The Brain Trauma Foundation. The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care. Use of barbiturates in the control of intracranial hypertension.
High-dose barbiturate therapy is efficacious in lowering ICP and decreasing mortality in the setting of uncontrollable ICP refractory to all other conventional medical and surgical ICP-lowering treatments. Utilization of barbiturates for the prophylactic treatment of ICP is not indicated. The potential complications attendant on this form of therapy mandate that its use be limited to critical care providers and that appropriate systemic monitoring be undertaken to avoid or treat any hemodynamic instability. When barbiturate coma is utilized, consideration should also be given to monitoring arteriovenous oxygen saturation as some patients treated in this fashion may develop oligemic cerebral hypoxia.


Temperature acquisition as a function of the computer-based biofeedback system utilized: an exploratory analysis.
Thermal biofeedback is widely used to treat various clinical disorders. Given its widespread utility, and the variability among the biofeedback systems currently on the market, it is important to investigate which systems are most effective for training various skills. This study compared the performance of normal subjects on two different computer-biofeedback systems. Results indicated a significant difference in subject performance between the two systems. Limitations and implications of these findings are discussed.


Conversion to sirolimus in pediatric renal transplant patients: a single-center experience.
We studied efficacy and safety of conversion from CNI- to SRL-based immunosuppression in 92 kidney TX recipients, mainly due to CAN (69%). Median time of conversion was 31 months (r: 0.3-165); median time of follow-up: 36 months (r: 2-102). In the whole group mean eGFR increased from 53 ± 22 to 67 ± 26mL/min/1.73 m(2) at three months (p = 0.02) and did not change subsequently. Patients with grade I CAN had higher eGFR than those with grade II CAN. Patient and graft survival was 96% and 70% 10 yr after conversion. Patients with grade I CAN had better graft survival than those with grade II CAN: 89% vs. 65% at six yr (p = 0.02) post conversion. There were two episodes of BPAR. Baseline proteinuria >20 mg/kg/day (HR: 10) and baseline eGFR <50 mL/min/1.73 m(2) (HR: 8) were independent predictors of graft loss. Sixty-seven of 92 subjects had ≥1 AEs: diarrhea (n = 52), urinary tract infections (n = 35), and lower respiratory tract infections (n = 12) were the most frequent. Patients with >2 AEs had SRL blood levels >9 ng/mL at month 3 (p = 0.01). In conclusion, patients converted from CNI to SRL had good graft survival and tolerable but frequent AEs. Independent predictors of graft loss were baseline proteinuria and eGFR.


Reduced disparities and improved surgical outcomes for Asian Americans with colorectal cancer.
Studies suggest Asian Americans may have improved oncologic outcomes compared with other ethnicities. We hypothesized that Asian Americans with colorectal cancer would have improved surgical outcomes in mortality, postoperative complications (POCs), length of stay (LOS), and readmissions compared with other racial/ethnic groups. We queried the 2011-2014 American College of Surgeons National Surgical Quality Improvement Program for patients who underwent surgery for colorectal cancer and stratified patients by race. Primary outcome was 30-d mortality with secondary outcomes including POCs, LOS, and 30-d readmission. Stepwise backward logistic regression analyses and incident rate ratio calculations were performed to identify risk factors for disparate outcomes. Of the 28,283 patients undergoing colorectal surgery for malignancy, racial/ethnic groups were divided into Caucasian American (84%), African American (12%), or Asian American (4%). On unadjusted analyses, compared with other racial/ethnic groups, Asian Americans were more likely to have normal weight, not smoke, and had lower American Society of Anesthesiologists score of 1 or 2 (P < 0.001). Postoperatively, Asian Americans had the shortest LOS and the lowest rates of complications due to ileus, respiratory, and renal complications (P < 0.001). There were no racial differences in 30-d mortality or readmission. On adjusted analyses, Asian American race was independently associated with less postoperative ileus (odds ratio 0.8, 95% confidence interval 0.66-0.98, P < 0.001) and decreased LOS by 13% and 4% compared with African American and Caucasian American patients, respectively (P < 0.001). Asian Americans undergoing surgery for colorectal cancer have shorter LOS and fewer POCs when compared with other racial/ethnic groups without differences in 30-d mortality or readmissions. The mechanism(s) underlying these disparities will require further study, but may be a result of patient, provider, and healthcare system differences.


Chemical chaperones reduce ER stress and adipose tissue inflammation in high fat diet-induced mouse model of obesity.
Obesity, which is characteristic by chronic inflammation, is defined as abnormal or excessive fat accumulation in adipose tissues. Endoplasmic reticulum (ER) stress is increased in adipose tissue of obese state and is known to be strongly associated with chronic inflammation. The aim of this study was to investigate the effect of ER stress on adipokine secretion in obese mice and explore the potential mechanisms. In this study, we found high-fat diet induced-obesity contributed to strengthened ER stress and triggered chronic inflammation in adipose tissue. Chemical chaperones, 4-PBA and TUDCA, modified metabolic disorders and decreased the levels of inflammatory cytokines in obese mice fed a high-fat diet. The alleviation of ER stress is in accordance with the decrease of free cholesterol in adipose tissue. Furthermore chemical chaperones suppress NF-κB activity in adipose tissue of obese mice in vivo. In vitro studies showed IKK/NF-κB may be involved in the signal transduction of adipokine secretion dysfunction induced by ER stress. The present study revealed the possibility that inhibition of ER stress may be a novel drug target for metabolic abnormalities associated with obesity. Further studies are now needed to characterize the initial incentive of sustained ER stress in obese.


A prospective study on ultrasound-guided compression therapy or thrombin injection for treatment of iatrogenic false aneurysms in patients receiving full-dose anti-platelet therapy.
False aneurysms (FA) develop at the puncture site in up to 6% of percutaneous cardiovascular procedures. Previous management included surgery or manual compression. Recently, selective injection of thrombin has been proposed as an alternative. However, there has been no direct comparison of thrombin injection to manual compression. To study the effectiveness of manual compression compared to that of thrombin injection in patients with false aneurysms on full-dose aspirin and clopidogrel. METHODS AND PROTOCOL: All patients with a clinically suspected FA after percutaneous invasive procedures were recruited for the study. The patients were examined with color ultrasound (7.5 MHz transducer). The minimum and maximum diameters of the false aneurysm and the distance between the surface and the false aneurysm were measured online. Under local anesthesia, manual compression was applied under sonographic guidance in all patients. If compression stopped flow into the false aneurysm, manual compression was applied for a maximum of 40 min followed by compression bandage for a minimum of 12 hours. If compression failed, thrombin was injected under ultrasound guidance. Thirty-six patients had a FA. Their age ranged from 58 to 90 years (mean 71+/-9 years). All patients were taking aspirin (median dose 100 mg per day) and clopidogrel (median dose 75 mg per day). Additionally, 24 patients had received subcutaneous heparin (7500 to 12 500 units) or enoxaprin (0.4-1.0 ml) 3 to 12 hours before treatment. The mean width of the false aneurysm was 22.1+/-3 mm, mean length 33.6+/-35.4 mm, and mean depth 19.5+/-8.2 mm. In six patients (17%), ultrasound-guided manual compression was tolerated, succeeding after 5 to 31 minutes. Thirty patients received thrombin injections (100-1800 units, mean 880+/-470 units, median 800 units). Complete thrombosis occurred in 28 patients (93%). Surgery was performed in the other two patients. The thrombin injection was not associated with any complications. In particular, there were no peripheral vascular complications. In patients with FA taking aspirin and clopidogrel, selective thrombin injection is more effective than manual compression.


Methylotrophic bacteria in sustainable agriculture.
Excessive use of chemical fertilizers to increase production from available land has resulted in deterioration of soil quality. To prevent further soil deterioration, the use of methylotrophic bacteria that have the ability to colonize different habitats, including soil, sediment, water, and both epiphytes and endophytes as host plants, has been suggested for sustainable agriculture. Methylotrophic bacteria are known to play a significant role in the biogeochemical cycle in soil ecosystems, ultimately fortifying plants and sustaining agriculture. Methylotrophs also improve air quality by using volatile organic compounds such as dichloromethane, formaldehyde, methanol, and formic acid. Additionally, methylotrophs are involved in phosphorous, nitrogen, and carbon cycling and can help reduce global warming. In this review, different aspects of the interaction between methylotrophs and host plants are discussed, including the role of methylotrophs in phosphorus acquisition, nitrogen fixation, phytohormone production, iron chelation, and plant growth promotion, and co-inoculation of these bacteria as biofertilizers for viable agriculture practices.


Structurally stable Bacillus subtilis cloning vectors.
Cloning of long DNA segments (greater than 5 kb) in Bacillus subtilis is often unsuccessful when naturally occurring small (less than 10 kb) plasmids are used as vectors. In this work we show that vectors derived from the large (26.5 kb) plasmids pAM beta 1 and pTB19 allow efficient cloning and stable maintenance of long DNA segments (up to 33 kb). The two large plasmids differ from the small ones in several ways. First, replication of the large plasmids does not lead to accumulation of detectable amounts of ss DNA, whereas the rolling-circle replication typical for small plasmids does. In addition, the replication regions of the two large plasmids share no sequence homology with the corresponding regions of the known small plasmids, which are highly conserved. Taken together, these observations suggest that the mode of replication of the large plasmids is different from that of small plasmids. Second, short repeated sequences recombine much less frequently when carried on large than on small plasmids. This indicates that large plasmids are structurally much more stable than small ones. We suggest that the high structural stability of large plasmids is a consequence of their mode of replication and that plasmids which do not replicate as rolling circles should be used whenever it is necessary to clone and maintain long DNA segments in any organism.


Body surface maps and the conventional 12-lead ECG compared by studying their performances in classification of old myocardial infarction.
The performance of body surface potential maps and the 12-lead ECG in the detection of old myocardial infarction has been compared in a two-group (54 normals; 52 infarctions) classification procedure (linear discriminant analysis). Three methods for data reduction of body surface maps were compared: 1) time integration, 2) one-step reduction in eigenvectors and 3) two-step reduction in spatial and temporal eigenvectors. Features were taken from the reduction variables by a stepwise selection procedure. From 90% to 93% correct classifications could be obtained using three features from the map data over the initial 30 ms (Q interval) of the QRS wave for all three methods considered. Using the 100 ms (QRS) interval 86% correct classifications were obtained using method 1, and up to 90% and 87% for methods 2 and 3, respectively. In a further analysis the classification based on body surface maps was compared to the one based on the 12-lead ECG. The 12-lead ECG was treated as a restricted set of the body surface mapping leads, so the same methods of data reduction, feature extraction and classification could be applied to both sets of data. Applying method 1 (time integration) 89% correct classifications were obtained using data taken from the 30 ms interval of the 12-lead ECG and a subsequent reduction to three features. When using the 100 ms interval the result was 79% also using three features. The results of method 2 applied to the 12-lead ECG were 89% (30 ms interval, three features) and 78% (100 ms interval, three features).


