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FGF14 modulates resurgent sodium current in mouse cerebellar Purkinje neurons.
Rapid firing of cerebellar Purkinje neurons is facilitated in part by a voltage-gated Na+ (NaV) 'resurgent' current, which allows renewed Na+ influx during membrane repolarization. Resurgent current results from unbinding of a blocking particle that competes with normal channel inactivation. The underlying molecular components contributing to resurgent current have not been fully identified. Here, we show that the NaV channel auxiliary subunit FGF14 'b' isoform, a locus for inherited spinocerebellar ataxias, controls resurgent current and repetitive firing in Purkinje neurons. FGF14 knockdown biased NaV channels towards the inactivated state by decreasing channel availability, diminishing the 'late' NaV current, and accelerating channel inactivation rate, thereby reducing resurgent current and repetitive spiking. Critical for these effects was both the alternatively spliced FGF14b N-terminus and direct interaction between FGF14b and the NaV C-terminus. Together, these data suggest that the FGF14b N-terminus is a potent regulator of resurgent NaV current in cerebellar Purkinje neurons.
[Drug-related Anaphylactic Shocks: Under-reporting and PMSI.]
Aim. To evaluate the value of research in the case-mix database to identify cases of drug-related anaphylactic or anaphylactoid shock. Methods. Hospital stays of patients discharged from the University Hospital of Saint-Etienne between July 1st 2009 and June 30th 2012. Five codes from the international classification of diseases were selected: T88.6, T88.2, J39.3, T80.5 and T78.2. Results. Among 89 cases identified by the programme for medicalization of information system (programme de medicalisation des systemes d'information, PMSI), 40 were selected (45%). Of these, 16 cases were spontaneously reported by physicians. The unspecific code "anaphylactic shock unspecified (T78.2)" was coded for 57.5% of cases. Conclusion. The study confirms the interest of the PMSI as a tool for health monitoring, in addition to spontaneous reporting. Nevertheless, coding with insufficient precision about the causal role of the drug, requires a return to the medical record and so an important time consuming process.
Fever Evaluation Cost and Time to Treatment in the General Surgery Patient Can be Reduced by Using a Fever Practice Guideline.
OBJECTIVES: Evaluation of surgical patients with fever and leukocytosis (FAL) for an infection source often results in unnecessary laboratory and radiographic tests. The average cost of an FAL work-up ranges from $2200 to $5600. Lack of a systematic approach drives costs higher than necessary. We evaluated differences in time to treatment and costs using usual methods of FAL work-ups versus FAL work-ups using an established fever practice guideline (FPG). METHODS: In phase I, a retrospective electronic chart review was conducted for 82 adult surgery patients who underwent FAL work-ups to determine time from initial temperature presentation to fever treatment and total cost per fever evaluation. In phase II, an established FPG was applied to 30 intensive care unit patients from the original group of 82 using phase I data points. Differences in cost and time to treatment were compared using a paired t-test. RESULTS: Mean time to fever treatment decreased from 51.57 hours pre-FPG use to 11.23 hours afterward (p < 0.001), a 78% reduction in time to definitive treatment. Mean cost of FAL work-up decreased from $1,009.73 without FPG use to $399.00 with a 60% reduction in costs. CONCLUSIONS: Using a standardized FPG, FAL work-up time to treatment and cost can be significantly reduced.
Factors Associated With Obesity: A Case-Control Study of Young Adult Singaporean Males.
A case-control study among Singapore Armed Forces' newly enlisted Servicemen was conducted to examine factors associated with male obesity. Four hundred and fifty-nine individuals from the Obese Basic Military Training program were selected as "cases" (average age: 19.5, body mass index: 30.4) and another 340 individuals were selected from the Normal Basic Military Training program as "controls" (average age: 19.3, body mass index: 21.4). Information such as family background, socioeconomic factors, and lifestyle practices were captured using facilitator-led questionnaires. Several variables were significantly associated with obesity after adjustments for possible confounders. These include childhood obesity (odds ratio [OR] = 2.06), less than an hour of exercise per day (OR = 2.97), Indian ethnicity (OR = 2.22), specific education backgrounds (especially that of Institute of Technical Education-OR = 2.75), father's employment at nonmanagerial/professional jobs (OR = 1.52), mother's employment at managerial/professional jobs (OR = 2.02), regular smoking (OR = 1.73) and alcohol consumption (OR = 2.26), 6 hours or less of sleep (OR = 3.73), obesity among family members (OR = 1.86 for mother; OR = 2.98 for siblings), parental history of diabetes mellitus (OR = 2.22 for father; OR = 2.70 for mother), and eating at inexpensive local food stalls (OR = 1.82). Our study found that a number of factors, ranging from personal and family backgrounds to lifestyle choices, were significantly associated with obesity among male youths.
The Ketamine Analog Methoxetamine: A New Designer Drug to Threaten Military Readiness.
Recent years have seen the emergence and proliferation of "legal highs" or "designer drugs," compounds purposefully designed as legal alternatives to controlled substances of abuse. This article describes methoxetamine, a dissociative drug belonging to the arylcyclohexylamine class including phencyclidine and ketamine. Methoxetamine acts principally on the glutamatergic N-methyl-D-aspartate receptor and the serotonin receptor. It is sold as a white or off-white powder. Marketed as a "bladder friendly" alternative to ketamine, preliminary research suggests renal and cystic toxicity similar to ketamine. Methoxetamine is primarily ingested nasally, though also orally, intramuscularly, intravenously, and rectally. Users report dissociative features and, at higher doses, an "m-hole" experience akin to ketamine's "k-hole" described as extreme depersonalization and derealization. The 13 cases of acute methoxetamine toxicity described in the literature are summarized. The toxidrome consists of dissociation/delirium, sympathetic activation, and cerebellar symptoms. Methoxetamine is not detected in standard urine drug tests and there are no reliable laboratory findings. Management of acute methoxetamine toxicity is supportive, consisting of benzodiazepines, antiemetics, intravenous fluids, and respiratory support as indicated. Should methoxetamine conform to the observed 2-year lag of designer drugs migrating from Europe to the United States usage may increase in early 2014.
Use and Abuse of Prescribed Opioids, Central Nervous System Depressants, and Stimulants Among U.S. Active Duty Military Personnel in FY 2010.
OBJECTIVES: This study establishes rates of use/abuse of Schedule II-IV prescription medications in U.S. active duty military personnel, and characterizes correlates of such use/abuse. METHODS: All active duty personnel serving for 12 months during fiscal year 2010 were included. Data were obtained from medical and pharmacy claims and drug screening results. Logistic regression models were used to examine predictors of drug use, along with bivariate analyses to compare abuse of prescribed and illegal drugs. RESULTS: Nearly one-third of active duty service members received at least one prescription for opioids, central nervous system depressants, or stimulants, with 26.4% having received at least one prescription for opioids. About 0.7%, 1.4%, and 0.6% of the total force received >90-day prescriptions for opioids, central nervous system depressants, or stimulants, respectively. Battlefield injury, receipt of psychotropic medications, and substance abuse adverse events were predictive of >90-day supply of opioids. About 0.7% of the total force had documented known drug abuse for prescribed drugs compared to 0.4% for illegal drug abuse. CONCLUSIONS: We recommend systematic monitoring of prescriptions for controlled substances which may carry serious consequences, evaluation of the impact of controlled substances on military readiness, and examination of the rationale for prescribing controlled drugs.
Stellate Ganglion Block Used to Treat Symptoms Associated With Combat-Related Post-Traumatic Stress Disorder: A Case Series of 166 Patients.
OBJECTIVE: Report the successful use of stellate ganglion blocks (SGBs) in 166 active duty service members with multiple combat deployments experiencing anxiety symptoms associated with post-traumatic stress disorder (PTSD). BACKGROUND: Successful treatment of PTSD symptoms with SGB has been reported previously. This is the largest published case series evaluating SGB with a minimum of 3 months follow-up. METHODS: Following clinical interview including administration of the PTSD Checklist (PCL), 166 service members with symptoms of PTSD elected to receive a SGB. All patients received a SGB on the right side at the level of the sixth cervical vertebrae (C6). The PCL was administered the day before treatment to establish a baseline, repeated 1 week later, and then monthly out to 3 months. A positive response was considered to be an improvement in the PCL score by 10 or greater points. Follow-up PCL scores from 3 to 6 months were obtained and analyzed for 166 patients. RESULTS: In a military population with multiple combat deployments, over 70% of the patients treated had a clinically significant improvement in their PCL score which persisted beyond 3 to 6 months postprocedure. CONCLUSION: Selective blockade of the right cervical sympathetic chain at the C6 level is a safe and minimally invasive procedure that may provide durable relief from anxiety symptoms associated with PTSD.
Identifying Classes of Veterans With Multiple Risk Factors.
