients older than 70 years admitted to the intensive care unit (cases) and 100 patients younger than 70 years (controls). The matching criterion was the severity of illness at admission to the intensive care unit as estimated by the simplified acute physiological score (SAPS II) without including age in its calculation. Mortality in the intensive care unit was higher, but not statistically significant, in the older group: 26% vs. 19% (p = 0.23). Patients older than 70 years had a longer duration of mechanical ventilation (median 7 vs. 3 days) and longer stay in the intensive care unit (median 8 vs. 5 days). There were no differences in organ dysfunctions, except for a higher incidence of respiratory failure in the older group (p < 0.001). The use of invasive procedures was similar in both groups. There were more orders for the withholding/withdrawal of treatment in patients older than 70 years (9 vs. 3%, p = 0.07). In our study, age was not related with a significant higher mortality. In the older patients included in our study the survival was greater than 70% with a similar resource utilization except for a longer stay in the intensive care unit.


Multidimensional assessment of motor function in a child with cerebral palsy following intrathecal administration of baclofen.
This case report describes an 11-year-old boy with spastic diplegia whose reflex status, range of motion (ROM), strength, and motor performance were measured before and after implantation of an indwelling system for delivery of intrathecally administered baclofen. Before baclofen use, the subject experienced clonus that interfered with walking, needed assistance with transfers, and was unable to independently put on underwear and socks. Measures of spasticity, kinematics and electromyographic activity during voluntary movements, ROM, Gross Motor Function Measure (GMFM) scores, and self-reports of change were obtained at baseline, before and after bolus baclofen injection, during a double-blind placebo-controlled clinical trial of baclofen administration via an indwelling pump, and after 1 and 2 years of baclofen therapy. Spasticity, Babinski reflexes, clonus, strength, and coactivation of antagonist muscles during voluntary movement were decreased shortly after baclofen administration began. Hip and ankle ROM increased, upper-extremity movement speed increased, independence in dressing and transfers improved, and orthoses were discarded. After 1 and 2 years, GMFM scores were 7.8% and 6.4% above baseline, respectively; the subject won a fitness award. After 2 years, ROM was worse than at baseline and concerns regarding hip subluxation arose. Single-joint movement control and independence improved and spasticity decreased during baclofen administration.


Obstruction enhances rho-kinase pathway and diminishes protein kinase C pathway in carbachol-induced calcium sensitization in contraction of α-toxin permeabilized guinea pig detrusor smooth muscle.
We investigated the relative important role of rho kinase (ROK) and protein kinase C (PKC) pathways in carbachol (CCh)-induced Ca(2+) sensitization in α-toxin permeabilized Guinea pig detrusor smooth muscle (DSM) following bladder outlet obstruction (BOO). Bladder outlet obstruction was created by placement of a silver jeweler's jump rings loosely round the urethro-vesical junction of Guinea pigs. Sham operated Guinea pig underwent a similar protocol without application of the ring and served as control. α-Toxin permeabilized DSM strips from control Guinea pigs and those subjected to 6-8 weeks of BOO were mounted horizontally for isometric force recording in 100 µl relaxing solution on perspex block. The effect of ROK inhibitor (Y-27632) and PKC inhibitor (GF-109203X) on CCh-induced Ca(2+) sensitization was studied during sustained contraction. Permeabilized DSM strips were also stimulated by cumulative increase of Ca(2+) concentration compared to that in control in the presence and in the absence of sensitization-induced PKC activator, phorbol 12,13-dibutyrate. Ca(2+) sensitization-induced by CCh was greater in BOO compared to controls. This muscarinic agonist-induced Ca(2+) sensitization was inhibited by Y-27632 or GF-109203X. The inhibitory effect of Y-27632 (5 µM) was greater while the inhibitory effect of GF-109203X (5 µM) was smaller in BOO compared to that in controls. Phorbol 12,13-dibutyrate (1 µM) markedly increased Ca(2+) sensitivity in controls but not in BOO. Our findings provide the first evidence that BOO enhances the ROK pathway and diminishes the PKC pathway in CCh-induced Ca(2+) sensitization in contraction of permeabilized Guinea pig DSM and suggest that inhibitors of ROK might potentially relieve bladder dysfunction related to BOO.


Common household activities are associated with elevated particulate matter concentrations in bedrooms of inner-city Baltimore pre-school children.
Asthma disproportionately affects inner-city, minority children in the U.S. Outdoor pollutant concentrations, including particulate matter (PM), are higher in inner-cities and contribute to childhood asthma morbidity. Although children spend the majority of time indoors, indoor PM exposures have been less extensively characterized. There is a public health imperative to characterize indoor sources of PM within this vulnerable population to enable effective intervention strategies. In the present study, we sought to identify determinants of indoor PM in homes of Baltimore inner-city pre-school children. Children ages 2-6 (n=300) who were predominantly African-American (90%) and from lower socioeconomic backgrounds were enrolled. Integrated PM(2.5) and PM(10) air sampling was conducted over a 3-day period in the children's bedrooms and at a central monitoring site while caregivers completed daily activity diaries. Homes of pre-school children in inner-city Baltimore had indoor PM concentrations that were twice as high as simultaneous outdoor concentrations. The mean indoor PM(2.5) and PM(10) concentrations were 39.5+/-34.5 and 56.2+/-44.8 microg/m(3), compared to the simultaneously measured ambient PM(2.5) and PM(10) (15.6+/-6.9 and 21.8+/-9.53 microg/m(3), respectively). Common modifiable household activities, especially smoking and sweeping, contributed significantly to higher indoor PM, as did ambient PM concentrations. Open windows were associated with significantly lower indoor PM. Further investigation of the health effects of indoor PM exposure is warranted, as are studies to evaluate the efficacy of PM reduction strategies on asthma health of inner-city children.