Occlusal wear of provisional implant-supported restorations.
Implant-supported provisional restorations should be resistant to occlusal wear. The purpose of this laboratory study was to evaluate three-body wear of three indirect laboratory composite resins, five chair side bis-acryl resin-based materials, and two chair side methacrylate-based materials used to fabricate provisional implant-supported restorations. The materials were handled and cured according to the manufacturers' instructions. The three-body wear was measured 1 day, 3 days, 7 days, 4 weeks, and 8 weeks after curing using the ACTA wear device. Wear rate decreased significantly after 8 weeks compared with the first day for all tested materials, except for Estenia C&B. The three-body wear of two indirect laboratory composite resins, that is, Estenia C&B and Solidex, was significantly less compared with all other tested materials used for fabricating provisional implant-supported restorations. Of the chair side materials, the wear rate of Protemp Crown Paste was significantly less compared with the others materials used to fabricate chair side provisional implant-supported restorations. The methacrylate-based materials, Temdent Classic and Trim, showed extreme high wear rates. Based on the results of this laboratory study on long-term wear, the use of indirect composite resin is preferred over chair side methacrylate-based materials when the provisional implant-supported restoration has to be in service for a long period of time. Of the investigated materials, only Estenia C&B and Solidex showed wear rate comparable with posterior resin composites.


Gas-phase stability and thermodynamics of ligand-bound, binary complexes of chloramphenicol acetyltransferase reveal negative cooperativity.
The biological role of the bacterial chloramphenicol (Chl)-resistance enzyme, chloramphenicol acetyltransferase (CAT), has seen renewed interest due to the resurgent use of Chl against multi-drug-resistant microbes. This looming threat calls for more rationally designed antibiotic derivatives that have improved antimicrobial properties and reduced toxicity in humans. Herein, we utilize native ion mobility spectrometry-mass spectrometry (IMS-MS) to investigate the gas-phase structure and thermodynamic stability of the type I variant of CAT from Escherichia coli (EcCATI) and several EcCATI:ligand-bound complexes. EcCATI readily binds multiple Chl without incurring significant changes to its gas-phase structure or stability. A non-hydrolyzable acetyl-CoA derivative (S-ethyl-CoA, S-Et-CoA) was used to kinetically trap EcCATI and Chl in a ternary, ligand-bound state (EcCATI:S-Et-CoA:Chl). Using collision-induced unfolding (CIU)-IMS-MS, we find that Chl dissociates from EcCATI:S-Et-CoA:Chl complexes at low collision energies, while S-Et-CoA remains bound to EcCATI even as protein unfolding occurs. Gas-phase binding constants further suggest that EcCATI binds S-Et-CoA more tightly than Chl. Both ligands exhibit negative cooperativity of subsequent ligand binding in their respective binary complexes. While we observe no significant change in structure or stability to EcCATI when bound to either or both ligands, we have elucidated novel gas-phase unfolding and dissociation behavior and provided a foundation for further characterization of alternative substrates and/or inhibitors of EcCATI.


Lysosomal Membrane Stability in Hemocytes and Micronuclei in Gills of Perumytilus purpuratus Lamarck 1819 (Bivalvia: Mytilidae) Exposed to Copper.
The aim of this study was to determine the cytotoxic and genotoxic effects of copper on the bivalve Perumytilus purpuratus. The individuals were exposed to three copper concentrations: 1, 30 and 45 μg L-1 for 24, 48 and 96 h. Lysosomal membrane stability in hemocytes was determined through the neutral red retention time (NRRT) and micronucleus (MN) frequency tests in hemocytes and gills. The results show that the NRRT decreased significantly at 30 μg L-1 after 48 h of exposure. The frequency of MN was significantly greater in gills after 24 h in all concentrations tested. Copper is cytotoxic from 30 μg L-1 and genotoxic from 1 μg L-1. The use of these biomarkers of effects in P. purpuratus is proposed as an early warning tool for monitoring in environmental assessment of coastal ecosystems impacted by mining activities.


Mechanisms of haem and non-haem iron absorption: lessons from inherited disorders of iron metabolism.
Our current state of knowledge of the mechanism and regulation of intestinal iron absorption has been critically dependent on the analysis of inherited disorders of iron homeostasis in both humans and other animal species. Mutations in DMT1 and Ireg1 have revealed that these molecules are major mediators of iron transport across the brush border and basolateral membranes of the enterocyte, respectively. Similarly, the iron oxidase hephaestin has been shown to play an important role in basolateral iron efflux. The analysis of a range of human iron loading disorders has provided very strong evidence that the products of the HFE, TfR2, hepcidin and hemojuvelin genes comprise integral components of the machinery that regulates iron absorption and iron traffic around the body. Engineered mouse strains have already proved very effective in helping to dissect pathways of iron homeostasis, and in the future they will continue to provide important insights into the absorption of both inorganic and haem iron by the gut.


Origin of axoplasmic RNA in the squid giant fiber.
The origin of axoplasmic RNA in the squid giant fiber was investigated after exposure of the giant axon or of the giant fiber lobe to [3H]uridine. The occurrence of a local process of synthesis was indicated by the accumulation of labeled axoplasmic RNA in isolated axons incubated with the radioactive precursor. Similar results were obtained in vivo after injection of [3H]uridine near the stellate nerve at a sizable distance from the ganglion. Exposure of the giant fiber lobe to [3H]uridine under in vivo and in vitro conditions was followed by the appearance of labeled RNA in the axoplasm and in the axonal sheath. While the latter process is attributed to incorporation of precursor by sheath cells, a sizable fraction of the radioactive RNA accumulating in the axoplasmic is likely to originate from neuronal perikarya by a process of axonal transport.


Diagnostic value of anteroposterior diameter of fetal renal pelvis during second and third trimesters in predicting postnatal surgery among Korean population: useful information for antenatal counseling.
To establish prognostic data regarding fetal hydronephrosis using the anteroposterior diameter (APD) and the need for interventional surgery in the Korean population. A total of 187 children with an APD of ≥ 4 mm on obstetric ultrasound scans at any gestational age were retrospectively reviewed. The affected renal units were divided into 2 groups: surgical and nonsurgical. The ultrasound findings were compared at 3 gestational ages: second trimester (15-26 weeks' gestation), early third trimester (27-33 weeks' gestation), and late third trimester (34-40 weeks' gestation). The area under the receiver operating characteristic curve was 0.770, 0.828, and 0.812 at the second, early third, and late third trimesters, respectively. A 100% sensitivity for predicting postnatal surgery could be achieved at a cutoff APD of 5 mm during the second trimester, 8 mm during the early third trimester, and 10 mm during the late third trimester if scheduled antenatal ultrasound scans were performed. A cutoff APD of 11 mm during the second trimester was of diagnostic value in selecting children at risk of postnatal surgery with an odds ratio of 5.13 (95% confidence interval 1.62-16.25), with relatively high sensitivity and specificity. With a cutoff of 15 mm during the early third and late third trimesters, the odds ratio was 11.51 (95% confidence interval 5.05-26.23) and 6.94 (95% confidence interval 3.30-14.57), respectively. Compared with an APD of 10 mm, the most commonly used standard cutoff value in predicting postnatal hydronephrosis and its outcome, an APD cutoff of 5, 8, and 10 mm during the second, early third, and late third trimesters, respectively, is more specific in predicting the need for postnatal surgical intervention in the Korean population.


[Coronary intervention. 2012 update].
In-stent restenosis and stent thrombosis are still the main topics of any update on coronary intervention. One of the challenging issues in the past year lay in answering the question of whether the data on first-generation drug-eluting stents are still relevant in the light of newer stent designs and drugs. Other issues include new strategies in antiplatelet therapy, treatment of in-stent restenosis, particularly drug-eluting stent restenosis, treatment of multivessel and left-main disease, as well as the latest developments in bioresorbable polymers and "scaffolds". In the light of demographic changes, the main challenge for the interventional community is to build an evidence base for the adequate treatment of elderly patients in order to resolve uncertainties in the treatment of this challenging patient group.


Accumulation of nitrite and sulfite in yeast cells and synergistic depletion of the intracellular ATP content.
When nitrite or sulfite are applied to yeast cells below pH 5.0, an enormous intracellular accumulation occurs. It is assumed that nitrite and sulfite penetrate the cell membrane in their undissociated forms as nitrous acid (pK = 3.3) or sulfurous acid (pK = 1.8), respectively. Due to the neutral intracellular pH they are trapped inside the cell in their anionic forms, which are impermeable to the cell membrane. It has previously been shown that sulfite causes a rapid depletion of the ATP content of yeast cells [Schimz, K.L. and Holzer, H. (1979) resp. Hinze et al. as above]. Similarly, millimolar concentrations of nitrite decrease the ATP level to less than 10% of the initial value. Nitrite and sulfite in combination deplete the ATP content of yeast cells much stronger than expected for the sum of the separate effects of these compounds ("synergistic effect").


Epilepsy care in Zambia: a study of traditional healers.
Most people with epilepsy (PWE) reside in developing countries with limited access to medical care. In sub-Saharan Africa (SSA), traditional healers (THs) play a prominent role in caring for PWE, yet little is known about epilepsy care by THs. We conducted a multimethod, qualitative study to better understand the epilepsy care delivered by THs in Zambia. We conducted focus-group discussions with THs, in-depth semistructured interviews with a well-recognized TH at his place of work, and multiple informal interviews with healthcare providers in rural Zambia. THs recognize the same symptoms that a neurologist elicits to characterize seizure onset (e.g., olfactory hallucinations, jacksonian march, automatisms). Although THs acknowledge a familial propensity for some seizures and endorse causes of symptomatic epilepsy, they believe witchcraft plays a central, provocative role in most seizures. Treatment is initiated after the first seizure and usually incorporates certain plant and animal products. Patients who do not experience further seizures are considered cured. Those who do not respond to therapy may be referred to other healers. Signs of concomitant systemic illness are the most common reason for referral to a hospital. As a consequence of this work, our local Epilepsy Care Team has developed a more collaborative relationship with THs in the region. THs obtain detailed event histories, are treatment focused, and may refer patients who have refractory seizures to therapy to other healers. Under some circumstances, they recognize a role for modern health care and refer patients to the hospital. Given their predominance as care providers for PWE, further understanding of their approach to care is important. Collaborative relationships between physicians and THs are needed if we hope to bridge the treatment gap in SSA.