As researchers examine the efficacy of interventions that simultaneously target more than 1 symptom, it is important to identify ways to help guide research and program development. This study used electronic medical record data to examine the covariation of multiple risk factors regularly assessed among primary care patients. It also examined the health care utilization of those patients identifying where the health care system came in contact with them to help identify the ideal locations these interventions may be most often used. We obtained data for six risk factors, as well as the number of primary care, mental health, and emergency department visits, from Veteran patients with a primary care visit. There were three main groups of primary care patients, identified using latent class analysis and regression. Although the smallest group, the "High Treatment Need" group, had an increased probability of screening positive for all four risk factors, the post-traumatic stress disorder screen was a significant discriminator of this group from the others. Results show that this group had the greatest number of encounters in all health care locations suggesting significant opportunities for intervention. However, future research is needed to examine the current interventions offered and potential avenues where risk factors may be addressed simultaneously.
Injury Epidemiology of U.S. Army Special Operations Forces.
Musculoskeletal injuries have long been a problem in general purpose forces, yet anecdotal evidence provided by medical, human performance, and training leadership suggests musculoskeletal injuries are also a readiness impediment to Special Operations Forces (SOF). The purpose of this study was to describe the injury epidemiology of SOF utilizing self-reported injury histories. Data were collected on 106 SOF (age: 31.7 +/- 5.3 years, height: 179.0 +/- 5.5 cm, mass: 85.9 +/- 10.9 kg) for 1 year before the date of laboratory testing and filtered for total injuries and those with the potential to be preventable based on injury type, activity, and mechanism. The frequency of musculoskeletal injuries was 24.5 injuries per 100 subjects per year for total injuries and 18.9 injuries per 100 subjects per year for preventable injuries. The incidence of musculoskeletal injuries was 20.8 injured subjects per 100 subjects per year for total injuries and 16.0 injured subjects per 100 subjects per year for preventable injuries. Preventable musculoskeletal injuries comprised 76.9% of total injuries. Physical training (PT) was the most reported activity for total/preventable injuries (PT Command Organized: 46.2%/60.0%, PT Noncommand Organized: 7.7%/10.0%, PT Unknown: 3.8%/5.0%). Musculoskeletal injuries impede optimal physical readiness/tactical training in the SOF community. The data suggest a significant proportion of injuries are classified as preventable and may be mitigated with human performance programs.
A Review of Mild Traumatic Brain Injury Diagnostics: Current Perspectives, Limitations, and Emerging Technology.
Mild traumatic brain injury (mTBI) or concussion is a common battlefield and in-garrison injury caused by transmission of mechanical forces to the head. The energy transferred in such events can cause structural and/or functional changes in the brain that manifest as focal neurological, cognitive, or behavioral dysfunction. Current diagnostic criteria for mTBI are highly limited, variable, and based on subjective self-report. The subjective nature of the symptoms, both in quantity and quality, together with their large overlap in other physical and behavioral maladies, limit the clinician's ability to accurately diagnose, treat, and make prognostic decisions after such injuries. These diagnostic challenges are magnified in an operational environment as well. The Department of Defense has invested significant resources into improving the diagnostic tools and accuracy for mTBI. This focus has been to supplement the clinician's examination with technology that is better able to objectify brain dysfunction after mTBI. Through this review, we discuss the current state of three promising technologies-soluble protein biomarkers, advanced neuroimaging, and quantitative electroencephalography-that are of particular interest within military medicine.
Insomnia Treatment Experience and Preferences Among Veterans Affairs Primary Care Patients.
Insomnia is common, but undertreated, among primary care patients. Within the Veterans Health Administration (VA), increasing attention has been given to the treatment of insomnia within primary care settings, but little research has examined Veterans' treatment preferences. We examined preferences for sleep treatment among VA primary care patients. Participants (N = 126: 98% male, 89% white; M age = 60 years) completed a brief survey. On the basis of Insomnia Severity Index scores, 22% reported subthreshold and 13% moderate insomnia. Fifty percent reported having issues with sleep (falling asleep, staying asleep, or sleeping too much) in the past 12 months; among these, only 44% reported any discussion of medication (34%) or other strategies (32%) to improve sleep with medical providers. The most preferred treatment approach was to work it out on one's own, followed by consulting the primary care provider (PCP). The most preferred modality was a one-on-one meeting with the PCP, followed by a one-on-one meeting with the behavioral health provider. In conclusion, VA primary care patients preferred handling sleep problems on their own, but if seeking help, they preferred working with PCPs over behavioral health providers. The majority of Veterans preferred individual treatment and strategies other than medication.
Residual Injury, Appearance-Related Concerns, Symptoms of Post-Traumatic Stress Disorder, and Depression Within a Treatment-Seeking Veteran Sample.
This study explored the associations among injury-related appearance changes experienced during deployment/combat, symptom severity of post-traumatic stress disorder and depression, and body image distress within a treatment-seeking veteran population (n = 91). Thirty-three percent of the sample reported having an appearance-related residual injury experienced during combat or deployment (n = 30). A subsample, who completed the body image distress measure (n = 69), was divided into two groups: those with an appearance-related residual injury (n = 22) and those without an appearance-related residual injury (n = 47). Correlational analyses revealed significant, positive correlations between body image distress and depression symptom severity. Results also showed a trend relationship between body image distress and post-traumatic stress disorder symptom severity for those with an appearance-related residual injury although correlations were nonsignificant among these constructs for those without an appearance-related residual injury. Multiple regression analyses revealed that body image distress was a unique predictor of depression symptom severity, controlling for residual injury status. Implications of these findings for exploring the psychological impact of residual injury were discussed.
Bioassay-guided fractionation of extracts from Easter lily (Lilium longiflorum) flowers reveals unprecedented structural variability of steroidal glycoalkaloids.
Several Lilium species are nephrotoxic in cats (Felis silvestris catus), among them Easter lilies (Lilium longiflorum). Although clinical trials have been carried out, the causative toxic phytochemicals have not yet been identified. We thus aimed to determine the toxic constituents of Easter lily flowers applying a bioassay-guided approach based on a feline kidney cell line model. The bioassay-guided fractionation traced the observed cytotoxicity to a complex mixture of compounds that were tentatively identified as steroidal glycoalkaloids of the solasodine-type, based on multiple-fragmentation ion trap and high-resolution mass spectrometry. The glycoalkaloids in the active fraction possessed trisaccharide chains, and at least 16 different congeners could be separated using liquid chromatography-mass spectrometry. The two principal compounds were solasodine trisaccharides containing two hexose and one deoxy-hexose unit. In the remaining 14 analogues, one or two of the hydroxyl groups of the second hexose from the aglycone were acetylated. In addition, some of the analogues appeared to be carbonate esters. Esterification of steroidal glycoalkaloids in plants has only been reported once and was in accordance with higher antifungal activity of the acetylated versus the parent congener. Our pilot study shows that esterification of steroidal glycoalkaloids in Lilium species might be common resulting in an array of different analogues with largely unexplored structural variability and bioactivity.
Validation of the Chinese-language Brief Sensation Seeking Scale: Implications for risky riding behaviors of parental motorcyclists and their child passengers.
Motorcycles are the leading cause of road traffic deaths in the Western Pacific and Southeast Asia, where Mandarin Chinese is the most commonly used language. Sensation seeking (SS) is reported to correlate with many risky motor vehicle behaviors, and therefore a culture-adapted Chinese instrument is needed to assess this personality trait in Chinese-speaking motorcycling populations. The standard front and blinded-backward process was carried out to formulate the Chinese-language Brief Sensation Seeking Scale (C-BSSS). 193 parental motorcyclists who rode with their young children were interviewed concerning their SS levels, demographics, riding behaviors, and the driving/riding experiences. A random sample of 30 subjects was re-interviewed 1-2 weeks later to examine the test-retest reliability. Psychometric analyses revealed satisfactory item characteristics, internal consistency, intraobserver reliability, and interobserver reliability. Additionally, parental motorcyclists who had the following characteristics were more likely to be the high sensation seekers (SSers), including male, younger age, presenting risky motor vehicle behaviors of themselves (e.g., higher riding speeds, operating after drinking, using a mobile phone while operating, and receiving a traffic ticket), and carrying child passengers who demonstrated dangerous motorcycling behaviors (e.g., a younger age, non-helmeted, and overloaded). We conclude that the C-BSSS is a useful and reliable measure of SS for ethnic Chinese populations. This instrument may be helpful to develop the future prevention strategy of motorcycle injuries in Chinese parental motorcyclists and their young child passengers.
Sperm morphological normality under high magnification predicts laboratory and clinical outcomes in couples undergoing ICSI.