Naltrexone at low doses upregulates a unique gene expression not seen with normal doses: Implications for its use in cancer therapy.
It has been reported that lower doses of the opioid antagonist naltrexone are able to reduce tumour growth by interfering with cell signalling as well as by modifying the immune system. We have evaluated the gene expression profile of a cancer cell line after treatment with low-dose naltrexone (LDN), and assessed the effect that adapting treatment schedules with LDN may have on enhancing efficacy. LDN had a selective impact on genes involved with cell cycle regulation and immune modulation. Similarly, the pro-apoptotic genes BAD and BIK1 were increased only after LDN. Continuous treatment with LDN had little effect on growth in different cell lines; however, altering the treatment schedule to include a phase of culture in the absence of drug following an initial round of LDN treatment, resulted in enhanced cell killing. Furthermore, cells pre-treated with LDN were more sensitive to the cytotoxic effects of a number of common chemotherapy agents. For example, priming HCT116 with LDN before treatment with oxaliplatin significantly increased cell killing to 49±7.0 vs. 14±2.4% in cultures where priming was not used. Interestingly, priming with NTX before oxaliplatin resulted in just 32±1.8% cell killing. Our data support further the idea that LDN possesses anticancer activity, which can be improved by modifying the treatment schedule.


Contribution of the traT gene to serum resistance among clinical isolates of enterobacteriaceae.
Antimicrobial resistance plasmids containing the traT gene confer resistance to serum bactericidal activity upon some laboratory strains of Escherichia coli. We have examined the DNA of Enterobacteriaceae from human extraintestinal infections to determine the frequency of traT-like genes. DNA sequences homologous with traT were found among 58% of Escherichieae but among none of the Klebsielleae or Proteeae tested and were found as frequently among serum-sensitive E. coli as among serum-resistant strains. Sequences related to traT were always associated with large plasmids. The potential contribution of traT-containing plasmids to serum resistance of clinical isolates is discussed.


FIST, a sword and shield fusokine for cancer immunotherapy.
To antagonize tumor-derived TGFβ contemporaneously to anticancer immunotherapy, we genetically engineered a fusion protein coupling IL-2 and the ectodomain of TGFβ receptor II (Fusion of Interleukin-2 and Soluble TGFβ receptor - a.k.a. FIST). FIST possesses intriguing gain-of-function properties and induces potent activation of IL2-receptor expressing cells and inhibits tumor-derived angiogenesis. Thus FIST constitutes a first-in-class biological that couples anti-angiogenesis to an immune antitumor response.


[Inhibition of rat heart and brain cyclic 3',5'-adenosine monophosphate phosphodiesterase under the influence of neurohormone "C"].
In vitro studies of the effect of neurohormone C on cyclic AMP phosphodiesterase activity of heart and brain showed that amounts of neurohormone equal to 5 ng inhibited significantly the activity of phos-phodiestherase in heart and even more strongly in brain. A comparison of the effect of the neurohormone with that of theophylline (10 mM) showed that very small amounts of the neurohormone brought about inhibition of enzyme activity that was equal to that observed from much larger concentrations of the theophylline. It is proposed that the inhibition of phosphodiestherase activity is of importance in the mechanism of the action of the neurohormone.


Analysis of completeness for spontaneous reporting of disease-modifying therapies in multiple sclerosis.
Introduction: Considering the need for effective postmarketing surveillance of disease-modifying therapies (DMTs) in multiple sclerosis (MS), we analyzed the potential of the spontaneous reports for safety signal detection, verifying the completeness of the reports in the FDA Adverse Event Reporting System (FAERS).Methods: All reports with DMTs for MS considered the primary suspect cause of ADRs and registered between January 2004 and June 2019 were selected. The vigiGrade completeness score was applied and reports with a score greater than 0.80 were considered well documented. Descriptive statistical analysis and comparisons of well-documented reports by DMTs were performed.Results: A total of 297,926 reports were analyzed. The lowest completeness rates were observed for type of report (13.5%), dose (62.7%), and time from treatment start to the ADR (79.0%). Overall, 80.8% of reports were classified as well documented and those related to natalizumab had the highest proportion (92.4%, p < 0.001), while the lowest was observed for reports sent in 2017 (53.1%, p < 0.001) and for teriflunomide (48.5%, p < 0.001).Conclusions: The high proportion of well-documented reports for DMTs indicates that they can be a valuable source for safety signal detection. A more careful analysis should be performed for data from the groups identified with low completeness to avoid the disclosure of spurious results.


Discovery of potential urine-accessible metabolite biomarkers associated with muscle disease and corticosteroid response in the mdx mouse model for Duchenne.
Urine is increasingly being considered as a source of biomarker development in Duchenne Muscular Dystrophy (DMD), a severe, life-limiting disorder that affects approximately 1 in 4500 boys. In this study, we considered the mdx mice-a murine model of DMD-to discover biomarkers of disease, as well as pharmacodynamic biomarkers responsive to prednisolone, a corticosteroid commonly used to treat DMD. Longitudinal urine samples were analyzed from male age-matched mdx and wild-type mice randomized to prednisolone or vehicle control via liquid chromatography tandem mass spectrometry. A large number of metabolites (869 out of 6,334) were found to be significantly different between mdx and wild-type mice at baseline (Bonferroni-adjusted p-value < 0.05), thus being associated with disease status. These included a metabolite with m/z = 357 and creatine, which were also reported in a previous human study looking at serum. Novel observations in this study included peaks identified as biliverdin and hypusine. These four metabolites were significantly higher at baseline in the urine of mdx mice compared to wild-type, and significantly changed their levels over time after baseline. Creatine and biliverdin levels were also different between treated and control groups, but for creatine this may have been driven by an imbalance at baseline. In conclusion, our study reports a number of biomarkers, both known and novel, which may be related to either the mechanisms of muscle injury in DMD or prednisolone treatment.


Comparison of the inhibitory effect of topical cyclosporine A 0.1% and topical anti-VEGF application in an experimental model of corneal neovascularization.
The aim of this study was to compare the effects of topical cyclosporine 0.1% and bevacizumab on experimentally induced corneal neovascularization in a rat model. A total of 30 adult Sprague-Dawley rats were used in this experimental study. The central cornea of the rats was cauterized chemically. The rats were randomly enrolled into three groups as follows: Group 1 received bevacizumab 1%, Group 2 received cyclosporine 0.1%, and Group 3 received isotonic saline twice a day for 28 days. Slit-lamp examination of all rats was performed at the 3rd and 28th day. The rats were then sacrificed, and the corneas were excised. The number of blood vessels, state of inflammation, and collagen formation were evaluated histopathologically in the corneal sections. Corneal opacity and edema grades were significantly lower in Group 2 than in Group 3 (p=0.04 and 0.00, respectively). In the histopathological examination, Group 2 demonstrated significantly lesser number of blood vessels than Group 3 (p=0.001). Regarding collagen formation, Group 2 exhibited more regular collagen formation than Groups 1 and 3 (p=0.03). Inflammation grades were significantly lower in Groups 1 and 2 than in Group 3 (p=0.014 and 0.001, respectively). Topical bevacizumab is effective in inhibiting newly formed corneal neovascularization. The topical cyclosporine 0.1% treatment appears to be more effective than the topical bevacizumab treatment.