Successful management of junctional tachycardia by hypothermia after cardiac operations in infants.
Junctional ectopic tachycardia is an early postoperative complication after intracardiac repair of congenital heart disease, especially in infants. Because of the high ventricular rate and the usually poor response to antiarrhythmic drugs, this condition is associated with a high morbidity and mortality. The purpose of this study was to assess the safety and efficacy of moderate body surface hypothermia in the treatment of postoperative junctional ectopic tachycardia in infants. Six consecutive infants with postoperative junctional ectopic tachycardia (mean age at operation, 14 weeks) were treated with surface cooling. The decision to start treatment was based on the definition of a critical heart rate (180 to 200 beats/min) in the presence of junctional ectopic tachycardia diagnosed according to established criteria. Moderate hypothermia (rectal temperature between 32 degrees and 34 degrees C) was achieved by placing ice bags on the child's body surface. The patients were sedated, mechanically ventilated, and paralyzed. Mean interval between diagnosis of tachycardia and initiation of hypothermia was 4 hours. Rectal temperature was rapidly (within 1 hour) lowered to 32 degrees to 34 degrees C in all 6 patients. This significantly lowered the tachycardia rate from 219 +/- 27 beats/min to 165 +/- 25 beats/min (mean +/- standard deviation; p < 0.001). Three patients with signs of low cardiac output had restoration of stable hemodynamics once the tachycardia rate had been decreased by hypothermia. Cooling was maintained for a period of 24 to 88 hours (mean, 59 hours). No serious side effects were observed. Early institution of moderate hypothermia by body surface cooling was a safe and efficient measure to control ventricular rate in infants with postoperative junctional ectopic tachycardia.


Long-acting versus short-acting methylphenidate for paediatric ADHD: a systematic review and meta-analysis of comparative efficacy.
To synthesise existing knowledge of the efficacy and safety of long-acting versus short-acting methylphenidate for paediatric attention deficit hyperactivity disorder (ADHD). Systematic review and meta-analysis. Electronic literature search of CENTRAL, MEDLINE, PreMEDLINE, CINAHL, EMBASE, PsychINFO, Scopus and Web of Science for articles published in the English language between 1950 and 2012. Reference lists of included studies were checked for additional studies. Randomised controlled trials of paediatric ADHD patients (<18 years), comparing a long-acting methylphenidate form to a short-acting methylphenidate form. Two authors independently selected trials, extracted data and assessed risk of bias. Continuous outcomes were compared using standardised mean differences (SMDs) between treatment groups. Adverse events were compared using risk differences between treatment groups. Heterogeneity was explored by subgroup analysis based on the type of long-acting formulation used. Thirteen RCTs were included; data from 882 participants contributed to the analysis. Meta-analysis of three studies which used parent ratings to report on hyperactivity/impulsivity had an SMD of -0.30 (95% CI -0.51 to -0.08) favouring the long-acting forms. In contrast, three studies used teacher ratings to report on hyperactivity and had an SMD of 0.29 (95% CI 0.05 to 0.52) favouring the short-acting methylphenidate. In addition, subgroup analysis of three studies which used parent ratings to report on inattention/overactivity indicate that the osmotic release oral system generation long-acting formulation was favoured with an SMD of -0.35 (95% CI -0.52 to -0.17), while the second generation showed less efficacy than the short-acting formulation with an SMD of 0.42 (95% CI 0.17 to 0.68). The long-acting formulations presented with slightly more total reported adverse events (n=578) as compared with the short-acting formulation (n=566). The findings from this systematic review indicate that the long-acting forms have a modest effect on the severity of inattention/overactivity and hyperactivity/impulsivity according to parent reports, whereas the short-acting methylphenidate was preferred according to teacher reports for hyperactivity.


The effect of Bailemian on neurotransmitters and gut microbiota in p-chlorophenylalanine induced insomnia mice.
Bailemian (BLM) is reportedly used for the treatment of insomnia as a traditional Chinese medicine in China for many years. However, the anti-insomnia mechanisms of BLM are still unknown. The present study aims to investigate the anti-insomnia activity of BLM by evaluating its influence on the relevant neurotransmitters and gut microbiota in p-chlorophenylalanine (PCPA) induced insomnia mice. The results indicated that the level of GABA, 5-HT, DA, and NE is significantly decreased in the PCPA-induced insomnia model group compared with the control group, while the level of Glu is higher than the control group. Treatment with BLM could ameliorate the symptoms of insomnia and significantly modulate the levels of the neurotransmitters mentioned above in brain and colonic faeces. Furthermore, the structure and composition of gut microbiota were changed after the administration of BLM and can increase the percentage of beneficial bacterial species in gut microbiota. These results indicated that Bailemian could ameliorate the symptoms of insomnia, and its effects may be through modification of the neurotransmitters levels and gut microbiota composition.


Testing a hierarchy-of-effects model: pathways from awareness to outcomes in the VERB campaign 2002-2003.
The McGuire hierarchy-of-effects (HOE) model, used extensively in mass-media interventions to describe the mechanisms for understanding effects, has not been tested in physical activity campaigns. Data collected at baseline (2002) and follow-up (2003) surveys in the VERB evaluation were used in structural equation modeling to test pathways and hierarchies of campaign effects. Population-based cohort of youth aged 9-13 years (N=2364) for whom complete baseline and follow-up data were available. Awareness of the VERB campaign, understanding of the VERB message, attitude toward being active, outcome expectations, and physical activity participation. Among youth aged 9-13 years (tweens) in the study cohort, significant paths were identified between awareness and understanding (0.72, p<0.001) and between understanding and being physically active (0.11, p<0.05). At baseline there was a high prevalence of positive attitudes and outcome expectations, and these were not influenced by change in understanding or awareness. Among inactive tweens only, the same paths were identified except that, in this subgroup, attitude was related to physical activity (0.13, p<0.05), and awareness was more strongly related to physical activity than it was for the whole sample (0.14, p<0.01). These findings provided limited support for the HOE model and suggest that increased awareness and understanding were the key proximal effects that led to behavior change. A distinct sequence of effects, which bypassed attitudes and outcome expectations, was found for these U.S. young people. The findings could inform the design of future campaigns to address youth physical activity.


Risk factors for developing subglottic and tracheal stenosis from the medical intensive care unit.
Endotracheal intubation is a common procedure in the medical intensive care unit (MICU), but it carries risk of complications including, but not limited to, subglottic stenosis (SGS) and tracheal stenosis (TS). Current literature suggests identifiable risk factors for the development of airway complications. This study is a comprehensive evaluation of potential risk factors in patients who developed SGS and TS following endotracheal intubation in our MICU. Patients intubated in our MICU were identified from 2013 to 2019. Diagnoses of SGS or TS within 1 year of MICU admission were identified. Data extracted included age, sex, body measurements, comorbidities, bronchoscopies, endotracheal tube size, tracheostomy, social history, and medications. Patients with prior diagnosis of airway complication, tracheostomy, or head and neck cancer were excluded. Univariate and multivariate logistic regressions were performed. A total of 136 patients with TS or SGS were identified out of a sample of 6603 patients intubated in the MICU. Cases were matched to controls who did not develop airway stenosis based on identical Charlson Comorbidity Index scores. Eighty six controls were identified with a complete record of endotracheal/tracheostomy tube size, airway procedures, sociodemographic data, and medical diagnosis. Regression analysis showed that SGS or TS were associated with tracheostomy, bronchoscopy, chronic obstructive pulmonary disease, current tobacco use, gastroesophageal reflux disease, systemic lupus erythematosus, pneumonia, bronchitis, and numerous medication classes. Various conditions, procedures, and medications are associated with an increased risk of developing SGS or TS. 4.


[A clearance method of measuring tissue blood flow using electrochemical generation of hydrogen].
Practical approaches are elaborated as to application of the clearance method using electrochemical hydrogen generation to measure volume blood flow velocity in human and animal organs and tissues. Results from this elaboration and analysis of the obtained experimental data are presented. Some specific features of the method are described.


CD109-mediated degradation of TGF-β receptors and inhibition of TGF-β responses involve regulation of SMAD7 and Smurf2 localization and function.
Transforming growth factor-β (TGF-β) is a multifunctional cytokine that regulates a wide variety of cellular processes including proliferation, differentiation, and extracellular matrix deposition. Dysregulation of TGF-β signaling is associated with several diseases such as cancer and tissue fibrosis. TGF-β signals through two transmembrane proteins known as the type I (TGFBR1) and type II (TGFBR2) receptors. The levels of these receptors at the cell surface are tightly regulated by several mechanisms, including degradation following recruitment of the E3 ubiquitin ligase SMAD ubiquitination regulatory factor (Smurf) 2 by SMAD7. In addition, TGF-β co-receptors can modulate TGF-β signaling receptor activity in a cell-specific manner. We have previously identified a novel TGF-β co-receptor, CD109, a glycosyl phosphatidylinositol (GPI)-anchored protein that negatively regulates TGF-β signaling. Despite CD109's potential relevance as a regulator of TGF-β action in vivo, the mechanisms by which CD109 regulates TGF-β signaling are still incompletely understood. Previously, we have shown that CD109 downregulates TGF-β signaling by promoting TGF-β receptor localization into the lipid raft/caveolae compartment and by enhancing TGF-β receptor degradation. Here, we demonstrate that CD109 enhances SMAD7/Smurf2-mediated degradation of TGFBR1 in a ligand-dependent manner. Moreover, we show that CD109 regulates the localization and the association of SMAD7/Smurf2 with TGFBR1. Finally, we demonstrate that CD109's inhibitory effect on TGF-β signaling and responses require SMAD7 expression and Smurf2 ubiquitin ligase activity. Taken together, these results suggest that CD109 is an important regulator of SMAD7/Smurf2-mediated degradation of TGFBR1.


Modulation of human velocity storage sampled during intermittently-illuminated optokinetic stimulation.
When a stationary human subject is suddenly exposed to constant-velocity full-field optokinetic stimulation, slow-phase eye velocity rapidly approaches stimulus velocity without the gradual build-up ("velocity storage") readily seen in other species. Subsequent to extinguishing illumination, the presence of velocity storage is suggested by the persistence of a gradually-declining component of optokinetic after-nystagmus (OKAN). In the past, characterizing modulation of velocity storage has been tedious. It is now shown that such modulation can be characterized by periodic "sampling" of OKAN using "intermittently-illuminated" optokinetic stimuli (light-on: 9.7 s; darkness: 2 s). Six subjects viewed an intermittently-illuminated optokinetic drum turning with a square wave angular velocity profile of 60 deg/s peak amplitude and 0.01 Hz frequency. The resulting modulation of velocity storage was approximately exponential with time constant, T = 5-11 s, and asymptote, A = 10-17 deg/s. A significant negative correlation was observed between T and A values. In a given subject, T and A values agreed (generally within +/- 20%) with values obtained employing previously-used methods, suggesting that velocity storage behaved linearly during periodic optokinetic stimuli of less than 60 deg/s. The new method of sampling OKAN permits the use of arbitrary stimulus profiles required to observe, or to confidently predict, velocity storage response during natural behavioural movements, which was not feasible with older methods. Sampling also increases the ease and speed (roughly three-fold) of data acquisition.