The objective of this study was to evaluate whether 'motile sperm organelle morphology examination' (MSOME) is correlated with the outcome of ICSI. A total of 14400 spermatozoa from 72 couples undergoing ICSI were analysed by MSOME (x6600) and graded into four groups: grade I, normal form and no vacuoles; grade II, normal form and lesser than or equal to 2 small vacuoles; grade III, normal form greater than 2 small vacuoles or at least one large vacuole and grade IV, large vacuole and abnormal head shapes or other abnormalities. The correlations between the proportion of morphologically normal spermatozoa (grade I + II) and ICSI outcomes were assessed. The proportion of grade I+ II spermatozoa was lower in patients with oligoasthenoteratozoospermia (OAT) compared to patients with other types of semen alterations (10.6% vs. 17.0%, p = 0.001). The proportion of grade I+ II spermatozoa was positively correlated with blastocyst formation (S = 8.31, R2:13.5%, p = 0.014) and implantation rates (S = 8.32, R2: 7.9%, p = 0.030). The proportion of grade I + II spermatozoa was higher in patients with ongoing pregnancy in comparison with those who had a miscarriage (23.2% vs. 10.8%, p = 0.007). Sperm morphological normality was lower in oligoasthenoteratozoospermia patients but correlated with blastocyst formation, implantation and miscarriage rates in couples undergoing ICSI. MSOME may be valuable in predicting ICSI outcomes.
Low pertussis toxin antibody levels in two regional cohorts of Canadian pregnant women.
Infants under 6 months of age are at greatest risk of mortality and severe morbidity from pertussis disease. Interventions that increase pertussis protection in newborns are therefore a clear public health imperative. The objective of this study was to assess maternal pertussis toxin antibody (anti-PT) level as a potential source of mother-to-child transfer of pertussis-associated antibodies that may reduce neonatal risk of pertussis disease. Anti-PT level was assessed in a 2013 cohort of pregnant women from two regions in two Canadian provinces, British Columbia and Nova Scotia. Basic demographics, health, and pertussis immunization history were collected, along with blood specimens. Anti-PT levels were compared for self-reported vaccination status and prior pertussis disease. To assess secular trend, a parallel analysis was also undertaken, using anonymized residual sera from a 1996-1997 cohort of pregnant women in British Columbia. A total of 169 pregnant women participated in the prospective study - 50 from Nova Scotia and 119 from British Columbia. The mean and median age of participants from both sites was 31 years of age (range 16-42 years). The lower limit of quantification of the anti-PT assay was 10 ELISA units per milliliter (EU/ml). Overall, 59% of women had anti-PT levels less than 10EU/ml and anti-PT level did not differ with time since last self-reported pertussis vaccination (chi2(2)=3.166, p=0.205). Among a 1996-1997 cohort of pregnant women in British Columbia, 51% had anti-PT levels less than 10EU/ml. Our study found that most pregnant women in two geographically disparate health regions in Canada have low residual anti-PT levels, may be vulnerable to pertussis infection themselves, and would unlikely be a source of passive ante- or postnatal transfer of anti-PT to their newborn.
Soluble ST2 in heart failure.
In addition to routine clinical laboratory tests (including natriuretic peptides and cardiac troponins), other biomarkers are gaining attention for their utility in heart failure (HF) management. Among them, soluble ST2 (sST2) a novel biomarker integrating inflammation, fibrosis, and cardiac stress has been included in the 2013 ACCF/AHA guideline for additive risk stratification of patients with acute and chronic HF. sST2 is an interleukin-1 (IL-1) receptor family member, is secreted into the circulation and functions as a "decoy" receptor for IL-33, inhibiting IL-33/ST2 signaling. Blood concentrations of sST2 are increased in various diseases such as inflammatory diseases and heart diseases and are considered a valuable prognostic marker in both conditions. sST2 lacks disease specificity and, therefore, is not a valuable marker for the diagnosis of HF. In acute and chronic HF, however, sST2 is strongly associated with measures of HF severity and poor outcome. Several studies in patients with HF indicate that serial measurement of sST2 has prognostic value and could have a potential role in future biomarker-directed therapy. In this review, the role of sST2 as a HF biomarker will be discussed, specifically addressing analytical considerations of measuring sST2 as well as the clinical applications of measurement of sST2 for the diagnosis, prognosis and monitoring of acute and chronic HF.
An Improved Flow Cytometric Immunobead Array to Detect Autoantibodies in Plasma from Patients with Immune Thrombocytopenic Purpura.
BACKGROUND: Autoantibodies against platelet glycoproteins (GPs) play an important role in immune thrombocytopenic purpura (ITP). This study was to develop an improved flow cytometric immunobead array (FCIA) assay to detect platelet autoantibodies in ITP patient plasma. METHODS: Plasma samples were isolated from 71 ITP patients and 136 non-ITP controls and incubated with platelets from normal individuals. After washing, platelets were lysed and the platelet lysates were incubated with polystyrene microbeads coupled with monoclonal antibodies against human GPs IX (SZ1), Ib (SZ2), IIIa (SZ21), IIb (SZ22), and P-selectin (SZ51). Platelet GP-autoantibody complexes were detected by flow cytometry using a FITC-labeled secondary antibody. RESULT: Autoantibodies against platelet GPIb, GPIIb, GPIIIa, GPIX and P-selectin were detected in plasma from ITP patients, as indicated by high mean fluorescent intensity values when microbeads with antibodies SZ1, SZ2, SZ21, SZ22, and SZ51 were used. In ROC analysis, values of the area under the curve were 0.74, 0.83, 0.80, 0.79 and 0.87, respectively. Compared with the previously reported assays, this new FCIA eliminated the need of isolating platelets from ITP patients without compromising assay sensitivity and accuracy in predicting ITP. CONCLUSION: This simplified FICA assay may be more suitable for ITP diagnosis in clinical laboratory settings.
ACOUSTIC TRAPPING FOR BACTERIA IDENTIFICATION IN POSITIVE BLOOD CULTURES WITH MALDI-TOF MS.
Matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is current-ly changing the clinical routine for identification of microbial pathogens. One important application is the rap-id identification of bacteria for the diagnosis of bloodstream infections (BSI). A novel approach based on acoustic trapping and an integrated selective enrichment target (ISET) microchip that improves the sample preparation step for this type of analysis is presented. The method is evaluated on clinically relevant samples in the form of Escherichia coli infected blood-cultures. It is shown that non-contact acoustic trapping enables capture, enrichment and washing of bacteria directly from the complex background of crude blood cultures. The technology replaces centrifugation-based separation with a faster and highly automated sample prepara-tion method that minimizes manual handling of hazardous pathogens. The presented method includes a solid phase extraction step that was optimized for enrichment of the bacterial proteins and peptides that are used for bacterial identification. The acoustic trapping-based assay provided correct identification in 12 out 12 cases of E. coli positive blood cultures with an average score of 2.19+/-0.09 compared to 1.98+/-0.08 when using the standard assay. This new technology opens up for the possibility to automate and speed up an important and widely used diagnostic assay for bloodstream infections.
Image Analysis for the Quantitative Comparison of Stress Fibers and Focal Adhesions.
Actin stress fibers (SFs) detect and transmit forces to the extracellular matrix through focal adhesions (FAs), and molecules in this pathway determine cellular behavior. Here, we designed two different computational tools to quantify actin SFs and the distribution of actin cytoskeletal proteins within a normalized cellular morphology. Moreover, a systematic cell response comparison between the control cells and those with impaired actin cytoskeleton polymerization was performed to demonstrate the reliability of the tools. Indeed, a variety of proteins that were present within the string beginning at the focal adhesions (vinculin) up to the actin SFs contraction (non-muscle myosin II (NMMII)) were analyzed. Finally, the software used allows for the quantification of the SFs based on the relative positions of FAs. Therefore, it provides a better insight into the cell mechanics and broadens the knowledge of the nature of SFs.
Gr-1+CD11b+ Immature Myeloid Cells (IMC) Promote Resistance of Pro-Inflammatory T Cells to Suppression by Regulatory T Cells in Atherosclerotic Apo E- Deficient Mice.
Accumulating evidence indicates that both defects in Treg numbers and/or function as well as resistance of effector T cells to suppression may contribute to the development of human chronic inflammatory diseases. However, which mechanism involved in the progression of atherosclerosis remains unclear. In this study, we evaluated the production and function of CD4+ inflammatory and regulatory T cells in atherosclerosis-prone mice. We found that the hyperactivity and unresponsiveness to Treg-mediated suppression of inflammatory CD4+ T cells occurred in the progression of atherosclerosis, though Treg cells were present in very large numbers and fully functional. We further found that Gr-1+CD11b+ immature myeloid cells were significantly accumulated in atherosclerotic Apo E-/- mice, and they promoted resistance of inflammatory CD4+ T cells to Treg-mediated suppression in vitro and in vivo. we further confirmed that Gr-1+CD11b+ immature myeloid cells produced high level of interleukin 6 which was at least partially responsible for inducing unresponsiveness of inflammatory CD4+ T cells to suppression via activation of Jak/Stat signaling pathway. Taken together, these findings might provide new insights to explore potential targets for immune therapeutic intervention in atherosclerosis.