Parallel Monte Carlo methods for physical mapping of chromosomes.
Reconstructing a physical map of a chromosome from a genomic library presents a central computational problem in genetics. Physical map reconstruction in the presence of errors is a problem of high computational complexity. Parallel Monte Carlo methods for a maximum likelihood estimation-based approach to physical map reconstruction are presented. The estimation procedure entails gradient descent search for determining the optimal spacings between probes for a given probe ordering. The optimal probe ordering is determined using a simulated Monte Carlo algorithm. A two-tier parallelization strategy is proposed wherein the gradient descent search is parallelized at the lower level and the simulated Monte Carlo algorithm is simultaneously parallelized at the higher level. Implementation and experimental results on a network of shared-memory symmetric multiprocessors (SMPs) are presented.


High sensitivity non-invasive detection of calcifications deep inside biological tissue using Transmission Raman Spectroscopy.
The aim of this research was to develop a novel approach to probe non-invasively the composition of inorganic chemicals buried deep in large volume biological samples. The method is based on advanced Transmission Raman Spectroscopy (TRS) permitting chemical specific detection within a large sampling volume. The approach could be beneficial to chemical identification of the breast calcifications detected during mammographic X-ray procedures. The chemical composition of a breast calcification reflects the pathology of the surrounding tissue, malignant or benign and potentially the grade of malignancy. However, this information is not available from mammography, leading to excisional biopsy and histopathological assessment for a definitive diagnosis. Here we present, for the first time, a design of a new high performance deep Raman instrument and demonstrate its capability to detect type II calcifications (calcium hydroxyapatite) at clinically relevant concentrations and depths of around 40 mm in phantom tissue. This is around double the penetration depth achieved with our previous instrument design and around two orders of magnitude higher than that possible when using conventional Raman spectroscopy.


Clustering of loci controlling species differences in male chemical bouquets of sympatric Heliconius butterflies.
The degree to which loci promoting reproductive isolation cluster in the genome-that is, the genetic architecture of reproductive isolation-can influence the tempo and mode of speciation. Tight linkage between these loci can facilitate speciation in the face of gene flow. Pheromones play a role in reproductive isolation in many Lepidoptera species, and the role of endogenously produced compounds as secondary metabolites decreases the likelihood of pleiotropy associated with many barrier loci. Heliconius butterflies use male sex pheromones to both court females (aphrodisiac wing pheromones) and ward off male courtship (male-transferred antiaphrodisiac genital pheromones), and it is likely that these compounds play a role in reproductive isolation between Heliconius species. Using a set of backcross hybrids between H. melpomene and H. cydno, we investigated the genetic architecture of putative male pheromone compound production. We found a set of 40 significant quantitative trait loci (QTL) representing 33 potential pheromone compounds. QTL clustered significantly on two chromosomes, chromosome 8 for genital compounds and chromosome 20 for wing compounds, and chromosome 20 was enriched for potential pheromone biosynthesis genes. There was minimal overlap between pheromone QTL and known QTL for mate choice and color pattern. Nonetheless, we did detect linkage between a QTL for wing androconial area and optix, a color pattern locus known to play a role in reproductive isolation in these species. This tight clustering of putative pheromone loci might contribute to coincident reproductive isolating barriers, facilitating speciation despite ongoing gene flow.


Development of the tendon of Todaro during the human embryonic and fetal periods.
This study covers the development of Todaro's tendon during human embryonic and fetal periods. The tendon primordium first appears when human embryos attain a CR length of 22 mm, but it only becomes well-defined at 24 mm CR length. The tissue that will form the tendon proceeds exclusively from the inferior endocardial cushion. The tendon establishes a close relationship with the base of the septum secundum during its path towards the right venous valve, carrying myocardial tissue out and forming the fasciculus limbicus inferior to muscular tissue. The tendon's relationship with the superior aspect of the atrioventricular node primordium during the first part of its path is of particular interest. The relationship is most intriguing when the node morphology is least defined. This would explain the possible embryogenesis of extra atrioventricular nodes. We also consider Todaro's tendon to be largely responsible for the development of the sinus band which protrudes as a crest inside the right atrium. This band is particularly well-developed in the fetal heart and provides an explanation for the large sub-Eustachian sinus cavity.


[Cutaneous non-Langerhans cells histiocytoses as cause of central diabetes insipidus].
The histiocytoses are rare diseases caused by alterations in the monocyte-histiocytic series with several clinical findings. Among the cutaneous syndromes of non-Langerhans cells, xanthoma disseminatum is the only disease of this group that has been classically associated to the central diabetes insipidus (CDI). The case reported describes a 30-year-old man that two years after presenting with CDI developed non confluent disseminated cutaneous brown papular lesions throughout the body. The histopathology, immunohistochemistry, and electronic microscopy were compatible with the diagnosis of non-Langerhans histiocytoses, suggesting the diagnosis of juvenile xanthogranuloma. The endocrine-metabolic evaluation did not show other alterations besides CDI in a 10-year follow up. The magnetic resonance of hypophysis showed absence of the pituitary hyperintense sign (bright spot). The radiologic and scinthigraphic evaluation of the bones did not show the presence of osteolytic lesions. This case prints out the importance of skin examination in cases of CDI and its association with cutaneous non-Langerhans histiocytoses in a broader spectrum, rather then restricted to the cases of xanthoma disseminatum.