Nivalenol production byFusarium poae.
Fusarium sp. were isolated from Swedish nivalenol containing grain and tested for toxin production. OnlyF. poae, 6 of 10 isolates, produced nivalenol. Highest production (44.7 μg/g) was obtained cultured on rice during 4 week at room temperature and under near UV-light. FiveF. poae isolates from other countries did not produce nivalenol but T-2/HT-2 toxin. One Swedish isolate produced both types of trichothecenes. Treatment with fungicides in aF. poae infected experimental field reduced the nivalenol concentration in the harvested grain.


Activation of silenced tumor suppressor genes in prostate cancer cells by a novel energy restriction-mimetic agent.
Targeting tumor metabolism by energy restriction-mimetic agents (ERMAs) has emerged as a strategy for cancer therapy/prevention. Evidence suggests a mechanistic link between ERMA-mediated antitumor effects and epigenetic gene regulation. Microarray analysis showed that a novel thiazolidinedione-derived ERMA, CG-12, and glucose deprivation could suppress DNA methyltransferase (DNMT)1 expression and reactivate DNA methylation-silenced tumor suppressor genes in LNCaP prostate cancer cells. Thus, we investigated the effects of a potent CG-12 derivative, CG-5, vis-à-vis 2-deoxyglucose, glucose deprivation and/or 5-aza-deoxycytidine, on DNMT isoform expression (Western blotting, RT-PCR), DNMT1 transcriptional activation (luciferase reporter assay), and expression of genes frequently hypermethylated in prostate cancer (quantitative real-time PCR). Promoter methylation was assessed by pyrosequencing analysis. SiRNA-mediated knockdown and ectopic expression of DNMT1 were used to validate DNMT1 as a target of CG-5. CG-5 and glucose deprivation upregulated the expression of DNA methylation-silenced tumor suppressor genes, including GADD45a, GADD45b, IGFBP3, LAMB3, BASP1, GPX3, and GSTP1, but also downregulated methylated tumor/invasion-promoting genes, including CD44, S100A4, and TACSTD2. In contrast, 5-aza-deoxycytidine induced global reactivation of these genes. CG-5 mediated these epigenetic effects by transcriptional repression of DNMT1, which was associated with reduced expression of Sp1 and E2F1. SiRNA-mediated knockdown and ectopic expression of DNMT1 corroborated DNMT1's role in the modulation of gene expression by CG-5. Pyrosequencing revealed differential effects of CG-5 versus 5-aza-deoxycytidine on promoter methylation in these genes. These findings reveal a previously uncharacterized epigenetic effect of ERMAs on DNA methylation-silenced tumor suppressor genes, which may foster novel strategies for prostate cancer therapy.


Synthesis of porphyrinoids with silane anchors and their covalent self-assembling and metallation on solid surface.
We have synthesized a set of porphyrin and phthalocyanine compounds with two different silane anchors. Syntheses of the anchor-substituted chromophores have been carried out via hydrosilylation of alkene derivatives, catalyzed by platinum complexes. The reduction side-process was suppressed using specific anchor/catalyst pairs, and the silane-containing compounds were successfully isolated from hydrogenated by-products in pure form with good yields. The target porphyrinoids having stable reactive silane anchors possess the ability to self-assemble on metal oxides and quartz surfaces and optical fibers. Covalent attachment is done in one-step, which makes the bonding process fast and easy. Immobilized chromophores were further converted by on-surface reactions into Zn(II) and Mg(II) metal complexes. The metallation time was found to be as fast as 1 min for Zn ion. Bonding densities calculated from the absorbances of the deposited layers give rough estimations for packing of the molecules on various substrates and evidence for monomolecular layers formation.


Genetic analysis of genomic imprinting: an Imprintor-1 gene controls inactivation of the paternal copy of the mouse Tme locus.
The Thp deletion on mouse chromosome 17 is lethal when inherited from the mother, because it deletes the T-associated maternal effect (Tme) locus, the paternal copy of which is inactivated by genomic imprinting. We have found a paternally nonimprinted Tme variant in crosses of Thp females with Mus m. musculus males. The data are consistent with the existence of a single Tme-unlinked gene, Imprintor-1 (Imp-1), with two alleles, one of which only causes imprinting at the Tme locus. Imp-1 is unlinked to the gene for cation-dependent Man-6-P receptor and acts prezygotically. Although Tme and Igf2r were thought to be identical, they show different patterns of imprinting in interspecies hybrids. The apparent nonequivalence of the Igf2r gene and Tme results in occurrence of viable mice lacking an active Igf2r gene. These mice are bigger at birth than their normal littermates, in accord with the proposed function of the IGF-II/Man-6-P receptor.


Nuts and Bolts of Oil and Temperature in Topical Preparations of Salicylic Acid.
Traditional formulations of salicylic acid in ointment bases have disadvantages of being greasy and irritant due to free crystals. To explore the method for selection of oils and their ratio for topical preparation on the basis of equilibrium solubility study of salicylic acid and to evaluate temperature effect. Scanning and calibration curve of salicylic acid in methanol were developed. Among available oils, those that had no interference of absorbance of salicylic acid were short-listed for screening purpose. Selections of oils were carried out on the basis of equilibrium solubility study. Compatibility study was made by Fourier Transform Infra-Red spectroscopy analysis. Primitive study of oil mixtures was done. Selections of the ratio of oils were carried out on basis of constrained simplex-centroid design. Salicylic acid had shown linearity in the range of 15-65 μg/mL in methanol at wavelength maximum (300 nm). From the equilibrium solubility study, Parker Neem® Oil (11.81 ± 0.5 mg/g), Isopropyl Myristate (11.29 ± 0.04 mg/g), Mogra Oil (9.62 ± 0.94 mg/g) were selected. The study possessed the same main Fourier transform infra-red peaks of salicylic acid in the salicylic acid-oils physical mixture. 58.64% Parker Neem® oil and 41.36% isopropyl myristate mixture was selected as optimized batch with the desirability of 0.391. The oils mixture could be selected for topical preparation of salicylic acid like paste, cream, ointment etc.


Rectal perforation after procedure for prolapse and hemorrhoids: possible causes.
Our aim was to explore possible causes of rectal perforation occurring in patients who undergo the procedure for prolapse and hemorrhoids. We evaluated data from cases of rectal perforation that occurred after the procedure for prolapse and hemorrhoids in China in conjunction with case reports from the international medical literature. We identified 7 patients from 5 hospitals in 2 provinces of China who had rectal perforation after the procedure despite having received prophylactic antibiotic treatment. Two patients had a disrupted staple line and 5 had perforations on the rectum wall above the intact staple line. Six patients presented with symptoms in the first 3 days after the procedure. Three patients had concomitant disease: 1 had concomitant constipation and internal rectal prolapse, 1 had concomitant constipation, and 1 had concomitant liver cirrhosis ascites that was not diagnosed preoperatively. Of the 15 cases of rectal perforation found in the literature, 3 patients had an intact staple line and 5 patients had a ruptured staple line. The cone-shaped tip of the anvil, concomitant rectal prolapse and pelvic floor descent, and concomitant ascites are possible causes of rectal perforation after the procedure for prolapse and hemorrhoids.


French national diagnostic and care protocol for Kawasaki disease.
Kawasaki disease (KD) is an acute vasculitis with a particular tropism for the coronary arteries. KD mainly affects male children between 6 months and 5 years of age. The diagnosis is clinical, based on the international American Heart Association criteria. It should be systematically considered in children with a fever, either of 5 days or more, or of 3 days if all other criteria are present. It is important to note that most children present with marked irritability and may have digestive signs. Although the biological inflammatory response is not specific, it is of great value for the diagnosis. Because of the difficulty of recognising incomplete or atypical forms of KD, and the need for urgent treatment, the child should be referred to a paediatric hospital as soon as the diagnosis is suspected. In the event of signs of heart failure (pallor, tachycardia, polypnea, sweating, hepatomegaly, unstable blood pressure), medical transfer to an intensive care unit (ICU) is essential. The standard treatment is an infusion of IVIG combined with aspirin (before 10 days of fever, and for a minimum of 6 weeks), which reduces the risk of coronary aneurysms. In case of coronary involvement, antiplatelet therapy can be maintained for life. In case of a giant aneurysm, anticoagulant treatment is added to the antiplatelet agent. The prognosis of KD is generally good and most children recover without sequelae. The prognosis in children with initial coronary involvement depends on the progression of the cardiac anomalies, which are monitored during careful specialised cardiological follow-up.


Oral rapid HIV testing in the dental setting: Experiences from three dental hygiene clinics.
Oral rapid HIV testing (ORHT) is implemented in the dental setting to make individuals aware of their possibly undiagnosed HIV infection. The testing process and characteristics of clients willing to receive ORHT has yet, however, to be systematically collected. Three dental hygiene clinics located in academic institutions implemented ORHT from March 2016 to April 2017. 231 persons received ORHT; all had non-reactive results. Most had seen a primary care provider in the past year (n = 130), had had a previous ORHT (n = 111), and described themselves as extremely likely or likely to accept a chairside screening in the future (n = 169). The main reason cited for accepting ORHT was that it was free (n = 138). In order to ensure everyone living with HIV is aware of their infection, HIV testing should be expanded into non-traditional settings. The dental setting may help achieve this important public health milestone.


Tubal sterilization by laparoscopy or hysteroscopy: which is the most cost-effective procedure?
By using the activity-based cost/management (ABC/M) system we computed and compared costs needed for laparoscopic tubal sterilization (LTS) and Essure hysteroscopic tubal occlusion (EHTO). We found that total health costs related to consultation and presurgery did not differ between LTS and EHTO; EHTO has low recovery unit costs but is more costly for the operating theater, mainly due to Essure microinserts.