Development of CpG-Oligodeoxynucleotides for Effective Activation of Rabbit TLR9 Mediated Immune Responses.
CpG-oligodeoxynucleotides (CpG-ODN) are potent immune stimuli being developed for use as adjuvants in different species. Toll-like receptor 9 (TLR9) is the cellular receptor for CpG-ODN in mammalian cells. The CpG-ODN with 18-24 deoxynucleotides that are in current use for human and mouse cells, however, have low activity with rabbit TLR9. Using a cell-based activation assay, we developed a type of CpG-ODN containing a GACGTT or AACGTT motif in 12 phosphorothioate-modified deoxynucleotides with potent stimulatory activity for rabbit TLR9. The developed CpG-ODN have higher activities than other developed CpG-ODN in eliciting antigen-nonspecific immune responses in rabbit splenocytes. When mixed with an NJ85 peptide derived from rabbit hemorrhagic disease virus, they had potent activities to boost an antigen-specific T cell activation and antibody production in rabbits. Compared to Freund's adjuvant, the developed CpG-ODN are capable of boosting a potent and less toxic antibody response. The results of this study suggest that both the choice of CpG-motif and its length are important factors for CpG-ODN to effectively activate rabbit TLR9 mediated immune responses.
Characterization of Clostridium difficile Isolates from Human Fecal Samples and Retail Meat from Pennsylvania.
Abstract A study was conducted to determine the prevalence of Clostridium difficile and characterize C. difficile isolates from human stool and retail grocery meat samples. Human stool samples (n=317) were obtained from a clinical laboratory and meat samples (n=303) were collected from 8 retail grocery stores from October 2011 through September 2012 from Centre County of Pennsylvania and were examined for C. difficile. C. difficile was isolated from 16.7% of stool samples (n=317) and 6.9%, 11.5%, 14.5%, and 7.8% of beef (n=72), pork (n=78), turkey (n=76), and chicken (n=77) samples, respectively. Six different toxin gene profiles were detected in all human and meat isolates of C. difficile based on the presence or absence of toxin genes tcdA, tcdB, and cdtA and cdtB. Interestingly, 75.6% of the human C. difficile isolates lacked any deletion in the tcdC gene (139-bp), whereas a 39-bp deletion was observed in 61.3% of the C. difficile strains isolated from meat samples. C. difficile from meat samples were more susceptible to clindamycin, moxifloxacin, vancomycin, and metronidazole than C. difficile isolates from human samples. Twenty-five different ribotypes were identified in human and meat C. difficile isolates. In conclusion, significant genotypic and phenotypic differences were observed between human and meat isolates of C. difficile; however, a few C. difficile isolates from meat-in particular ribotypes 078, PA01, PA05, PA16, and PA22 with unique profiles (toxin gene, tcdC gene size and antimicrobial resistance profiles)-were similar to human C. difficile isolates.
Hospital Disaster Response Using Business Impact Analysis.
Introduction The catastrophic Great East Japan Earthquake in 2011 created a crisis in a university-affiliated hospital by disrupting the water supply for 10 days. In response, this study was conducted to analyze water use and prioritize water consumption in each department of the hospital by applying a business impact analysis (BIA). Identifying the minimum amount of water necessary for continuing operations during a disaster was an additional goal. Problem Water is essential for many hospital operations and disaster-ready policies must be in place for the safety and continued care of patients. METHODS: A team of doctors, nurses, and office workers in the hospital devised a BIA questionnaire to examine all operations using water. The questionnaire included department name, operation name, suggested substitutes for water, and the estimated daily amount of water consumption. Operations were placed in one of three ranks (S, A, or B) depending on the impact on patients and the need for operational continuity. Recovery time objective (RTO), which is equivalent to the maximum tolerable period of disruption, was determined. Furthermore, the actual use of water and the efficiency of substitute methods, practiced during the water-disrupted periods, were verified in each operation. RESULTS: There were 24 activities using water in eight departments, and the estimated water consumption in the hospital was 326 (SD = 17) m3 per day: 64 (SD = 3) m3 for S (20%), 167 (SD = 8) m3 for A (51%), and 95 (SD = 5) m3 for B operations (29%). During the disruption, the hospital had about 520 m3 of available water. When the RTO was set to four days, the amount of water available would have been 130 m3 per day. During the crisis, 81% of the substitute methods were used for the S and A operations. CONCLUSION: This is the first study to identify and prioritize hospital operations necessary for the efficient continuation of medical treatment during suspension of the water supply by applying a BIA. Understanding the priority of operations and the minimum daily water requirement for each operation is important for a hospital in the event of an unexpected adverse situation, such as a major disaster. Suginaka H , Okamoto K , Hirano Y , Fukumoto Y , Morikawa M , Oode Y , Sumi Y , Inoue Y , Matsuda S , Tanaka H . Hospital disaster response using business impact analysis. Prehosp Disaster Med. 2014;29(5):1-8 .
Both Central and Peripheral Auditory Systems Are Involved in Salicylate-Induced Tinnitus in Rats: A Behavioral Study.
OBJECTIVE: This study was designed to establish a low dose salicylate-induced tinnitus rat model and to investigate whether central or peripheral auditory system is involved in tinnitus. METHODS: Lick suppression ratio (R), lick count and lick latency of conditioned rats in salicylate group (120 mg/kg, intraperitoneally) and saline group were first compared. Bilateral auditory nerves were ablated in unconditioned rats and lick count and lick latency were compared before and after ablation. The ablation was then performed in conditioned rats and lick count and lick latency were compared between salicylate group and saline group and between ablated and unablated salicylate groups. RESULTS: Both the R value and the lick count in salicylate group were significantly higher than those in saline group and lick latency in salicylate group was significantly shorter than that in saline group. No significant changes were observed in lick count and lick latency before and after ablation. After ablation, lick count and lick latency in salicylate group were significantly higher and shorter respectively than those in saline group, but they were significantly lower and longer respectively than those in unablated salicylate group. CONCLUSION: A low dose of salicylate (120 mg/kg) can induce tinnitus in rats and both central and peripheral auditory systems participate in the generation of salicylate-induced tinnitus.
Physical Activity versus Cardiorespiratory Fitness: Two (Partly) Distinct Components of Cardiovascular Health?
Physical activity (PA) and cardiorespiratory fitness (CRF) both have inverse relationships to cardiovascular (CV) morbidity and mortality. Recent position papers and guidelines have identified the important role of both of these factors in CV health. The benefits of PA and CRF in the prevention of CV disease and risk factors are reviewed. In addition, assessment methodology and utilization in the research and clinical arenas are discussed. Finally, the benefits, methodology, and utilization are compared and contrasted to better understand the two (partly) distinct components and their impact on CV health.
Physical Activity and Cardiorespiratory Fitness as Major Markers of Cardiovascular Risk: Their Independent and Interwoven Importance to Health Status.
The evolution from hunting and gathering to agriculture, followed by industrialization, has had a profound effect on human physical activity (PA) patterns. Current PA patterns are undoubtedly the lowest they have been in human history, with particularly marked declines in recent generations, and future projections indicate further declines around the globe. Non-communicable health problems that afflict current societies are fundamentally attributable to the fact that PA patterns are markedly different than those for which humans were genetically adapted. The advent of modern statistics and epidemiological methods has made it possible to quantify the independent effects of cardiorespiratory fitness (CRF) and PA on health outcomes. Based on more than five decades of epidemiological studies, it is now widely accepted that higher PA patterns and levels of CRF are associated with better health outcomes. This review will discuss the evidence supporting the premise that PA and CRF are independent risk factors for cardiovascular disease (CVD) as well as the interplay between both PA and CRF and other CVD risk factors. A particular focus will be given to the interplay between CRF, metabolic risk and obesity.
More than 10 Million Steps in the Right Direction: Results from the First American Heart Association Scientific Sessions Walking Challenge.
In 2013, the Global Congress theme at the American Heart Association (AHA) Annual Scientific Sessions was Physical Activity (PA). As a key component of the Congress, iHealth working in collaboration with AHA provided a Bluetooth-enabled wireless PA and sleep tracker to up to 2,000 Scientific Sessions attendees. Approximately 1,850 Scientific Sessions attendees registered for, received an PA tracker and participated in the Walking Challenge. More than 10 million steps were walked by participants (10,703,504) during the 2.5days of the Walking Challenge. This translates into almost 6000 miles walked (5976.3 miles) and 656,716 calories burned by participants during the Challenge. The Global Congress of PA held at Scientific Sessions 2013 not only extensively reviewed the science of PA as a powerful/independent and, most importantly, modifiable cardiovascular risk factor, but it also provided evidence from a fun and entertaining challenge that PA as a risk behavior can be assessed and targeted. We just took 10 million steps in the right direction. Join us and make your steps count!