Modular design principle based on compartmental drug delivery systems.
The current manufacturing solutions for oral solid dosage forms are fundamentally based on technologies from the 19th century. This approach is well suited for mass production of one-size-fits-all products; however, it does not allow for a straight-forward personalization and mass customization of the pharmaceutical end-product. In order to provide better therapies to the patients, a need for innovative manufacturing concepts and product design principles has been rising. Additive manufacturing opens up a possibility for compartmentalization of drug products, including design of spatially separated multidrug and functional excipient compartments. This compartmentalized solution can be further expanded to modular design thinking. Modular design is referring to combination of building blocks containing a given amount of drug compound(s) and related functional excipients into a larger final product. Implementation of modular design principles is paving the way for implementing the emerging personalization potential within health sciences by designing compartmental and reactive product structures that can be manufactured based on the individual needs of each patient. This review will introduce the existing compartmentalized product design principles and discuss the integration of these into edible electronics allowing for innovative control of drug release.


EMG-based Simultaneous Estimations of Joint Angle and Torque during Hand Interactions with Environments.
It is necessary to control contact force through modulation of joint stiffness in addition to the position of our limb when manipulating an object. This is achieved by contracting the agonist muscles in an appropriate magnitude, as well as, balancing it with contraction of the antagonist muscles. Here we develop a decoding technique that estimates both the position and torque of a joint of the limb in interaction with an environment based on activities of the agonist-antagonistic muscle pairs using electromyography in real time. The long short-term memory (LSTM) network that is capable of learning time series of a longtime span with varying time lags is employed as the core processor of the proposed technique. We tested both the unidirectional LSTM network and bidirectional LSTM network. A validation was conducted on the wrist joint moving along a given trajectory under resistance generated by a robot. The decoding approach provided an agreement of greater than 93% in kinetics (i.e. torque) estimation and an agreement of greater than 83% in kinematics (i.e. angle) estimation, between the actual and estimated variables, during interactions with an environment. We found no significant differences in performance between the unidirectional LSTM and bidirectional LSTM as the learning device of the proposed decoding method.


Methanolic effect of Clerodendrum myricoides root extract on blood, liver and kidney tissues of mice.
The present study deals with the toxicological investigations of chronic treatment with methanol root extract of Clerodendrum myricoides on body weight, hematological and biochemical parameters, and liver and kidney tissue sections. Mice treated with 100mg/kg bw/day of methanol extract showed no behavioral changes. However, there was a general reduction of activity in mice treated with 400mg/kg bw/day methanol extract and LD50 treated mice showed hypoactivity, grooming, prostration, piloroerection and irritation during administration towards the last days of the treatment period. The body weight gain difference in the 100mg/kg bw/day methanol extract treated group was not significant, while those of the others were significant as compared with the controls. Hematological results for the RBC count, HCT, MCV, MCH and MCHC in methanol extract treated mice showed no significant changes at both doses of treatments as compared with the controls. However, the value of lymphocytes was found significantly increased at 100 and 400mg/kg bw/day methanol extract. Similarly, HGB was significantly increased at 100 and 400mg/kg bw/day of methanol extract treated groups. On the other hand, WBC and platelets count were significantly decreased after treatment with 400mg/kg bw/day methanol extract. ALT, ALP, AST and urea values were significantly increased respectively at 100mg/kg bw/day and 400mg/kg bw/day methanol extract. Several histopathological changes of liver and kidney were observed in the extract treated mice as compared to the controls. Such histopathological changes observed in both liver and kidneys were inflammations and hydropic degenerations of hepatocytes at both doses of methanol. In addition, in the LD50 treated mice of the extracts there were also hemorrhages and signs in congestion of glomeruli of the kidney. chronic treatment with Clerodendrum myricoides extracts in mice causes reduction in body weight gain, damage to liver & kidney and changes in some hematological & biochemical parameters. It is therefore, suggested that further studies are needed for minimization of the observed side effects, while maintaining the claimed medicinal values of the extract.


Chia (Salvia hispanica L.), a Pre-Hispanic Food in the Treatment of Diabetes Mellitus: Hypoglycemic, Antioxidant, Anti-Inflammatory, and Inhibitory Properties of α-Glucosidase and α-Amylase, and in the Prevention of Cardiovascular Disease.
Diabetes mellitus (DM) is considered one of the major health diseases worldwide, one that requires immediate alternatives to allow treatments for DM to be more effective and less costly for patients and also for health-care systems. Recent approaches propose treatments for DM based on that; in addition to focusing on reducing hyperglycemia, they also consider multitargets, as in the case of plants. Among these, we find the plant known as chia to be highlighted, a crop native to Mexico and one cultivated in Mesoamerica from pre-Hispanic times. The present work contributes to the review of the antidiabetic effects of chia for the treatment of DM. The antidiabetic effects of chia are effective in different mechanisms involved in the complex pathogenesis of DM, including hypoglycemic, antioxidant, and anti-inflammatory mechanisms, and the inhibition of the enzymes α-glucosidase and α-amylase, as well as in the prevention of the risk of cardiovascular disease. The tests reviewed included 16 in vivo assays on rodent models, 13 clinical trials, and 4 in vitro tests. Furthermore, chia represents advantages over other natural products due to its availability and its acceptance and, in addition, as a component of the daily diet worldwide, especially due to its omega-3 fatty acids and its high concentration of dietary fiber. Thus, chia in the present work represents a source of antidiabetic agents that would perhaps be useful in novel clinical treatments.


Protective Effects of Sinomenine on CFA-Induced Inflammatory Pain in Rats.
BACKGROUND The purpose of this study was to investigate the effects of sinomenine (SIN) on CFA-induced inflammatory pain in rats, and to explore the underlying molecular mechanisms. MATERIAL AND METHODS To determine the potential influences of SIN in the pathogenesis of inflammatory pain, an inflammatory pain (IP) mouse model was established and rats were treated with SIN (30 mg/kg). Behavioral tests were used to assess the MWT and TWL of the rats. ELISA assay was used to detect the level of inflammation cytokines. Western blotting and qRT-PCR were carried out to measure the related protein and mRNA expression level, respectively. RESULTS We found that the MWT and TWL of the CFA-treated rats were markedly lower than that of the control rats, and they were significantly increased by SIN administration. The results suggest that IP rats had higher levels of TNF-α, IL-1β and IL-6 compared with the control rats. SIN administration decreased the levels of TNF-α, IL-1β, and IL-6. In addition, we found that p-p65 and p-p38 expression notably decreased after SIN treatment in IP rats. Moreover, the results showed that SIN inhibited Cox-2 and PGE2 expression in IP rats. CONCLUSIONS The data indicate that SIN had a protective role in inflammatory pain through repressing inflammatory mediators via preventing the p38MAPK-NF-κB pathway.