Characterization of a polyriboadenylate polymerase from vaccinia virions.
A poly(A) polymerase with a molecular weight of approximately 80,000 containing 51,000 and 35,000 molecular weight subunits, was purified by affinity chromatography from vaccinia virus cores. The enzyme had a pH optimum of about 8.6, was dependent on divalent cations, and had considerably more activity with Mn-2+ than Mg-2+. At equimolar concentrations, other ribonucleoside triphosphates inhibited poly(A) polymerase activity by less than 10%; NaCl was extremely inhibitory at concentrations above 0.1 M. Under standard assay conditions, poly(A) polymerase activity was stimulated more than 10-fold by poly(C), but to small extent or not at all by other homopolyribonucleotides or natural RNA species unless they were first subjected to partial hydrolysis and alkaline phosphatase treatment. The ineffectiveness of most long polyribonucleotides was attributed to enzyme binding to internal regions. Short poly- or oligoribonucleotides prepared from natural or synthetic RNAs, except poly(G), exhibited similar priming abilities, and isotope transfer experiments indicated the covalent attachment of poly(A) to cytidylate, uridylate, and inosinate residues. Experiments with a series of uridylate oligomers indicated that the minimum effective primer length was four to six nucleotides. Partially digested DNA and short poly- and oligodeoxyribonucleotides of dT, dC, and dI, but not of dA and dG, also acted as effective primers for the poly(A) polymerase.


Naloxone Prescribing Practices in a Freestanding Rehabilitation Hospital.
The study aims to determine whether PM&R physicians offer naloxone per CDC Guidelines to patients at the highest risk of complications from opioid treatment and if there is a difference between inpatient and outpatient naloxone prescribing. A retrospective chart review on 389 adults(outpatient n = 166; inpatient n = 223) from May 4 to May 31, 2022 at an academic rehabilitation hospital. Prescribed medications and comorbidities were evaluated to determine if CDC criteria for offering naloxone were met, and if naloxone was offered. 129 opioid prescriptions were written for 102 outpatients; 61 qualified for naloxone(MME range 10-1080, mean 158.08). On inpatient, 68 patients received 86 opioid prescriptions; 35 qualified for naloxone(MME range 3.75-246, mean 62.36). Overall, there was a significantly lower rate of opioid prescriptions for inpatients(30.49%) than outpatients(61.45%)(p < 0.0001), a non-significant lower rate of inpatient(51.47%) than outpatient(59.80%) "at-risk" prescriptions(p = 0.351), and a weakly significant lower rate of naloxone prescribing for inpatient(2.86%) than outpatient visits(8.20%)(p < 0.0519). At this rehabilitation hospital, there was a low rate of naloxone prescribing by inpatient and outpatient providers, with a higher rate occurring in the outpatient than inpatient setting. More research is needed to understand this prescribing trend to determine potential interventions.


PPP2R1A regulates migration persistence through the NHSL1-containing WAVE Shell Complex.
The RAC1-WAVE-Arp2/3 signaling pathway generates branched actin networks that power lamellipodium protrusion of migrating cells. Feedback is thought to control protrusion lifetime and migration persistence, but its molecular circuitry remains elusive. Here, we identify PPP2R1A by proteomics as a protein differentially associated with the WAVE complex subunit ABI1 when RAC1 is activated and downstream generation of branched actin is blocked. PPP2R1A is found to associate at the lamellipodial edge with an alternative form of WAVE complex, the WAVE Shell Complex, that contains NHSL1 instead of the Arp2/3 activating subunit WAVE, as in the canonical WAVE Regulatory Complex. PPP2R1A is required for persistence in random and directed migration assays and for RAC1-dependent actin polymerization in cell extracts. PPP2R1A requirement is abolished by NHSL1 depletion. PPP2R1A mutations found in tumors impair WAVE Shell Complex binding and migration regulation, suggesting that the coupling of PPP2R1A to the WAVE Shell Complex is essential to its function.


All-cause and liver-related mortality risk factors in excessive drinkers: Analysis of data from the UK biobank.
High alcohol intake is associated with increased mortality. We aimed to identify factors affecting mortality in people drinking extreme amounts of alcohol. We obtained information from the UK Biobank on approximately 500,000 participants aged 40-70 years at baseline assessment in 2006-2010. Habitual alcohol intake, lifestyle and physiological data, laboratory test results, and hospital diagnoses and death certificate data (to June 2020) for 5136 men (2.20% of male participants) and 1504 women (0.60%) who reported consuming ≥80 or ≥50 g/day, respectively, were used in survival analysis. Mortality hazard ratios for these excessive drinkers, compared to all other participants, were 2.02 (95% CI 1.89-2.17) for all causes, 1.89 (1.69-2.12) for any cancer, 1.87 (1.61-2.17) for any circulatory disease, and 9.40 (7.00-12.64) for any liver disease. Liver disease diagnosis or abnormal liver function tests predicted not only deaths attributed to liver disease but also those from cancers or circulatory diseases. Mortality among excessive drinkers was also associated with quantitative alcohol intake; diagnosed alcohol dependence, harmful use, or withdrawal syndrome; and current smoking at assessment. People with chronic excessive alcohol intake experience decreased average survival, but there is substantial variation in their mortality, with liver abnormality and alcohol dependence or other alcohol use disorders associated with a worse prognosis. Clinically, patients with these risk factors and high alcohol intake should be considered for early or intensive management. Research can usefully focus on the factors predisposing to dependence or liver abnormality.


Public health actions to improve palliative care in Germany: results of a three-round Delphi study.
In previous studies, key targets for public health initiatives to improve palliative care in Germany were defined. The aim of this study was the identification and prioritisation of actions to achieve these targets. A three-round Delphi study with 107 stakeholders acting on the meso and macrolevel of the healthcare system was undertaken. First round: proposing actions for each of the key targets; second round: assessment of the actions regarding their relevance; third round: ranking of the actions. 37 actions were generated (first round) of which 14 actions were rated as relevant (second round). In the third round, the action ranked highest was "close collaboration between specialist palliative care services, general practitioners and community nursing services", followed by "Implementing specialist palliative care in the community consequently" and "Strengthening generalist palliative care through training and education of general practitioners and nursing services". The range and the ranking of the actions provide an empirical basis to improve palliative care in Germany on different levels of policy, education and clinical practice. A focus should be on strengthening the collaboration between primary health care providers and specialist palliative care services.


Effectiveness and safety of sofosbuvir-based regimens plus an NS5A inhibitor for patients with HCV genotype 3 infection and cirrhosis. Results of a multicenter real-life cohort.
Patients with HCV genotype 3 (GT3) infection and cirrhosis are currently the most difficult to cure. We report our experience with sofosbuvir+daclatasvir (SOF+DCV) or sofosbuvir/ledipasvir (SOF/LDV), with or without ribavirin (RBV) in clinical practice in this population. This was a multicenter observational study including cirrhotic patients infected by HCV GT3, treated with sofosbuvir plus an NS5A inhibitor (May 2014-October 2015). In total, 208 patients were included: 98 (47%) treatment-experienced, 42 (20%) decompensated and 55 (27%) MELD score >10. In 131 (63%), treatment was SOF+DCV and in 77 (37%), SOF/LDV. Overall, 86% received RBV. RBV addition and extension to 24 weeks was higher in the SOF/LDV group (95% vs 80%, P=.002 and 83% vs 72%, P=.044, respectively). A higher percentage of decompensated patients were treated with DCV than LDV (25% vs 12%, P=.013). Overall, SVR12 was 93.8% (195/208): 94% with SOF+DCV and 93.5% with SOF/LDV. SVR12 was achieved in 90.5% of decompensated patients. Eleven treatment failures: 10 relapses and one breakthrough. RBV addition did not improve SVR (RR: 1.08; P=.919). The single factor associated with failure to achieve SVR was platelet count <75×10E9/mL (RR: 3.50, P=.019). In patients with MELD <10, type of NS5A inhibitor did not impact on SVR12 (94% vs 97%; adjusted RR: 0.49). Thirteen patients (6.3%) had serious adverse events, including three deaths (1.4%) and one therapy discontinuation (0.5%), higher in decompensated patients (16.7% vs 3.6%, P<.006). In patients with GT3 infection and cirrhosis, SVR12 rates were high with both SOF+DCV and SOF/LDV, with few serious adverse events.


Detection of carbamic and organophosphorous pesticides in water samples using a cholinesterase biosensor based on Prussian Blue-modified screen-printed electrode.
In the present paper, a comparative study using Co-phthalocyanine and Prussian Blue-modified screen-printed electrodes, has been performed. Both the electrodes have demonstrated an easiness of preparation together with high sensitivity towards thicoholine (LOD=5 x 10(-7) and 5 x 10(-6) M for Co-phthalocyanine and Prussian Blue, respectively) with high potentialities for pesticide measurement. Prussian Blue-modified screen-printed electrodes were then selected for successive enzyme immobilization due to their higher operative stability demonstrated in previous works. AChE and BChE enzymes were used and inhibition effect of different pesticides was studied with both the enzymes. AChE-based biosensors have demonstrated a higher sensitivity towards aldicarb (50% inhibition with 50 ppb) and carbaryl (50% inhibition with 85 ppb) while BChE biosensors have shown a higher affinity towards paraoxon (50% inhibition with 4 ppb) and chlorpyrifos-methyl oxon (50% inhibition with 1 ppb). Real samples were also tested in order to evaluate the matrix effect and recovery values comprised between 79 and 123% were obtained.


Arabinose 5-phosphate analogues as mechanistic probes for Neisseria meningitidis 3-deoxy-D-manno-octulosonate 8-phosphate synthase.
3-Deoxy-D-manno-octulosonate 8-phosphate (KDO8P) synthase catalyses the condensation reaction between phosphoenolpyruvate and D-arabinose 5-phosphate (D-A5P) in a key step in lipopolysaccharide biosynthesis in Gram-negative bacteria. The KDO8P synthase from Neisseria meningitidis was cloned into Escherichia coli, overexpressed and purified. A variety of D-A5P stereoisomers were tested as substrates, of these only D-A5P and l-X5P were substrates. The Asn59Ala mutant of N. meningitidis KDO8P synthase was constructed and this mutant retained less than 1% of the wild-type activity. These results are consistent with a catalytic mechanism for this enzyme in which the C2 and C3 hydroxyl groups of D-A5P and Asn59 are critical.


Complementary Roles of Near-Infrared Spectroscopy and Intravascular Ultrasound in the Prediction of Periprocedural Myocardial Injury.
Lipid-rich plaque detected by near-infrared spectroscopy (NIRS) and attenuated plaque detected by intravascular ultrasound (IVUS) predict periprocedural myocardial injury (MI) following percutaneous coronary intervention (PCI). Although echolucent plaque detected by IVUS was reported to be associated with a no-reflow phenomenon in acute myocardial infarction, it remains unclear whether echolucent plaque is predictive of periprocedural MI following elective PCI. We aimed to elucidate whether echolucent plaque is independently associated with periprocedural MI after elective PCI and whether the predictive ability for periprocedural MI is improved by the combination of NIRS and IVUS. This retrospective study included 121 lesions of 121 patients who underwent elective NIRS-IVUS-guided stent implantation. Periprocedural MI was defined as post-PCI cardiac troponin T > 70 ng/L. A maximum 4-mm lipid core burden index > 457 was regarded as lipid-rich plaque. Echolucent plaque was defined as the presence on IVUS of an echolucent zone and attenuated plaque as an attenuation arc > 90°. Periprocedural MI occurred in 39 lesions. In multivariable analysis, echolucent plaque, attenuated plaque, and lipid-rich plaque were independent predictors of periprocedural MI. Adding echolucent plaque and attenuated plaque to lipid-rich plaque improved the predictive performance (C statistic 0.825 vs 0.688; P = 0.001). Periprocedural MI increased with the number of predictors: 3% [1/39], 29% [10/34], 47% [14/30], and 78% [14/18] for 0, 1, 2, and 3 predictors, respectively (P < 0.001). Echolucent plaque is a major predictor of periprocedural MI, independently from lipid-rich plaque and attenuated plaque. Compared with NIRS alone, the combination of NIRS with IVUS signatures improves the predictive ability.