Effects of Virtual Speaker Density and Room Reverberation on Spatiotemporal Thresholds of Audio-Visual Motion Coherence.
The present study examined the effects of spatial sound-source density and reverberation on the spatiotemporal window for audio-visual motion coherence. Three different acoustic stimuli were generated in Virtual Auditory Space: two acoustically "dry" stimuli via the measurement of anechoic head-related impulse responses recorded at either 1 degrees or 5 degrees spatial intervals (Experiment 1), and a reverberant stimulus rendered from binaural room impulse responses recorded at 5 degrees intervals in situ in order to capture reverberant acoustics in addition to head-related cues (Experiment 2). A moving visual stimulus with invariant localization cues was generated by sequentially activating LED's along the same radial path as the virtual auditory motion. Stimuli were presented at 25 degrees /s, 50 degrees /s and 100 degrees /s with a random spatial offset between audition and vision. In a 2AFC task, subjects made a judgment of the leading modality (auditory or visual). No significant differences were observed in the spatial threshold based on the point of subjective equivalence (PSE) or the slope of psychometric functions (beta) across all three acoustic conditions. Additionally, both the PSE and beta did not significantly differ across velocity, suggesting a fixed spatial window of audio-visual separation. Findings suggest that there was no loss in spatial information accompanying the reduction in spatial cues and reverberation levels tested, and establish a perceptual measure for assessing the veracity of motion generated from discrete locations and in echoic environments.
Adenoid Cystic Carcinoma in the Cavernous Sinus Diagnosed with the Endoscopic Endonasal Approach.
A 42-year-old woman presented with right oculomotor, abducens, and trigeminal palsy. Neuroimaging revealed a small lesion in the right cavernous sinus mimicking meningioma. Because the symptoms gradually worsened, the patient underwent an endoscopic endonasal transsphenoidal surgery for tumor biopsy. Histological examination of the surgical specimen revealed adenoid cystic carcinoma (ACC). Before and after the operation, no evidence of other primary lesions could be detected. The patient was treated with stereotactic radiosurgery (SRS). ACC in the cavernous sinus can be difficult to diagnosis before histological confirmation, because it is extremely rare as a primary lesion and resembles a cavernous sinus meningioma on neuroimaging studies. Two years after the first SRS, the tumor recurred along the trigeminal nerve and SRS was performed again. Our study illustrates that in case in which a lesion in the cavernous sinus progresses on neurological and neuroimaging studies, a biopsy should be taken to provide most accurate diagnosis and treatment.
A Case of Primary Dural Lymphoma: Diffuse Large B-Cell Type.
Primary leptomeningeal lymphoma is very rare disease that is a subtype of primary central nervous system (CNS) lymphoma. Primary dural lymphoma is a subentity of primary leptomeningeal lymphoma and arises from the dura mater without systemic disease. A 47-year-old woman presented with an indolent mass in the right frontal region. The patient's physical examination demonstrated no focal neurological abnormality. Magnetic resonance imaging (MRI) study revealed a mass lesion in the right frontal region. The patient underwent a right frontal craniectomy and removal of tumor. Histological diagnosis was diffuse large B-cell lymphoma (DLBCL). The patient received chemotherapy with rituximab, cyclophosphamide, adriamycin, vincristine, and prednisolone (R-CHOP protocol) every 3 weeks for six cycles. The patient was discharged without neurological deficit and no evidence of tumor recurrence. There was no systemic dissemination of disease 72 months after the surgery. Until the optimal standard management protocol is established, the treatment should be with an individualized multidisciplinary approach and continued follow-up and clinical surveillance are recommended for every patient.
Cerebral Infarction Caused by Pituitary Apoplexy: Case Report and Review of Literature.
Pituitary apoplexy followed by cerebral infarction is rare. In this report, we present a 42-year-old man who had been diagnosed of pituitary adenoma presented with a sudden onset of unconsciousness, left hemiplegia and right ptosis. Investigations revealed the development of pituitary apoplexy. The extension of tumor mass compressed the supraclinoid portion of the right internal carotid artery, resulting in the cerebral infarction in the right anterior and middle cerebral artery territory. Left anterior cerebral artery territory infarction was also found, which could be caused by vasospasm provoked by pituitary apoplexy. The patient underwent decompression surgery via transsphenoidal approach after four weeks' conservative treatment, and pathological examination revealed hemorrhage and necrosis of the pituitary adenoma. His symptoms improved within five months' follow-up. Since pituitary apoplexy producing cerebral infarction is rare, clinicians should be alert to that possibility, and delayed transsphenoidal surgery following conservative management with steroids is the appropriate management of such an occurrence.
Gross Total Resection of Large Cervical Intramedullary Ependymoma: Demonstration of Microsurgical Techniques.
In adolescents and young adults, ependymomas are the most common intramedullary tumors in the spinal cord.These tumors arise from ependymal cell lining the ventricles and spinal canal. The clinical presentation of intramedullary ependymomas are variable and nonspecific. They usually present with diffuse back or neck pain as a chief complaint. Upper and lower motor neuron deficits, numbness which typically progresses from distal to proximal, are other common symptoms. Gross total resection of ependymomas can achieve long-term tumor control with preservation of function. Here we present a 29-year old man who presented with progressive weakness of the left leg, bowel and bladder incontinence. During surgery, somatosensory evoked potentials (SSEPs) and motor evoked potentials (MEPs) were used and we achieved gross total resection while preserving the spinal cord. The patient made excellent recovery and all of his preoperative deficitis improved completely. He returned to work on postoperative 2-month.
Clinical Results of Anterior Odontoid Screw Fixation for Type II Odontoid Fractures.
AIM: In this study, 31 patients with a diagnosis of Type II odontoid fractures were reported. All patients were treated with anterior transodontoid screw fixation and clinical outcomes were reported. MATERIAL and METHODS: In this study, the retrospective clinical analysis of 31 patients with traumatic type II odontoid fractures who were treated through anterior transodontoid fixation in Neurosurgery Department at VKV American Hospital between 1998 and 2012 was performed. The age, sex, cause of injury, diagnosis time, neurological examination before and after surgery, follow-up period were evaluated. The neurological status of patients was classified according to the Frankel scale. RESULTS: In 4 patients, 2 transodontoid screws were inserted. The mean hospital stay was 3.35 days. Posterior occipito-cervical fusion was done in 1 patient due to the lack of fusion in the first operation. No vascular injury, screw malposition, infection, neurologic deterioration, or complications were observed during the peroperative and postoperative stage. The mean postoperative follow-up period was 36 months after surgery. Radiological imaging of patients were performed at the early and late postoperative stage. CONCLUSION: We found satisfying fusion rates and better patient comfort during the postoperative period. We think that stabilization and fusion through a transodontoid screw is a minimal invasive method.
Choice for the Removal of Bloody Cerebrospinal Fluid in Postcoiling Aneurysmal Subarachnoid Hemorrhage: External Ventricular Drainage or Lumbar Drainage?
AIM: External ventricular drainage (EVD) and lumbar drainage (LD) are the most widely used procedures for continued bloody cerebrospinal fluid drainage. Each has his own advantages and disadvantages. Here, we compared complications and clinical outcomes in patients with World Federation of Neurosurgical Societies (WFNS) grade III aneurysmal subarachnoid hemorrhage (aSAH) who underwent coil placement followed by EVD or LD. MATERIAL and METHODS: In this prospective, controlled study, all patients with aSAH classified as WFNS grade III who underwent coil placement at our institution were divided randomly into 2 groups: the EVD group and the LD group. The ratios of intracerebral hemorrhage, vasospasm, infection, duration of catheter placement, hydrocephalus, and Glasgow outcome scale (GOS) after 2 months of onset were analyzed between the 2 groups. RESULTS: A total of 148 patients (mean age 56.8 years) were enrolled in this study. Seventy-six patients were assigned to the EVD group, and 72 patients were assigned to the LD group. The average time interval from stroke onset to surgery was 35.1 h. Compared with the EVD group, the LD group had a lower incidence of intracerebral hemorrhage, slightly higher rates of infection and hydrocephalus, and similar vasospasm and chronic hydrocephalus rates, durations of catheter placement, and GOS scores at 2 months after onset. CONCLUSION: In order to improve the clinical outcomes of patients with aSAH, we suggest that LD is better than EVD for patients with WFNS grade III aSAH who underwent coil placement.
Experience with the Second-Generation Wallis Interspinous Dynamic Stabilization Device Implanted in Degenerative Lumbar Disease: A Case Series of 50 Patients.