Osteopathic Manual Treatment for Pain Severity, Functional Improvement, and Return to Work in Patients With Chronic Pain.
Chronic non-cancer pain (CNCP) is associated with disability, poor quality of life (QOL), and failure to return to work (RTW). Osteopathic manipulative treatment (OMT) or osteopathic manual therapy (OMTh) are increasingly offered to patients with CNCP; however, the existing systematic reviews and meta-analyses in the literature that explore the effectiveness of OMTh have major limitations. To systematically evaluate the quality of evidence documenting the effectiveness of OMTh for patients with CNCP using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, and to evaluate the efficacy of OMTh in patients with CNCP through a meta-analysis of pooled data from previous studies. We searched online the databases Ovid, MEDLINE, Embase, OSTMED.DR, EMCare, Allied and Complementary Medicine Database (AMED), Physiotherapy Evidence Database (PEDro), and Cochrane Central Register of Controlled Trials (CENTRAL), as well as the bibliographic references of previous systematic review articles evaluating OMTh for pain severity, disability, QOL, or RTW outcomes. Eligibility included randomized controlled trials methodology, CNCP patients 18 years or older, use of previously validated assessment tools, use of OMTh as an active or combination intervention, and presence of a control or comparison group. We pooled studies based on the homogeneity between OMT comparator treatment and outcomes. Risk of bias was assessed with the Cochrane risk of bias tool and the quality of evidence was determined with GRADE. Sixteen randomized controlled trials (n=1158 patients) were eligible for data extraction. Moderate quality evidence showed that OMTh vs. standard care was significantly associated with a reduction in pain [standardized mean difference (95% CI)=[-.37 (-.58, -.17)] and disability [-.28 (-.46, -.10)], as well as improved QOL [.67 (.29, 1.05)]. Moderate quality evidence showed that OMTh plus exercise vs. exercise only was significantly associated with reduction in pain severity [-1.25 (-1.67, -.83)] and disability [-1.15 (-1.57, -.74)]. Moderate quality evidence showed that using visceral OMTh vs. general OMTh was significantly associated with reduction in pain severity [-.74 (-1.09, -.39)] and disability [-.52 (-.91, -.13)]. In comparison to physiotherapy, gabapentin, and OMTh plus gabapentin, OMTh did not show any significant effect for any of the outcomes. OMTh vs. standard care did not show significant improvement in RTW at 12 weeks, although the effect was significant at 8 weeks after OMTh. Moderate quality evidence suggests that OMTh is effective for CNCP patients. There was a significant association between visceral OMTh and reduced pain severity and disability. More robust, high-quality randomized controlled trials with larger sample sizes are required to further explore the effectiveness of the OMTh in the management of CNCP.


[Diagnostic image (303). A deeply tanned woman].
A 50-year-old woman complained of nausea, diarrhoea, tiredness and dizziness five weeks after a visit to Egypt. She was deeply tanned with hyperpigmentation on the metacarpophalangeal joints, palm of hand creases and buccal mucosa, due to Addison's disease.


Identification and verification of Hsp90-beta as a potential serum biomarker for lung cancer.
Hsp90-beta was investigated as prognostic factor because of its apparent association with tumorigenesis. The aim of this study was to investigate the expression of Hsp90-beta in lung cancer patients, to analyze the relationship with respect to the clinicopathological features and to assess whether Hsp90-beta as a potential serum marker for lung cancer. Expression of Hsp90-beta was examined using immunohistochemistry, in-situ hybridization, western blot and enzyme-linked immunosorbent assay. Sensitivities and specificities for Hsp90-beta serum test were determined using receiver operator characteristic curve and cutoff was defined based on 95% and 85% sensitivities. Lung cancer tissues exhibited higher expression of Hsp90-beta than the normal tissues (P < 0.05) and the serum Hsp90-beta of lung cancer patients also exhibited higher level than control groups (P < 0.05). Moreover, increased serum Hsp90-beta was significantly associated with the pathological grade and clinical stage of lung cancer patients (P < 0.05). Using receiver operator characteristic curve analysis, the cutoffs for distinguishing lung cancer from normal and benign groups were 1.155 and 1.158 ng/ml respectively. The sensitivities of Hsp90-beta for distinguishing lung cancer from normal and benign groups were 98.77% and 95.9%, and specificities were 88.33% and 72.7%. Up-regulation of serum Hsp90-beta was associated with pathological grade and clinical stage of lung cancer patients, which indicated that it could be considered molecular biomarker for diagnosis and prognosis of lung cancer.


Delivery of nitric oxide released from beta-Gal-NONOate activation by beta-galactosidase and its activity against Escherichia coli.
Beta-galactosyl-pyrrolidinyl diazeniumdiolates (beta-Gal-NONOate) is a new site-specific nitric oxide (NO)-releasing compound, which releases NO once activated by beta-galactosidase. In the present experiment, we used beta-Gal-NONOate as a bactericidal reagent to investigate its effectiveness of NO releasing. Through the evaluation of intracellular NO level and the comparison of survival of E. coli transformed with lacZ gene but treated with beta-Gal-NONOate and NONOate, respectively, it's evident that beta-Gal-NONOate had a higher bactericidal activity than conventional NONOate. While either beta-Gal-NONOate- or NONOate-treated E. coli without transferred lacZ gene showed low bactericidal activity. The results revealed that beta-Gal-NONOate was a potentially efficient NO donor, which took on a novel and promising approach to deliver NO into cells.