Is Healthcare Responsibility in Patients' Suicide Provable Beyond all Reasonable Doubt? An Analysis of Preventing Strategies and Medical Liability Through a Case Series.
As a result of the duty of care, the healthcare professional has an obligation of surveillance towards the patients that are under their treatment. According to that principle, the Italian Criminal Supreme Court declared a guilty sentence in many cases of psychiatric patients' suicide, recognizing the criminal liability of the healthcare personnel. This is true not only for suicides occurred inside the hospital, but also for the suicide of psychiatric outpatients. Only in a few cases, the Italian Supreme Court acquitted the healthcare personnel. This happened when it was recognized that the suicide event was unavoidable. Despite the fact that suicide risk is often unpredictable, this does not exclude medical liability. In this work we examine the judicial aspects of five cases of suicide of psychiatric patients, considering whether different preventive strategies could have been effective in preventing the suicide event. This work aims to understand whether the suicide of psychiatric patient is effectively preventable and - referring to healthcare responsibility under penal judgment - if that could be proven beyond all reasonable doubt.


Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study.
A randomized, double-blind, multicenter study was conducted to compare the anti-tumor activity of letrozole vs. tamoxifen in postmenopausal women with ER and/or PgR positive primary untreated breast cancer. Three hundred thirty-seven postmenopausal women with ER and/or PgR positive primary untreated breast cancer were randomly assigned once daily treatment with either letrozole 2.5 mg or tamoxifen 20 mg for four months. At baseline none of the patients were considered to be candidates for breast-conserving surgery (BCS) and 14% of the patients were considered inoperable. The primary endpoint was to compare overall objective response (CR + PR) determined by clinical palpation. Secondary endpoints included overall objective response on ultrasound and mammography and the number of patients who qualified for BCS. Overall objective response rate (clinical palpation) was statistically significantly superior in the letrozole group, 55% compared to tamoxifen, 36% (P < 0.001). Secondary endpoints of ultrasound response, 35% vs. 25% (P = 0.042), mammographic response, 34% vs. 16% (P < 0.001), and BCS, 45% vs. 35% (P = 0.022) between the letrozole and tamoxifen groups, respectively, showed letrozole to be significantly superior. Both treatments were well tolerated. This study shows that letrozole is more effective than tamoxifen as preoperative therapy in postmenopausal patients with ER and/or PgR positive primary untreated breast cancer and is at least as well tolerated.


Enactment versus conceptual encoding: equivalent item memory but different source memory.
It has been suggested that performing a physical action (enactment) is an optimally effective encoding task, due to the incorporation of motoric information in the episodic memory trace, and later retrieval of that information. The current study contrasts old/new recognition of objects after enactment to a conceptual encoding task of cost estimation. Both encoding tasks yielded high accuracy, and robust differences in brain activity as compared to new objects, but no differences between encoding tasks. These results are not supportive of the idea that encoding by enactment leads to the spontaneous retrieval of motoric information. When participants were asked to discriminate between the two classes of studied objects during a source memory task, perform-encoded objects elicited higher accuracy and different brain activity than cost-encoded objects. The extent and nature of what was retrieved from memory thus depended on its utility for the assigned memory test: object information during the old/new recognition test, but additional information about the encoding task when necessary for a source memory test. Event-related potentials (ERPs) recorded during the two memory tests showed two orthogonal effects during an early (300-800 msec) time window: a differentiation between studied and unstudied objects, and a test-type (retrieval orientation) effect that was equivalent for old and new objects. Later brain activity (800-1300 msec) differentiated perform- from cost-encoded objects, but only during the source memory test, suggesting temporally distinct phases of retrieval.


Lontophoretic administration of dexamethasone into the tarsocrural joint in horses.
To determine whether iontophoretic administration of dexamethasone to horses results in detectable concentrations in synovial fluid, plasma, and urine. 6 adult mares. Iontophoresis was used to administer dexamethasone. Treatments (4 mA for 20 minutes) were administered to a tarsocrural joint of each mare. The drug electrode contained 3 ml of dexamethasone sodium phosphate at a concentration of 4 or 10 mg/ml. Samples of synovial fluid, blood, and urine were obtained before and 0.5, 4, 8, and 24 hours after each treatment. All samples were tested for dexamethasone using an ELISA. Synovial fluid also was evaluated for dexamethasone, using high-performance liquid chromatography. The lower and upper limits of detection for dexamethasone in synovial fluid with the ELISA were 0.21 and 1.5 ng/ml, respectively. Dexamethasone administered at a concentration of 10 mg/ml was detected by the ELISA in synovial fluid of 5 mares from 0.5 to 24 hours and in urine of 4 mares from 0.5 to 8 hours after each treatment, but it was not detected in plasma. Mean synovial fluid concentration of dexamethasone was 1.01 ng/ml. Dexamethasone administered at a concentration of 4 mg/ml was detected by the ELISA in urine of 2 mares at 0.5 and 4 hours after treatment, but it was not detected in synovial fluid or plasma. Iontophoresis cannot be considered an effective method for delivery of dexamethasone to synovial fluid of horses, because drug concentrations achieved in this study were less than therapeutic concentrations.


The evolution of BIR domain and its containing proteins.
BIR domain and its containing proteins play critical roles in cell apoptosis and cell division. Here several lines of novelty were revealed based on a comprehensive evolutionary analysis of BIR domains in 11 representative organisms. First, the type II BIR domains in Survivin and Bruce showed more conservation compared with the type I BIR domains in the inhibitors of apoptosis proteins (IAPs). Second, cIAP was derived from a XIAP duplicate and emerged just after the divergence of invertebrates and vertebrates. Third, the three BIR domains of NAIP displayed significantly elevated evolutionary rates compared with the BIR domains in other IAPs.


Subscapularis-Sparing Approaches to Total Shoulder Arthroplasty: Ready for Prime Time?
To minimize the risk of subscapularis failure after shoulder replacement, a method of preserving the subscapularis while allowing access to the glenohumeral joint was developed. Only the inferior 30% to 50% of the subscapularis tendon is detached from the humerus, leaving the superior aspect attached to the lesser tuberosity. This subscapularis-sparing, minimally invasive approach to the glenohumeral joint was evaluated in 43 subjects with a minimum 2-year follow-up and subscapularis strength equal to the opposite side. The approach provided adequate exposure for shoulder replacement surgery and decreased risk of postoperative failure of the subscapularis tendon.


Down-regulation of Lsm1 is involved in human prostate cancer progression.
Elucidation of genetic alterations is an approach to understanding the underlying molecular mechanisms of progression of human prostate cancers. We have searched for genes differentially expressed in advanced prostate cancers using cDNA-representational difference analysis, and thereby isolated the Lsm1 as one of down-regulated gene. An Lsm1 expression vector was transfected into PC3 cells, normally featuring down-regulated Lsm1, and four transfectants were established. No differences in morphology or cell proliferation were evident in comparison with parent PC3 or PC3/mock-transfectants. In contrast, significant suppression of invasive potential or metastatic ability of Lsm1 transfectants was observed in the Matrigel chemoinvasion assay and in nude mice, respectively. With human prostate cancers, almost all of informative prostatectomised cases without neoadjuvant therapy showed allelic retention in the Lsm1 region, whereas refractory cancers frequently showed allelic loss in this region. No critical gene mutations were found in open reading frame of Lsm1 in prostate cancers examined by PCR-SSCP analysis, including localised and refractory cancers. These results suggest that Lsm1 is deeply involved in prostate cancer progression through its down-regulation, independent of any gene mutation.


The combined effect of permeation enhancement and proteolysis inhibition on the systemic exposure of orally administrated peptides: Salcaprozate sodium, soybean trypsin inhibitor, and teriparatide study in pigs.
Oral delivery of peptides and proteins is hindered by their rapid proteolysis in the gastrointestinal tract and their inability to permeate biological membranes. Various drug delivery approaches are being investigated and implemented to overcome these obstacles. In the discussed study conducted in pigs, an investigation was undertaken to assess the effect of combination of a permeation enhancer - salcaprozate sodium, and a proteolysis inhibitor - soybean trypsin inhibitor, on the systemic exposure of the peptide teriparatide, following intraduodenal administration. Results demonstrate that this combination achieves significantly higher Cmax and AUC (~10- and ~20-fold respectively) compared to each of these methodologies on their own. It was thus concluded that an appropriate combination of different technological approaches may considerably contribute to an efficient oral delivery of biological macromolecules.


The pedicled rectus femoris muscle flap for reconstruction of complicated abdominal wall defects.
Large or complicated abdominal wall defects caused by recurrent incisional hernias, infections or tumor resections often require the use of prosthetic mesh, local tissue transposition or even distant muscle flaps for proper reconstruction. Due to the sometimes discouraging results of meshes muscle flaps are an appreciated alternative. We followed up a series of cases to assess the value of the pedicled rectus femoris muscle flap. Follow up time ranged from 6 months to 4 years. 12 cases of reconstruction of the abdominal wall using pedicled rectus femoris muscle flaps after tumor resections, recurrent incisional hernias, and infection are presented. Abdominal wall stability was examined clinically. The aesthetic and the functional results were assessed using a standardized questionnaire. The loss of torque in the quadriceps muscle was evaluated using a dynamometer. In all but one patients a stable abdominal wall could be reconstructed. We saw no major complications. The loss of true muscular capacity in the quadriceps muscle of the operated leg was 19% compared to the nonoperated leg, but was tolerated very well. The donor site morbidity is moderate. The flap provides an easy and save possibility to reconstruct the abdominal wall. The rectus femoris muscle flap should be considered as an alternative for abdominal wall reconstruction.