AIM: This study aimed to evaluate the short- to medium-term outcomes of the second-generation Wallis interspinous dynamic stabilization device for treatment of lumbar degenerative disease. MATERIAL and METHODS: Fifty patients with lumbar degenerative disease treated from August 2007 to September 2009 were included in this retrospective study. The Japanese Orthopedic Association (JOA) score and the Oswestry Disability Index (ODI) were used for therapeutic efficacy evaluation. Odom's criteria were used to evaluate postoperative outcome with regard to symptoms. Anteroposterior X-rays were obtained after surgery. All patients were followed up for 2 years. RESULTS: Based on Odom's criteria, 22, 24 and 4 patients had excellent, good, and fair results respectively. The JOA score at 3, 12, and 24 months after surgery was significantly higher than before surgery (all p < 0.001), and the ODI score at 3, 12, and 24 months after surgery was significantly lower than before surgery (all p < 0.001). The posterior intervertebral disc height and the neural foramina height at 12 and 24 months after surgery was significantly higher than before surgery (both p < 0.001). CONCLUSION: Implantation of the second-generation Wallis interspinous dynamic stabilization device produced satisfactory clinical outcome at short- and medium-term follow-up in patients with lumbar degenerative disease.
Balloon-Assisted Endovascular Treatment of Intracranial Dural Arteriovenous Fistulas.
AIM: Most dural arteriovenous fistulas (DAVFs) can be treated safely and effectively with endovascular Onyx embolization. Balloon-assisted endovascular Onyx embolization of intracranial DAVFs is especially suitable for arterial protection and arterial flow reduction in complicated DAVFs. We systemically report our experience in the use of arterial balloon for Onyx embolization of DAVF and evaluate the clinical outcomes. MATERIAL and METHODS: Clinical records of 12 consecutive DAVFs patients (five women, seven men) treated with arterial balloon-assisted endovascular Onyx embolization were retrospectively collected to analysis their presenting symptoms, angiographic features, endovascular treatments, and clinical outcomes. RESULTS: Six patients presented with cortical venous reflux (CVR). Nine patients underwent transarterial (TA) and 3 patients underwent transvenous (TV) embolization. The balloons were used in 3 types of approach: arterial protection in TA embolization, arterial flow reduction in TA embolization and arterial protection in TV approach. Angiograms demonstrated complete obliteration of the fistula in 11 patients and partial occlusion in one. One patient had Onyx embolization-related complication of transient hemi-facial hypoesthesia. CONCLUSION: The Arterial balloon provides protection of intracranial artery and reduction of arterial flow in Onyx embolization of DAVF. This complementary method brought high cure rate.
Idiopathic Scoliosis.
Scoliosis refers to curves exceeding 10 degrees observed through posterioanterior direct radiography. In fact, the diagnosis for idiopathic scoliosis is accepted to exclude already available causes. The aim of this paper was to review the etiopathogenesis, classification systems and the treatment management of idiopathic scoliosis. A search in the National Library of Medicine (Pubmed) database using the key words 'idiopathic' and 'scoliosis' was performed. For the literature review, papers concerning the etiopathogenesis, classification and treatment were selected among these articles. A search in the National Library of Medicine (Pubmed) database using the key words 'idiopathic' and 'scoliosis' yielded 4518 articles published between 1947 and 2013. The main hypothesis put forward included genetic factors, hormonal factors, bone and connective tissue anomalies. King, Lenke, Coonrad and Peking Union Medical College (PUMC) classifications were the main classification systems for idiopathic scoliosis. Exercise, bracing and anterior, posterior or combined surgery when indicated are the choices for the treatment. Every idiopathic scoliosis case has to be managed to its own characteristics. It is the post-operative appearance that the surgeons are perhaps the least interested but the adolescent patients the most interested in. The aim of scoliosis surgery is to restore the spine without neurological deficit.
Efficacy and Safety of Carmustine Wafers in the Treatment of Glioblastoma Multiforme: A Systematic Review.
The aim of this study was to a conduct a systematic review of carmustine wafers (Gliadel wafers) for the treatment of glioblastoma multiforme (GBM) to assess the survival benefit and safety of this therapy. The inclusion criteria were 1) prospective or retrospective clinical trial; 2) patients who had undergone resection for primary GBM or first recurrence of GBM with or without carmustine wafer implantation; 3) patients with malignant gliomas that included GBM; 4) outcomes including survival analysis of the GBM population. Six trials met the inclusion criteria; four were randomized, controlled trials and two were retrospective. The trials varied with regard to the type of patients and interventions. In three of the trials, patients with GBM who received carmustine wafers had significantly longer median survival than patients who did not receive wafers. Implantation of carmustine wafers did not significantly improve progression-free survival. Carmustine wafers did not increase adverse effects. This systematic review suggests that carmustine wafers have demonstrated promise as an effective and tolerable treatment in comparison to other treatment strategies in patients with GBM.
Oxidative Stress Is Associated with an Increased Antioxidant Defense in Elderly Subjects: A Multilevel Approach.
BACKGROUND: Studies of associations between plasma GSH-Px activity and cardiovascular risk factors have been done in humans, and contradictory results have been reported. The aim of our study was to assess the association between the scavenger antioxidant enzyme glutathione peroxidase (GSH-Px) activity in plasma and the presence of novel and classical cardiovascular risk factors in elderly patients. METHODS: We performed a cross-sectional study with baseline data from a subsample of the PREDIMED (PREvencion con DIeta MEDiterranea) study in Spain. Participants were 1,060 asymptomatic subjects at high risk for cardiovascular disease (CVD), aged 55 to 80, selected from 8 primary health care centers (PHCCs). We assessed classical CVD risk factors, plasma oxidized low-density lipoproteins (ox-LDL), and glutathione peroxidase (GSH-Px) using multilevel statistical procedures. RESULTS: Mean GSH-Px value was 612 U/L (SE: 12 U/L), with variation between PHCCs ranging from 549 to 674 U/L (Variance = 1013.5; P<0.001). Between-participants variability within a PHCC accounted for 89% of the total variation. Both glucose and oxidized LDL were positively associated with GSH-Px activity after adjustment for possible confounder variables (P = 0.03 and P = 0.01, respectively). CONCLUSION: In a population at high cardiovascular risk, a positive linear association was observed between plasma GSH-Px activity and both glucose and ox-LDL levels. The high GSH-Px activity observed when an oxidative stress situation occurred, such as hyperglycemia and lipid oxidative damage, could be interpreted as a healthy defensive response against oxidative injury in our cardiovascular risk population.
CTLA4-Ig Preserves Thymus-Derived T Regulatory Cells.
BACKGROUND: CTLA-4 immunoglobulin fusion proteins (CTLA4-Ig) suppress immune reactions by blocking the T-cell costimulatory CD28-CD80-86 pathway and are used in clinical trials for diseases featuring exaggerated T-cell reactivity including autoimmune diseases and allograft rejection. However, because CTLA4-Ig has been suspected to interfere with T regulatory (Treg) cell homeostasis and function, recently, substantial concerns on CTLA4-Ig's potentially antitolerogenic effects have been raised. METHODS: We tested immunoregulatory CTLA4-Ig explicitly for its effect on Treg cell numbers, frequencies and function in an in vitro murine major histocompatibility complex mismatched setting using C57BL/6 bone marrow-derived dendritic cells as stimulators of allogeneic Balb/c Foxp3 T cells, which allowed for tracing Treg cells in a straightforward fashion. RESULTS: The presence of CTLA4-Ig in mixed leukocyte reactions-while dampening the global proliferative response of allostimulated Balb/c T cells-resulted in a relative increase of the frequency of thymus-derived CD4CD25Foxp3 Treg cells with intact suppressive activity. This relative increase was caused by a selective inhibitory effect of CTLA4-Ig on proliferating conventional T cells, whereas the proliferative capacity of Treg cells in cell cultures remained unaffected. Additionally, in the presence of CTLA4-Ig, the frequency of apoptosis was decreased in these cells. CONCLUSION: Our findings unequivocally demonstrate that CTLA4-Ig does not negatively affect Treg cell frequencies and function in vitro.
Association between alcohol-cue modulated startle reactions and drinking behavior in alcohol dependent patients - results of the PREDICT study.
Previous research on alcohol dependent patients has shown that variations in eyeblink startle response can be used as an indicator of their emotional responses to alcohol-related stimuli. Postulating that reactions on substance associated stimuli are controlled by either a negative or a positive affective processing system, we expect that abstinent alcoholics react differently (within-group) in the emotional evaluation of alcohol cues. Furthermore, we assumed the startle response to covary with medication response to acamprosate and naltrexone. We measured 74 detoxified inpatients' acoustic startle responses while they were being presented with alcohol-related images as well as affectively negative, neutral, and positive pictures before they were randomized to pharmacotherapy. Group-mean startle peak amplitudes were lowest for alcohol-related cues. The relative startle response (alcohol cues set in relation to the other stimulus categories) did not correlate with craving for alcohol (OCDS) or alcohol cue induced self-ratings of arousal, valence and craving. Patients with a lower percentage of abstinent days in the 90days prior to the last drinking day showed a lower ("more appetitive") startle response to alcohol cues. A survival analysis using the time to first heavy drinking day as the survival criterion revealed a significant interaction between alcohol-cue startle responses and medication type. The results indicate that the psycho-physiological measure of emotional evaluation of alcohol cues includes unconscious processing not reflected by conscious self-ratings. Furthermore, our result of a differential medication effect may encourage further studies to use biological characteristics to stratify patients as a step towards individualized treatment for alcohol dependence.