Simple and improved approaches to long-lasting, hydrophilic silicones derived from commercially available precursors.
Three types of commercially derived methylsilicone materials, Sylgard-184, Q(V)Q(H) (an MQ-based silicone containing no dimethylsiloxane, D units), and D(V)D(H) (a D-based silicone with no additives), were judiciously chosen to study the conditions under which long-lasting hydrophilicity after oxygen plasma treatment can be obtained. A 30 s plasma treatment time under controlled conditions was found to be optimal in terms of achieving the lowest initial advancing and receding contact angles of θ(A)/θ(R) = 10°/5° with undetectable surface damage. Vacuum treatment, a necessary step prior to plasma ignition that has been overlooked in previous studies, as well as room temperature curing were explored as means to remove low molecular weight species. For thin films (a few micrometers), 40 min vacuum treatment was sufficient to achieve low dynamic contact angles of θ(A)/θ(R) = 51-56°/38-43° on all three types of silicones measured more than 30 days after the plasma treatments. These values indicate superior hydrophilicity relative to what has been reported. The small and slow rise in contact angle over time is likely caused by the intrinsic nature of the silicone materials, i.e., surface reorientation of hydrophilic functional groups to the bulk and condensation of surface silanol groups, and is thus unavoidable. For thick films (∼1 mm), room temperature curing in addition to vacuum treatment was required to reduce hydrophobic recovery and to achieve long-lasting hydrophilicity. The final contact angles for thick samples were slightly higher than the corresponding thin film samples due to the greater "reservoir" depth and migration length for mobile species. In particular, Sylgard exhibited inferior performance among the thick samples, and we attribute this to the additives in its commercial formulation. Furthermore, unlike polydimethylsiloxane-based silicones, Q(V)Q(H) does not contain equilibration products of the Dn-type; its thin films perform as well as those of Sylgard and D(V)D(H). Silicones without D units are promising materials with intrinsically low hydrophobic recovery characteristics and long-lasting hydrophilicity after oxygen plasma treatment.


An Unusual Cause of Electrocardiographic Artefact: A Patient's Warming Blanket.
In electrocardiography, an electrocardiographic (ECG) artefact is used to indicate a misleading or confusing alteration in data or observation not arising from the heart. Although technological advancements have produced monitors that may provide accurate data and reliable heart rate alarms, interferences of the displayed electrocardiogram such as (but not limited to) electrical interference by outside sources, electrical noise from elsewhere in the body, poor contact and machine malfunction continue to occur. Artefacts are extremely common, and knowledge regarding them is necessary to prevent misinterpretation of a heart's rhythm, which can often lead to unnecessary and unwarranted diagnostic and interventional procedures. Here we report a case of ECG artefacts that occur owing to a patient's warming blanket and its consequences.


Ecosystem carbon stock influenced by plantation practice: implications for planting forests as a measure of climate change mitigation.
Uncertainties remain in the potential of forest plantations to sequestrate carbon (C). We synthesized 86 experimental studies with paired-site design, using a meta-analysis approach, to quantify the differences in ecosystem C pools between plantations and their corresponding adjacent primary and secondary forests (natural forests). Totaled ecosystem C stock in plant and soil pools was 284 Mg C ha(-1) in natural forests and decreased by 28% in plantations. In comparison with natural forests, plantations decreased aboveground net primary production, litterfall, and rate of soil respiration by 11, 34, and 32%, respectively. Fine root biomass, soil C concentration, and soil microbial C concentration decreased respectively by 66, 32, and 29% in plantations relative to natural forests. Soil available N, P and K concentrations were lower by 22, 20 and 26%, respectively, in plantations than in natural forests. The general pattern of decreased ecosystem C pools did not change between two different groups in relation to various factors: stand age (< 25 years vs. > or = 25 years), stand types (broadleaved vs. coniferous and deciduous vs. evergreen), tree species origin (native vs. exotic) of plantations, land-use history (afforestation vs. reforestation) and site preparation for plantations (unburnt vs. burnt), and study regions (tropic vs. temperate). The pattern also held true across geographic regions. Our findings argued against the replacement of natural forests by the plantations as a measure of climate change mitigation.


Significance, Errors, Power, and Sample Size: The Blocking and Tackling of Statistics.
Inferential statistics relies heavily on the central limit theorem and the related law of large numbers. According to the central limit theorem, regardless of the distribution of the source population, a sample estimate of that population will have a normal distribution, but only if the sample is large enough. The related law of large numbers holds that the central limit theorem is valid as random samples become large enough, usually defined as an n ≥ 30. In research-related hypothesis testing, the term "statistically significant" is used to describe when an observed difference or association has met a certain threshold. This significance threshold or cut-point is denoted as alpha (α) and is typically set at .05. When the observed P value is less than α, one rejects the null hypothesis (Ho) and accepts the alternative. Clinical significance is even more important than statistical significance, so treatment effect estimates and confidence intervals should be regularly reported. A type I error occurs when the Ho of no difference or no association is rejected, when in fact the Ho is true. A type II error occurs when the Ho is not rejected, when in fact there is a true population effect. Power is the probability of detecting a true difference, effect, or association if it truly exists. Sample size justification and power analysis are key elements of a study design. Ethical concerns arise when studies are poorly planned or underpowered. When calculating sample size for comparing groups, 4 quantities are needed: α, type II error, the difference or effect of interest, and the estimated variability of the outcome variable. Sample size increases for increasing variability and power, and for decreasing α and decreasing difference to detect. Sample size for a given relative reduction in proportions depends heavily on the proportion in the control group itself, and increases as the proportion decreases. Sample size for single-group studies estimating an unknown parameter is based on the desired precision of the estimate. Interim analyses assessing for efficacy and/or futility are great tools to save time and money, as well as allow science to progress faster, but are only 1 component considered when a decision to stop or continue a trial is made.


Brown adipose tissue triacylglycerol synthesis in rats adapted to a high-protein, carbohydrate-free diet.
Adaptation of rats to a high-protein, carbohydrate-free (HP) diet induced a marked reduction of brown adipose tissue (BAT) fatty acid (FA) synthesis from both 3H2O and [14C]glucose in vivo, with pronounced decreases in the activities of four enzymes associated with lipogenesis: glucose-6-phosphate dehydrogenase, malic enzyme, citrate lyase, and acetyl-CoA carboxylase. In both HP-adapted and control rats, in vivo incorporation of 3H2O and [14C]glucose into BAT glyceride-glycerol was much higher than into FA. It could be estimated that most of the glycerol synthetized was used to esterify preformed FA. Glycerol synthesis from nonglucose sources (glyceroneogenesis) was increased in BAT from HP rats, as evidenced by an increased capacity of tissue fragments to incorporate [1-14C]pyruvate into glycerol and by a fourfold increase in the activity of phosphoenolpyruvate carboxykinase activity, a key glyceroneogenic enzyme. The data suggest that high rates of glyceroneogenesis and of esterification of preformed FA in BAT from HP-adapted rats are essential for preservation of tissue lipid stores, necessary for heat generation when BAT is recruited in nonshivering thermogenesis.