Correlation between anatomic foot and ankle movement measured with MRI and with a motion analysis system.
Several studies have attempted to measure how well external markers track internal bone movement using pins drilled into the foot, but this is too invasive for the pediatric population. This study investigated how well a six segment foot model (6SFM) using external markers was able to measure bone movement in the foot compared to MRI measurements. The foot was moved into different positions using a plastic foot jig and measurements were taken with both systems. The aims were to: (1) Look at the correlation between movement tracked with an Electronic Motion Tracking System (EMTS) and by measurements derived from MRI images, specifically the principal intercept angles (PIAs) which are the angles of intersection between principal axes of inertia of bone volumes. (2) To see how well external motion measured by the 6SFM could predict PIAs. Four bone pairs had their movement tracked: Tibia-Calcaneus, Calcaneus-Cuboid, Navicular-1st Metatarsal, and 1st Metatarsal-Hallux. The results showed moderate correlation between measured PIAs and those predicted at the Tibia-Calcaneus, Navicular-1st Metatarsal, and 1st Metatarsal-Hallux joints. Moderate to high correlation was found between the PIA and movement in a single anatomic plane for all four joints at several positions. The 6SFM using the EMTS allows reliable tracking of 3D rotations in the pediatric foot, except at the Calcaneus-Cuboid joint.


Multifactorial intervention in diabetes care using real-time monitoring and tailored feedback in type 2 diabetes.
In 2011, we demonstrated that an individualized health management system employing advanced medical information technology, designated ubiquitous (u)-healthcare, was helpful in achieving glycemic control without hypoglycemia in patients with diabetes. Following this, we generated a new multidisciplinary u-healthcare system by upgrading our clinical decision support system (CDSS) rule engine and integrating a physical activity-monitoring device and dietary feedback into a comprehensive package. In a randomized, controlled clinical trial, patients with type 2 diabetes aged over 60 years were assigned randomly to a self-monitored blood glucose (SMBG) group (N = 50) or u-healthcare group (N = 50) for 6 months. The primary endpoint was the proportion of patients achieving glycated hemoglobin (HbA1c) <7 % without hypoglycemia. Changes in body composition and lipid profiles were also investigated. The u-healthcare group was educated to use a specially designed glucometer and an activity monitor that automatically transferred test results to a hospital-based server. An automated CDSS rule engine generated and sent patient-specific messages about glucose, diet, and physical activity to their mobile phones and a Web site. After 6 months of follow-up, the HbA1c level was significantly decreased in the u-healthcare group [8.0 ± 0.7 % (64.2 ± 8.8 mmol/mol) to 7.3 ± 0.9 % (56.7 ± 9.9 mmol/mol)] compared with the SMBG group [8.1 ± 0.8 % (64.9 ± 9.1 mmol/mol) to 7.9 ± 1.2 % (63.2 ± 12.3 mmol/mol)] (P < 0.01). The proportion of patients with HbA1c < 7 % without hypoglycemia was greater in the u-healthcare group (26 %) than in the SMBG group (12 %; P < 0.05). Body fat mass decreased and lipid profiles improved in the u-healthcare group but not in the SMBG group. This u-healthcare service provided effective management for older patients with type 2 diabetes (ClinicalTrial.Gov: NCT01137058).


Thromboprophylaxis in the oldest old with atrial fibrillation: between Scylla and Charybdis.
Within a few decades half of the patients with non-valvular atrial fibrillation (AF) will be older than 80 years. These patients are at particularly high risk of thromboembolism (Scylla) but also of the hemorrhagic complications of thromboprophylaxis (Charybdis). A frequent compromise is to use as antithrombotic agents instead of vitamin-K antagonists aspirin or other antiplatelet drugs, which are ineffective for thromboprophylaxis in the oldest old and definitely not free from a high risk of severe bleeding. All the new direct anticoagulants currently licensed (dabigatran, rivaroxaban, apixaban) are at least as effective as warfarin for thromboprophylaxis in AF, but the risk of the intracranial bleeding, the most feared complication of anticoagulant therapy, is at least halved. In the oldest patients of 80 years of age or more preliminary data, available so far only for dabigatran, indicate that the favorable outcomes of direct anticoagulants are also present in this subgroup, often left untreated for fear of intracranial bleeding. The choice between the different direct anticoagulants is driven by the presence or not of renal insufficiency, the presence and degree of multimorbidity and polypharmacy and by the likelihood or not of poor treatment adherence in patients who are often frail and with some degree of cognitive impairment.


Differential role of 5-HT1A and 5-HT1B receptors on the antinociceptive and antidepressant effect of tramadol in mice.
Tramadol, (1RS,2RS)-2-[(dimethylamine)-methyl]-1-(3-methoxyphenyl)-cyclohexanol hydrochloride, is an atypical analgesic which binds weakly to ì-opioid receptors and enhances the extra-neuronal concentration of noradrenaline and serotonin by interference with both the uptake and release mechanisms. The present study was undertaken to evaluate the potential role of 5-HT1A and 5-HT1B receptors on the analgesic and antidepressant-like effect of tramadol. The effect of either a selective 5-HT1A receptor antagonist (WAY 100635; N-2-[4-(2-methoxyphenyl-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexane carboxamide; 0.2-0.8, 8 mg/kg) or a selective 5-HT1B receptor antagonist (SB 216641; N-[3-(3-dimethylamino) ethoxy-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide; 0.2-0.8, 8 mg/kg) was investigated in mice in combination with tramadol by means of the hot-plate test, a phasic nociceptive model, and the forced swimming test, a paradigm aimed at screening potential antidepressants. The results showed that WAY 100635 enhanced the antinociceptive effect and produced a large decrease in the antidepressant-like effect of tramadol. In contrast, SB 216641 did not significantly modify either the analgesic or the antidepressant-like effects of tramadol. These findings suggest that 5-HT1A receptors modulate the analgesic and the antidepressant-like effects of tramadol in differing ways. The results suggest the involvement of the 5-HT1A autoreceptors from the raphe nuclei and spinal 5-HT1A receptors in the antinociceptive effect. In contrast, the 5-HT1A receptors located in the forebrain may be responsible for the blockade of the antidepressant-like effect of tramadol. 5-HT1B receptors seem not to modify these effects in the models investigated.


Two types of thalamic reticular cells in relation to the two visual thalamocortical systems in the rat.
We found in urethane-anesthetized rats that thalamic reticular (TR) cells responding to an electrical stimulus of the optic tract (OT) can be further subdivided into two types, viz. S- and L-type cells. S-type cells, which were selectively excited from area 17 of the visual cortex, were characterized by short latency responses (2.3-6.1 ms) to OT stimulation. TR cells activated antidromically from the dorsal lateral geniculate nucleus were all classified as S-type. Long OT latencies (5.2-15.3 ms) and selective excitation from area 18a were peculiar to L-type cells, which showed antidromic responses to the lateral posterior nucleus stimulation. Mapping studies documented that cells belonging to each type were segregated in the thalamic reticular nucleus; L-type cells were located in the most posterior part. It is suggested that S- and L-type cells are inhibitory interneurons modulating activity of geniculocortical and extrageniculocortical projection cells, respectively.


Lipid rafts orchestrate signaling by the platelet receptor glycoprotein VI.
The platelet collagen receptor glycoprotein VI (GPVI) couples to the immune receptor adaptor Fc receptor gamma-chain (FcRgamma) and signals using many of the same intracellular signaling molecules as immune receptors. Studies of immune receptor signaling have revealed a critical role for specialized areas of the cell membrane known as lipid rafts, which are enriched in essential signaling molecules. However, the role of lipid rafts in signaling in nonimmune cells such as platelets remains poorly defined. This study shows that GPVI-FcRgamma does not constitutively associate with rafts, but is recruited to lipid rafts following receptor stimulation in both GPVI-expressing RBL-2H3 cells and human platelets. FcRgamma is required for GPVI association with lipid rafts, as mutant GPVI receptors that do not couple to FcRgamma were unable to associate with lipid rafts after receptor clustering. Following GPVI stimulation in platelets, virtually all phosphorylated FcRgamma was found in lipid rafts, but inhibition of FcRgamma phosphorylation did not block receptor association with lipid rafts. This work demonstrates that lipid rafts orchestrate GPVI receptor signaling in platelets in a manner analogous to immune cell receptors and supports a model of GPVI signaling in which FcRgamma phosphorylation is controlled by ligand-dependent association with lipid rafts.


The mat- allele of Podospora anserina contains three regulatory genes required for the development of fertilized female organs.
In the filamentous fungus Podospora anserina, mating type is specified by a single locus with two alternate alleles, termed mat- and mat+. A previous study has shown that the mat+ sequence consists of 3.7 kb and contains a single gene relevant to the sexual cycle. This gene, called FPR1, encodes a protein with a HMG DNA-binding domain and is required for fertilization and for the development of the fertilized fruiting body. The mat- sequence, which is 4.7 kb in length, displays a more complex structure. We present here the characterization of two genes, called SMR1 and SMR2, which are present in the mat- allele along with the FMR1 gene. FMR1, whose role in the sexual cycle has been already partially described, encodes a protein with an alpha 1-domain and was shown to control fertilization. We demonstrate that these three genes are required for the developmental events that occur in the female organ after fertilization. The additional role of FMR1 requires a region of unknown function that is distinct from the alpha 1-domain. SMR1 encodes a protein with a putative acidic/hydrophobic alpha-helix, which has been proposed to be a feature common to transcriptional activators. The protein sequence deduced from SMR2 contains an HMG motif suggesting that it is a transcription factor.


Comparison of two simple models for prediction of short term mortality in patients after severe traumatic brain injury.
The subscale motor score of Glasgow Coma Scale (msGCS) and the Abbreviated Injury Score of head region (HAIS) are validated prognostic factors in traumatic brain injury (TBI). The aim was to compare the prognostic performance of a HAIS-based prediction model including HAIS, pupil reactivity and age, and the reference prediction model including msGCS in emergency department (ED), pupil reactivity and age. Secondary analysis of a prospective epidemiological study including patients after severe TBI (HAIS > 3) with follow-up from the time of accident until 14 days or earlier death was performed in Switzerland. Performance of prediction, based on accuracy of discrimination [area under the receiver-operating curve (AUROC)], calibration (Hosmer-Lemeshow test) and validity (bootstrapping with 2000 repetitions to correct) for optimism of the two prediction models were investigated. A non-inferiority approach was performed and an a priori threshold for important differences was established. The cohort included 808 patients [median age 56 {inter-quartile range (IQR) 33-71}, median motor part of GCS in ED 1 (1-6), abnormal pupil reactivity 29.0%] with a death rate of 29.7% at 14 days. The accuracy of discrimination was similar (AUROC HAIS-based prediction model: 0.839; AUROC msGCS-based prediction model: 0.826, difference of the 2 AUROC 0.013 (-0.007 to 0.037). A similar calibration was observed (Hosmer-Lemeshow X2 11.64, p = 0.168 vs. Hosmer-Lemeshow X2 8.66, p = 0.372). Internal validity of HAIS-based prediction model was high (optimism corrected AUROC: 0.837). Performance of prediction for short-term mortality after severe TBI with HAIS-based prediction model was non-inferior to reference prediction model using msGCS as predictor.