Can Continuous Subcutaneous Insulin Infusion Improve Health-Related Quality of Life in Patients with Shwachman-Bodian-Diamond Syndrome and Diabetes?
Abstract We report the first case of the use of continuous subcutaneous insulin infusion (CSII) in a patient with Shwachman-Bodian-Diamond syndrome (SBDS) and diabetes. An Italian boy received diagnosis of SBDS at the age of 7 months (SBDS gene mutation: c.183-184TA-->CT and c.258+2T-->C in compound heterozygous). The patient presented an impaired psychosocial functioning with difficulties in mental health, body pain experiences, attention deficit disorder, somatic complaints, behavioral and social problems. Total Intelligence Quotient (T-IQ) was within the normal range for age (T-IQ=109). The patient developed clinical diabetes at the age of 13 years (glycemia 282 mg/dL at 120 min of oral glucose tolerance test, glycosylated hemoglobin level of 7.5%, anti-beta-cell antibodies negative; glucagon test yielding a C peptide level at zero-time of 1.5 ng/mL and at 6 min of 2.0 ng/mL). Multiple daily injection therapy with insulin was started. Nevertheless, because of a relevant needle phobia and the recurrent hypoglycemia due to poor nutrition secondary to depression, after 3 years the patient started CSII. After 12 months a new evaluation showed (1) better social adaptation, (2) meliorated self-esteem and self-efficacy, (3) reduced psychosocial suffering, and (4) improved health-related quality of life, assessed by the Pediatric Quality of Life Inventory version 3.0 Diabetes Module. Thus CSII seems to be crucial to improve health-related quality of life in patients affected by diabetes and genetic disorders.
The complete mitochondrial genome of the spinner shark Carcharhinus brevipinna.
Abstract The mitochondrial genome of the spinner shark (Carcharhinus brevipinna) was determined in this study. It was 16,706 bp in length with the typical genomic organization and gene order as most vertebrates. Whole nucleotide base composition was 31.3% A, 25.3% C, 13.2% G and 30.1% T. Among the protein-coding genes, there are three overlapping reading-frames on the same strand, while one of it on the opposite strand. Two start codons (ATG and GTG) and three stop codons (AGG, TAG and TAA/T) were used in 13 protein-coding genes. The 22 tRNA ranged from 67 (tRNA-Cys and tRNA-Ser2) to 75 bp (tRNA-Leu1) in length. Only the tRNA-Ser2 could not fold into the typical clover-leaf structure, which lost the dihydrouridine (DHU) arm and replaced by a simple loop. The control region was 1064 bp in length and showed a higher AT content (66.8%) than the average value of whole mitogenome (61.4%).
Circulating microRNAs in patients with polycystic ovary syndrome.
Aim: To explore the pattern of expression of circulating miRNAs in patients with polycystic ovary syndrome (PCOS). Materials and methods: Microarray and qRT-PCR were used to investigate circulating miRNAs in PCOS during clinical diagnosis. The targets of dys-regulated miRNAs were predicted using bioinformatics, followed by function and pathway analysis using the databases of Gene Ontology and the KEGG pathway. Results: BMI, triglyceride, HOMA-IR, Testosterone and CRP levels were significantly higher, while estradiol was significantly lower in PCOS than in control groups. After SAM analysis, 5 circulating miRNAs were significantly up-regulated (let-7i-3pm, miR-5706, miR-4463, miR-3665, miR-638) and 4 (miR-124-3p, miR-128, miR-29a-3p, let-7c) were down-regulated in PCOS patients. Hierarchical clustering showed a general distinction between PCOS and control samples in a heat map. After joint prediction by different statistical methods, 34 and 41 genes targeted were up-and down-regulated miRNAs, in PCOS and controls, respectively. Further, GO and KEGG analyses revealed the involvement of the immune system, ATP binding, MAPK signaling, apoptosis, angiogenesis, response to reactive oxygen species and p53 signaling pathways in PCOS. Conclusions: We report a novel non-invasive miRNA profile which distinguishes PCOS patients from healthy controls. The miRNA-target database may provide a novel understanding of PCOS and potential therapeutic targets.
Editorial: Nanoscience Advances in Rheumatology and Immunology.
Improved understanding of the molecular mechanisms leading to autoimmunity have resulted in advances toward the diagnosis, management, and treatment of rheumatologic diseases. Many of these mechanisms overlap with inflammatory disease states and cancer, where nanoscience is increasingly being applied for pharmacologic and diagnostic purposes [1-6]. Additionally, nanoscience has furthered the study of cellular interactions within the in situ environment, thereby increasing the understanding of these complex, multi-system disorders [1, 7-9]. This Hot Topics review series intends to provide an overview of nanoscience, as it pertains to rheumatology and immunology, highlighting emerging technologies applied to rheumatologic models and with the potential for human use. This mini-series has a particular focus on imaging and drug delivery applications pertinent to autoimmune conditions as well as reviewing the pharmacology, clearance, and biodistribution of nanomaterials in inflammatory conditions and by immune cells. Nanotechnology involves the synthesis and utilization of materials - including but not limited to metals, oxides, lipids, polymers -- in the nanoscale range (1 to 1000 nm). Nanomaterial composition as well as the size, shape, charge, and surface coating contribute to unique nanomaterial characteristics that can be used for a variety of biomedical applications [1, 10]. Each of these independent variables influences the application, biodistribution, metabolism, and as anticipated, bystander toxicity. In the current era of biologic and monoclonal antibody-directed therapy for autoimmune disease, clinical and radiographic markers are becoming less sensitive to detect subtle disease activity, and there is an increasing demand for improved diagnostic imaging techniques and contrast agents. Because of the large surface to volume ratio and ease of functionalization, nanoparticles are particularly well suited for advanced imaging [1, 11] and may fill this gap. In the review by Rogers et al., the authors cite several examples of novel nanoparticle-based imaging strategies to identify inflammation and rheumatic disease in the early, pre-clinical stages and even at the cellular level [7, 12, 13]. Coupled with targeted molecular markers, multimodal nanoparticles carrying larger payloads than traditional contrast materials have the ability to increase the sensitivity and specificity of disease monitoring while retaining the anatomic detail of traditional imaging. In addition to the advantages nanomaterials provide as novel contrast agents in imaging, they can also be utilized in vaccination strategies or as drug carriers for targeted delivery to tissues [1, 14, 15]. This technology may improve upon current treatments or could provide therapies for some rheumatic illness, such as systemic lupus erythematosus or scleroderma, for which there are limited therapeutic options. In the review authored by Henderson and colleagues, a wide range of nanoparticle platforms including varied material composition and conjugated strategies are described as approaches to control the processes of drug release, targeted delivery, and degradation [16-19]. There is precedence for FDA approval of nanoparticle-based drug delivery for the treatment of infection and cancer in humans, and in some instances, this has decreased systemic toxicity while improving efficacy [20]. This same balance between targeted therapy and untoward side effects will need to be applied to medications designed for the rheumatic illnesses as the field advances. Many nanomaterials in the living organism are phagocytized by cells of the reticuloendothelial system, and in particular, these include the monocyte/macrophage cellular lineage [21]. In the review by Song et al., the authors discuss the complex interactions between nanoparticles and immune cells since this interplay can affect particle distribution, clearance, and potentially lead to off-target effects such as immune stimulation. Ultimately, these relationships between nanoparticles and immune system activation versus suppression will need to be clarified if their applications extend into treating primary disorders of the immune system such as autoimmunity. In Rheumatology, the role of nanoparticle based imaging, treatment-derived strategies, and pharmacokinetics and biodistribution has largely been conducted in preclinical models. Further in depth studies are needed to translate these exciting findings from animals to patients with rheumatologic or autoimmune conditions. Although some extrapolation can be made from the cancer and infectious disease arena, the chronicity of rheumatic disease will make clarifying the potential effects of nanomaterials in both short- and long-term applications germane to those patients as well as to others with chronic illness.
Chemotherapy or Targeted Therapy as Second-Line Treatment of Advanced Gastric Cancer. A Systematic Review and Meta-Analysis of Published Studies.