Primary liver cancers with nonalcoholic steatohepatitis.
Nine patients with hepatocellular carcinoma (HCC) in nonalcoholic steatohepatitis (NASH) (six men and three women, median age 71.5 years) and one patient with intrahepatic cholangiocarcinoma (ICC), a 50-year-old man, in NASH are described. Most patients were associated with obesity, diabetes, hypertension, hypercholesterolemia, or hypertriglyceridemia. Seven patients showed insulin resistance and hyperinsulinemia. All patients except one met the criteria for metabolic syndrome. An HCC or ICC diagnosis was confirmed by tumor biopsy, surgery or autopsy except in two patients, who were diagnosed by computed tomography or hepatic angiography. The underlying liver disease was liver cirrhosis in six patients and chronic liver disease including mild hepatic fibrosis in four patients. The treatment of liver cancers consisted of surgery, radio-frequency ablation (RFA), transcatheter arterial embolization and transcatheter arterial infusion. Although the follow-up period was relatively short (median 27.5 months, average 32.1 months), all postoperative and post-RFA patients have not had a recurrence of HCC to date, except for one patient who had a palliative operation with intra-arterial infusion of anticancer drugs through an implanted reservoir port. Older age and liver cirrhosis are considered risk factors for HCC in NASH, and regular screening of these patients is necessary. Diabetes may contribute to the development of ICC in NASH. Curative therapy (surgery or RFA) and weight loss by the active therapeutic intervention (nutritional care and exercise therapy) after curative therapy may help us improve the prognosis of HCC in NASH.


A Pilot Randomized Controlled Trial of a Phone-based Intervention for Smoking Cessation and Relapse Prevention in the Postpartum Period.
To pilot-test a Phone-based Postpartum Continuing Care (PPCC) protocol developed from existing evidence-based approaches to address both postpartum smoking relapse among low-income women who quit smoking during pregnancy and postpartum smoking increase among those who had cut down. One hundred thirty low-income pregnant women who were current or recently quit tobacco smokers were recruited at their first prenatal appointment and randomized to either a Control (standard care) or Experimental (standard care + PPCC) group. An intent-to-treat analysis was conducted on biochemically verified data from 6 in-person interviews during pregnancy and postpartum. Feasibility with regard to recruitment, randomization, assessment, and implementation of PPCC were assessed, along with acceptability among the target population. PPCC was found to be feasible and acceptable to some participants, but not all. There were no significant differences in tobacco products per day at 6 months postpartum between groups; however, effect sizes differed at 6 weeks compared with 6 months postpartum. Similarly, there were no significant differences between groups in cessation rate (24% in each group) and past 90-day tobacco use (59 vs 55 days, for Control and Experimental groups, respectively). The PPCC intervention did not differentially reduce tobacco use postpartum compared with a controlled comparison group, though it was found to be acceptable among a subpopulation of low-income pregnant women and feasible with regard to recruitment, randomization, assessment procedures, and implementation. Further research is needed to identify an intervention that significantly improves smoking relapse rates postpartum.


Hyperhomocysteinemia due to levodopa treatment as a risk factor for osteoporosis in patients with Parkinson's disease.
Parkinson's disease (PD) patients have been reported to have lower bone mineral density (BMD) and higher fracture risk than individuals without PD. We assessed the association between hyperhomocysteinemia due to levodopa intake and BMD in PD patients. We measured serum homocysteine (Hcy) concentrations and BMD in the proximal femur and lumbar spine of PD patients aged 55 years or older (n = 95) and three age-/gender-matched control subjects (n = 285). The prevalence of osteoporosis was higher in both men (2.5-fold) and women (1.7-fold) with PD than in controls, and adjusted odds ratios for osteoporosis were 3.57 (95% confidence interval [CI], 1.25-10.20) for men and 2.54 for women (95% CI, 1.31-4.93) with PD. Serum Hcy concentrations were significantly higher in PD patients (median = 13.0 micromol/l) than controls (median = 11.5 micromol/l) (P = 0.005). Serum Hcy concentrations were independently associated with BMD values at all proximal femur sites in all subjects (P = 0.005 to 0.012). In PD patients, higher serum Hcy concentrations were independently associated with higher fracture risk (P = 0.029). PD patients taking higher doses of levodopa had significantly higher serum Hcy concentrations (P = 0.013), and greater levodopa intake was associated with lower BMD values in some areas (P = 0.008 to 0.029). In conclusion, these findings indicate that hyperhomocysteinemia due to levodopa intake may be one additional risk factor for osteoporosis and fracture in PD patients. Reducing Hcy may be a therapeutic modality for treating osteoporosis in PD patients taking levodopa.


The new Nucleus 5 model cochlear implant: a new surgical technique and early clinical results.
The Nucleus 5 or CI500 series cochlear implants are the new generation of Nucleus(®) cochlear implants. The receiver-stimulator package has a low profile without a pedestal projecting from the medial surface. This study aimed to demonstrate that the new design can facilitate a minimally invasive surgical approach, without the need for tie-down sutures and without a seat drilled for the receiver-stimulator package. The surgical technique involved placing the device directly on the surface of the bone in a secure sub-periosteal pocket with a channel drilled for the lead. A well or ramped seat was not drilled and tie-down sutures were not used. Measurements were taken from the transmitting coil to the tragus and the coil to the lobule immediately after implantation, and serially thereafter to document implant position. To date, over 200 implants have been performed with the Nucleus 5 device. In all cases, healing was uneventful without major complications. Of 137 patients with at least 6-week follow-up data, 8% showed a measurement change of greater than 1 cm whereas only 4.4% demonstrated any clinically evident movement. None had any complications relating to migration and none required repositioning of the device. The new design can safely be inserted without drilling a well for the receiver-stimulator package. Some early post-operative movement of the package was observed which caused no clinical impact. This modified surgical technique reduces the risk of intracranial complications and reduces operating time.