Correction.
In the Careers article Life As An Independent Midwife in our February 24 issue, an interviewee suggested that insurance provided via Independent Midwives UK (IMUK) was insufficient to cover home births. IMUK has pointed out that the personal indemnity insurance product held by all IMUK members does cover home births and indeed the full scope of independent midwifery practice. We apologise for the error.


Calmodulin modulates initiation but not termination of spontaneous Ca2+ sparks in frog skeletal muscle.
Calmodulin is a ubiquitous Ca(2+) sensing protein that binds to and modulates the sarcoplasmic reticulum Ca(2+) release channel, ryanodine receptor (RYR). Here we assessed the effects of calmodulin on the local Ca(2+) release properties of RYR in permeabilized frog skeletal muscle fibers. Fluorescently labeled recombinant calmodulin in the internal solution localized at the Z-line/triad region. Calmodulin (0.05-5.0 micro M) in the internal solution (free [Ca(2+)](i) approximately 50-100 nM) initiated a highly cooperative dose-dependent increase in Ca(2+) spark frequency, with a half-maximal activation (K) of 1.1 micro M, a Hill coefficient (n) of 4.2 and a fractional maximal increase in frequency (R) of 17-fold. A non-Ca(2+) binding mutant of calmodulin elicited a similar highly cooperative dose-dependent increase in spark frequency (K = 1.0 micro M; n = 3.7; R = 12-fold). Spatiotemporal properties of Ca(2+) sparks were essentially unaffected by either wild-type or mutant calmodulin. An N-terminal extension of calmodulin, (N+3)calmodulin, that binds to but does not activate RYR at nM [Ca(2+)] in sarcoplasmic reticulum vesicles, prevented the calmodulin-induced increase in spark frequency. These data suggest that exogenous Ca(2+)-free calmodulin cooperatively sensitizes the Ca(2+) release channel to open, but that Ca(2+) binding to the added calmodulin does not play a significant role in the termination of Ca(2+) sparks.


Characterization of an alternatively spliced GADD45alpha, GADD45alpha1 isoform, in arsenic-treated epithelial cells.
A new GADD45alpha isoform, GADD45alpha1, was identified in the cellular response to arsenic. DNA sequencing and biochemical analyses suggested that GADD45alpha1 is derived from an alternative splicing of the GADD45alpha mRNA by skipping the region corresponding to exon2 of the gadd45alpha gene during mRNA maturation. In addition to the size difference due to the lack of 34 amino acids encoded by exon2, GADD45alpha1 and GADD45alpha proteins differ in their effects on cell proliferation and cell cycle transition. Unlike GADD45alpha, the GADD45alpha1 is unable to attenuate cell growth. In over-expression experiments, the full length GADD45alpha, but not the GADD45alpha1, sensitized cells to arsenic-induced prometaphase arrest of the cell cycle. Furthermore, GADD45alpha1 appears to be able to antagonize the function of the GADD45alpha on the G2/M phase cell cycle arrest as demonstrated in cotransfection experiment. Thus, these data suggest that the generation of the GADD45alpha1 isoform may not only offset but also antagonize the effects of arsenic and GADD45alpha on cell growth and cell cycle regulation.


Characterization of tetracycline resistance lactobacilli isolated from swine intestines at western area of Taiwan.
To investigate the frequency of tetracycline resistance (Tet-R) lactobacilli in pig intestines, a total of 256 pig colons were analyzed and found to contain typical colonies of Tet-R lactic acid bacteria in every sample, ranging from 3.2 × 10(3) to 6.6 × 10(5) CFU/cm(2). From these samples, a total of 159 isolates of Tet-R lactobacilli were obtained and identified as belonging to 11 species, including Lactobacillus reuteri, Lactobacillus amylovorus, Lactobacillus salivarius, Lactobacillus plantarum, Lactobacillus ruminis, Lactobacillus kefiri, Lactobacillus fermentum, Lactobacillus sakei, Lactobacillus coryniformis, Lactobacillus parabuchneri and Lactobacillus letivazi. Based on the EFSA (2008) breakpoints, all isolates, after MIC analysis, were qualified as Tet-R, from which the significant high Tet-R MIC(50) and MIC(90) values indicated an ecological distribution of Tet-R lactobacilli mostly with high resistance potency in pig colons. PCR-detection identified 5 tet genes in these isolates, the most predominant one being tet (W), followed by tet (M), (L), (K), and (Q). Their detection rates were 82.0%, 22.5%, 14.4%, 8.1% and 0.9%, respectively. Noteworthily, isolates of the same species carrying identical tet gene(s) usually had a wide different MIC values. Furthermore, strain-subtyping of these isolates by REP-PCR demonstrated a notable genotypic biodiversity % (average = 62%).


Association of Group Prenatal Care in US Family Medicine Residencies With Maternity Care Practice: A CERA Secondary Data Analysis.
Group prenatal care has been shown to improve both maternal and neonatal outcomes. With increasing adaption of group prenatal care by family medicine residencies, this model may serve as a potential method to increase exposure to and interest in maternity care among trainees. This study aims to describe the penetration, regional and program variations, and potential impacts on future maternity care practice of group prenatal care in US family medicine residencies. The CAFM Educational Research Alliance (CERA) conducted a survey of all US family medicine residency program directors in 2013 containing questions about maternity care training. A secondary data analysis was completed to examine relevant data on group prenatal care in US family medicine residencies and maternity care practice patterns. 23.1% of family medicine residency programs report provision of group prenatal care. Programs with group prenatal care reported increased number of vaginal deliveries per resident. Controlling for average number of vaginal deliveries per resident, programs with group prenatal care had a 2.35 higher odds of having more than 10% of graduates practice obstetrics and a 2.93 higher odds of having at least one graduate in the past 5 years enter an obstetrics fellowship. Residency programs with group prenatal care models report more graduates entering OB fellowships and practicing maternity care. Implementing group prenatal care in residency training can be one method in a multifaceted approach to increasing maternity care practice among US family physicians.


Calcitriol does not prevent bone loss in patients with asthma receiving corticosteroid therapy: a double-blind placebo-controlled trial.
Oral glucocorticoid therapy reduces bone mineral density (BMD) and increases fracture risk. It is uncertain whether inhaled glucocorticoids, the most commonly used long-term therapy for asthma, have a similar effect. If bone loss does occur, it is unclear whether this is preventable by calcitriol. Patients with asthma receiving inhalational plus intermittent oral glucocorticoids lose bone, and treatment with 0.5 microg/day of calcitriol will prevent bone loss. A 2-year randomized double-blind placebo-controlled trial. One hundred eight patients with asthma were stratified by gender, age, and inhaled glucocorticoid dose and treated with calcitriol (n=55) or placebo (n=53). There were 41 men (mean age 53.2+/-1.7 years) and 67 women (mean age 49.1+/-1 years) with moderate to severe asthma (requiring >/=800 microg/day of beclomethasone dipropionate or equivalent maintenance therapy). BMD values at the lumbar spine (LS) and femoral neck (FN) were measured at baseline and at 6, 12, and 24 months using dual x-ray absorptiometry. Changes in LS and FN BMD. Bone loss occurred in both groups at the FN (both p<0.03) and at the LS in the calcitriol (p<0.001), but not the control, group. Bone loss was not less in the calcitriol group at either site. Patients with asthma receiving inhalational plus intermittent short courses of oral glucocorticoids lose bone. Calcitriol is unlikely to be appropriate therapy against this bone loss.


Proton pump inhibitors and hypomagnesemia: A meta-analysis of observational studies.
Previous meta-analyses have suggested that there might be an association between the use of proton pump inhibitors (PPIs) and the development of hypomagnesemia, although the conclusions were no definitive. To provide an update on this topic, we performed a meta-analysis of all observational studies that examined the association between the use of PPIs and the development of hypomagnesemia. A literature search was conducted in MEDLINE, Scopus and Cochrane Central Register of Controlled Trials (January 1970 to June 2018) to identify observational studies that examined the association between the use of PPIs and the incidence and prevalence of hypomagnesemia. In the absence of randomized controlled trials, we focused primarily on observational studies, including cross-sectional, case-control, retrospective, and prospective cohort studies. There was no limitation on sample size or study duration. Random-effect models meta-analyses were used to compute pooled unadjusted and adjusted odds ratios (ORs) for binary variables. Sixteen observational studies were identified, including 13 cross-sectional studies, 2 case-control studies, and 1 cohort study, with a total of 131,507 patients. The pooled percentage of PPI users was 43.6% (95% confidence interval [CI] 25.0%, 64.0%). Among PPI users, 19.4% (95% CI 13.8%, 26.5%) had hypomagnesemia compared to 13.5% (95% CI 7.9%, 22.2%) among nonusers. By meta-analysis, PPI use was significantly associated with hypomagnesemia, with a pooled unadjusted OR of 1.83 (95% CI 1.26, 2.67; P = .002) and a pooled adjusted OR of 1.71 (95% CI 1.33, 2.19; P < .001). In subgroup analyses, high-dose PPI use was associated with higher odds for hypomagnesemia relative to low-dose PPI use (pooled adjusted OR 2.13; 95% CI 1.26, 3.59; P = .005). Our findings are in support of the results of the previous meta-analyses. Furthermore, we found a dose-response between the PPI use and development of hypomagnesemia.


Post-publication promotion in rheumatology: a survey focusing on social media.
The use of social media platforms (SMPs) in the field of scientific literature is a new and evolving realm. The past few years have seen many novel strategies to promote engagement of readers with articles. The aim of this study was to gauge the acceptance, opinion, and willingness to partake in the creation of online social media educative material among authors. We conducted a validated and anonymized cross-sectional e-survey with purposive sampling among authors of the Indian Journal of Rheumatology journal over a cloud-based platform (SurveyMonkey). Descriptive statistics are used and values expressed as the number of respondents (n) against each answer. Of 408 authors, 102 responded. We found that a large majority (74) supported promotions on SMPs. Visual abstracts (81) were the most preferred means for promotion. A reasonable proportion (54) of the authors held the view that they could make these materials for themselves, with little guidance. However, currently only a few (47) were doing so. Awareness on social media editors in rheumatology was dismal (4). Citations were the preferred metric of article visibility (95), followed by altmetrics (21). These findings suggest that authors support article promotions on SMPs, although most do not promote their articles. Graphical abstracts are the preferred means of promotions. Further, the opinion on logistics is divided, calling for larger studies to understand the factors that need to be addressed to bridge the gap.