Chemotherapy is a cornerstone in treatments of gastric cancer, but despite its benefit, less than 60% of patients receive salvage therapy in clinical practice. We performed a systematic review and meta-analysis based on trial data on the role of second-line treatment of advanced gastric cancer. MEDLINE/PubMed and Cochrane Library were searched for randomized phase III trials that compared active therapy to best supportive care in advanced gastric cancer. Data extraction was conducted according to the PRISMA statement. Summary HR for OS was calculated using a hierarchical Bayesian model and subgroup analysis was performed based on baseline Eastern Cooperative Oncology Group Performance Status (ECOG) performance status (0 vs. 1 or more). A total of 1,407 patients were evaluable for efficacy, 908 were treated in the experimental arms, with chemotherapy (231 pts) or with targeted therapies (677 pts). The risk of death was decreased by 18% (HR = 0.82; 95% CI, 0.79-0.85; posterior probability HR>/=1: <0.00001) with active therapies. Chemotherapy and ramucirumab were able to decrease this risk by 27% and 22%, respectively. No differences were found between chemotherapy and ramucirumab. In patients with ECOG = 0 a greater benefit was found for chemotherapy with a reduction of the risk of death by 43% and no benefits were found for ramucirumab or everolimus. In patients with ECOG = 1 or more a significant reduction of the risk of death by 32% was reported in patients treated with ramucirumab, even if no significant difference was reported between chemotherapy and ramucirumab. This analysis reports that active and available therapies are able to prolong survival in patients with advanced gastric cancer with a different outcome based on initial patient's performance status. New trials based on a better patient stratification are awaited.
Risk Factors for Acute Stroke among South Asians Compared to Other Racial/Ethnic Groups.
BACKGROUND: Studies of racial/ethnic variations in stroke rarely consider the South Asian population, one of the fastest growing sub-groups in the United States. This study compared risk factors for stroke among South Asians with those for whites, African-Americans, and Hispanics. METHODS: Data on 3290 stroke patients were analyzed to examine risk differences among the four racial/ethnic groups. Data on 3290 patients admitted to a regional stroke center were analyzed to examine risk differences for ischemic stroke (including subtypes of small and large vessel disease) among South Asians, whites, African Americans and Hispanics. RESULTS: South Asians were younger and had higher rates of diabetes mellitus, blood pressure, and fasting blood glucose levels than other race/ethnicities. Prevalence of diabetic and antiplatelet medication use, as well as the incidence of small-artery occlusion ischemic stroke was also higher among South Asians. South Asians were almost a decade younger and had comparable socioeconomic levels as whites; however, their stroke risk factors were comparable to that of African Americans and Hispanics. DISCUSSION: Observed differences in stroke may be explained by dietary and life style choices of South Asian-Americans, risk factors that are potentially modifiable. Future population and epidemiologic studies should consider growing ethnic minority groups in the examination of the nature, outcome, and medical care profiles of stroke.
Non-Native (Exotic) Snake Envenomations in the U.S., 2005-2011.
Non-native (exotic) snakes are a problematic source of envenomation worldwide. This manuscript describes the current demographics, outcomes and challenges of non-native snakebites in the United States (U.S.). We performed a retrospective case series of the National Poison Data System (NPDS) database between 2005 and 2011. There were 258 human exposures involving at least 61 unique exotic venomous species (average = 37 per year; range = 33-40). Males comprised 79% and females 21%. The average age was 33 years with 16% less than 20 years old. 70% of bites occurred in a private residence and 86% were treated at a healthcare facility. 35% of cases received antivenom and 10% were given antibiotics. This study is compared to our previous study (1994-2004) in which there was a substantial coding error rate. Software modifications significantly reduced coding errors. Identification and acquisition of appropriate antivenoms pose a number of logistical difficulties in the management of these envenomations. In the U.S., poison centers have valuable systems and clinical roles in the provision of expert consultation and in the management of these cases.
Synthesis, Characterization and In Vitro Study of Biocompatible Cinnamaldehyde Functionalized Magnetite Nanoparticles (CPGF Nps) For Hyperthermia and Drug Delivery Applications in Breast Cancer.
Cinnamaldehyde, the bioactive component of the spice cinnamon, and its derivatives have been shown to possess anti-cancer activity against various cancer cell lines. However, its hydrophobic nature invites attention for efficient drug delivery systems that would enhance the bioavailability of cinnamaldehyde without affecting its bioactivity. Here, we report the synthesis of stable aqueous suspension of cinnamaldehyde tagged Fe3O4 nanoparticles capped with glycine and pluronic polymer (CPGF NPs) for their potential application in drug delivery and hyperthermia in breast cancer. The monodispersed superparamagnetic NPs had an average particulate size of approximately 20 nm. TGA data revealed the drug payload of approximately 18%. Compared to the free cinnamaldehyde, CPGF NPs reduced the viability of breast cancer cell lines, MCF7 and MDAMB231, at lower doses of cinnamaldehyde suggesting its increased bioavailability and in turn its therapeutic efficacy in the cells. Interestingly, the NPs were non-toxic to the non-cancerous HEK293 and MCF10A cell lines compared to the free cinnamaldehyde. The novelty of CPGF nanoparticulate system was that it could induce cytotoxicity in both ER/PR positive/Her2 negative (MCF7) and ER/PR negative/Her2 negative (MDAMB231) breast cancer cells, the latter being insensitive to most of the chemotherapeutic drugs. The NPs decreased the growth of the breast cancer cells in a dose-dependent manner and altered their migration through reduction in MMP-2 expression. CPGF NPs also decreased the expression of VEGF, an important oncomarker of tumor angiogenesis. They induced apoptosis in breast cancer cells through loss of mitochondrial membrane potential and activation of caspase-3. Interestingly, upon exposure to the radiofrequency waves, the NPs heated up to 41.6 degrees C within 1 min, suggesting their promise as a magnetic hyperthermia agent. All these findings indicate that CPGF NPs prove to be potential nano-chemotherapeutic agents in breast cancer.

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Mutilingual Medical Corpus

Multilingual-Medical-Corpus a 3 billion word multilingual corpus for training LLMs adapted to the medical domain. Multilingual-Medical-Corpus includes four languages, namely, English, Spanish, French, and Italian.

📖 Paper: Medical mT5: An Open-Source Multilingual Text-to-Text LLM for The Medical Domain
🌐 Project Website: https://univ-cotedazur.eu/antidote

Corpus Description

Developed by: Iker García-Ferrero, Rodrigo Agerri, Aitziber Atutxa Salazar, Elena Cabrio, Iker de la Iglesia, Alberto Lavelli, Bernardo Magnini, Benjamin Molinet, Johana Ramirez-Romero, German Rigau, Jose Maria Villa-Gonzalez, Serena Villata and Andrea Zaninello
Contact: Iker García-Ferrero and Rodrigo Agerri
Website: https://univ-cotedazur.eu/antidote
Funding: CHIST-ERA XAI 2019 call. Antidote (PCI2020-120717-2) funded by MCIN/AEI /10.13039/501100011033 and by European Union NextGenerationEU/PRTR
Language(s) (NLP): English, Spanish, French, Italian
License: apache-2.0

Data sources and word counts by language.
Language	Source	Words
English	ClinicalTrials	127.4M
	EMEA	12M
	PubMed	968.4M
Spanish	EMEA	13.6M
	PubMed	8.4M
	Medical Crawler	918M
	SPACC	350K
	UFAL	10.5M
	WikiMed	5.2M
French	PubMed	1.4M
	Science Direct	15.2M
	Wikipedia - Médecine	5M
	EDP	48K
	Google Patents	654M
Italian	Medical Commoncrawl - IT	67M
	Drug instructions	30.5M
	Wikipedia - Medicina	13.3M
	E3C Corpus - IT	11.6M
	Medicine descriptions	6.3M
	Medical theses	5.8M
	Medical websites	4M
	PubMed	2.3M
	Supplement description	1.3M
	Medical notes	975K
	Pathologies	157K
	Medical test simulations	26K
	Clinical cases	20K

Open Source Models trained with Multilingual-Medical-Corpus:

	HiTZ/Medical-mT5-large	HiTZ/Medical-mT5-xl	HiTZ/Medical-mT5-large-multitask	HiTZ/Medical-mT5-xl-multitask
Param. no.	738M	3B	738M	3B
Task	Language Modeling	Language Modeling	Multitask Sequence Labeling	Multitask Sequence Labeling

Citation

@misc{garcíaferrero2024medical,
      title={Medical mT5: An Open-Source Multilingual Text-to-Text LLM for The Medical Domain}, 
      author={Iker García-Ferrero and Rodrigo Agerri and Aitziber Atutxa Salazar and Elena Cabrio and Iker de la Iglesia and Alberto Lavelli and Bernardo Magnini and Benjamin Molinet and Johana Ramirez-Romero and German Rigau and Jose Maria Villa-Gonzalez and Serena Villata and Andrea Zaninello},
      year={2024},
      eprint={2404.07613},
      archivePrefix={arXiv},
      primaryClass={cs.CL}
}

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Antidote Project

Collection

Data and models generated within the Antidote Project (https://univ-cotedazur.eu/antidote) • 17 items • Updated 6 days ago • 5