Detection of Merkel cell polyomavirus in formalin-fixed, paraffin-embedded tissue of Merkel cell carcinoma and correlation with prognosis.
Merkel cell carcinoma (MCC) is a rare, but highly aggressive primary cutaneous malignancy, showing neuroendocrine differentiation. In 2008, a novel member of the polyomavirus family, named Merkel cell polyomavirus (MCPyV) was identified in the genome of MCC tumors raising the possibility of an involvement in its pathogenesis. Due to the rarity of this tumor and current pathology practices, the most readily available tissue is archival formalin-fixed, paraffin-embedded (FFPE) material. In this study, we evaluated the presence of MCPyV in FFPE tissue and correlated its presence with tumor progression. Representative FFPE specimens from 18 tumors belonging to 14 patients with a diagnosis of MCC spanning the period from 2003 to 2008 were retrieved. Following DNA extraction, we performed PCR amplification and sequencing with four different MCPyV-specific primer pairs mapping within the T antigen and VP1 region. Overall, we detected MCPyV amplicons in 8/18 (44.4%) analyzed tumors from 7/14 (50%) cases. Two-year survival rate and median survival for the MCPyV-positive MCCs were 48% and 22.5 months, respectively and for the negative ones 69% and 51.3 months, respectively; however, the difference did not reach statistical significance (p=0.8). There was no significant correlation between the presence of the virus and the stage at presentation; however, tumors in the head and neck area had a lower frequency of viral positivity compared to those arising in the extremities suggesting a MCPyV-independent oncogenetic pathway perhaps, dependent on UV exposure, in a subset of these cases.


Environmental conditioning of incidence of tick-borne encephalitis in the south-eastern Poland in 1996-2006.
Epidemiological studies of tick-borne encephalitis (TBE) conducted in the Swietokrzyskie province (south- eastern Poland) in 1996-2006 demonstrated an increase in the number of registered TBE cases in the last 6 years of the study. The highest risk of TBE virus infections occurs in the summer-autumn period (seasonality factors 96.55% and 248.28%), i.e. in periods of the highest Ixodes ricinus activity in this region. An increased number of registered TBE cases were noted in the regions which provide ticks with favourable habitats and, simultaneously, where the TBE diagnosis and treatment for the inhabitants are more efficient. The increasing tendency in TBE incidence observed even in the non-endemic regions of the Swietokrzyskie province indicates the necessity of education in tick-borne disease prophylaxis and the need to elevate the level of public health care. Differences in the density and activity of various developmental Ixodes ricinus stages were observed in 4 localities in diverse biotopes located at different altitudes a.s.l. This justifies the necessity of environmental monitoring of the threats posed by ticks in various habitats, especially in those frequently visited by humans.


Expression and site-directed mutagenesis of hepatic glucokinase.
Soluble rat liver glucokinase was expressed at high levels at 22 degrees C in the BL21(DE3)pLysS strain of Escherichia coli. Aspartate-211 of yeast hexokinase has been implicated as a catalytic residue from crystallographic data. The corresponding residue in rat liver glucokinase, aspartate-205, was mutated to alanine and the expressed mutant had 1/500th of the activity of the wild type, with no change in the Km values for glucose or ATP. The results support a role for this residue as a base catalyst in the glucokinase reaction and, most probably, a similar role in the reactions of all members of the hexokinase family.


Expression of fibulin-1 predicted good prognosis in patients with colorectal cancer.
Fibulin-1, a multi-functional extracellular matrix protein, has been demonstrated to be involved in many kinds of cancer, while its function in colorectal cancer (CRC) is unclear. So here we investigated the expression and function of fibulin-1 in CRC. The expression of fibulin-1 mRNA variants named A, B, C and D in human colorectal cancer cells and colorectal cancer specimens were determined by RT-PCR. Fibulin-1 protein expression in colorectal cancer and normal colorectal mucosa tissue was evaluated by western blot, and was further validated by immunohistochemistry and enzyme-linked immunosorbent assay at serum level. The correlations between fibulin-1 expression and the clinicopathological features of colorectal cancers were evaluated by Chi-square test and Fisher's exact tests. The survival rates were calculated by the Kaplan-Meier method. Among fibulin-1 A-D variants, fibulin-1D is the predominant form expressed in colorectal cancer cell lines and colorectal cancer tissue, whereas only trace amounts of fibulin-1A-C were detectable. Fibulin-1 expressed higher in the CRC tissues and serum compared to normal control. So in the process of tumorigenesis of CRC, fibulin-1 is upregulated, however, high fibulin-1 expression showed longer survival time in colorectal cancer patients, especially in the patients with stage I/II. Low fibulin-1 expression was significantly associated with lymph node involvement, distant metastasis and Dukes' C and D stage (P < 0.05 for each). Fibulin-1 protein expression may be useful as a diagnosis and prognosis marker for colorectal cancer.


Bioaccumulation of arsenic compounds in aquacultural clams (Meretrix lusoria) and assessment of potential carcinogenic risks to human health by ingestion.
This study surveyed the total arsenic (As) and As species contents in clams (Meretrix lusoria) farmed in areas of hyperendemic blackfoot disease (BFD) in southwestern Taiwan. Total As and As species in sediment and pond water were also analyzed to examine the bioaccumulation of As in clams in their exposure environment. Moreover, potential carcinogenic risks associated with the ingestion of As in aquacultural clams were evaluated probabilistically. The average total As contents in medium-sized and small clams were 7.62 and 10.71 microg/g (dry wt), respectively. The content of the As species in this study was approximately 61% of the total As content. The other unquantified As species are possibly arsenocholine, arsenosugar and arsenolipid. The average ratios of inorganic As contents to total As contents in clams ranged from 12.3% to 14.0% which are much higher than that found in the farmed oyster (Crassostrea gigas), indicating that humans may expose to larger quantities of inorganic As by ingesting the same amount of clam as oyster. Using different ingestion rates derived by the average consumption method and the questionnaire method, the estimated risks to human health associated with consuming clams from the BFD area ranging from slightly to largely exceed the standard target risk. Based on the estimation of the TR model, a 0.18g/day-person of the safe ingestion rate of clams in the BFD region is recommended.