Natalizumab vs interferon beta 1a in relapsing-remitting multiple sclerosis: a head-to-head retrospective study.
No head-to-head study has been performed yet to assess whether natalizumab is more effective than classical immunomodulators in multiple sclerosis (MS). To retrospectively compare the efficacy of natalizumab vs IFN beta 1a SC (44 μg; Rebif(®) ) on clinical and radiological findings in two matched cohorts of patients with MS. We retrospectively enrolled two cohorts of 42 patients (F/M: 35/7) with relapsing-remitting multiple sclerosis treated with natalizumab or IFN beta 1a for at least 12 consecutive months. Outcome measures were annualized relapse rate (ARR), changes in expanded disability status scale (EDSS) score, and number of contrast-enhancing lesions (CELs) at magnetic resonance imaging (MRI). In both groups, the ARR in the 12 months of treatment was lower than in the 12 months before therapy (0.24 vs 1.50 in natalizumab-treated group, P < 0.0000; 0.55 vs 1.10 in IFN beta 1a-treated group, P = 0.0006), being the effect of natalizumab significantly stronger (P = 0.0125). EDSS reduction was significantly different between the two groups in favor of natalizumab (P = 0.0018). The frequency and number of CELs per patient were decreased in both groups. In the second year, the treatment affected ARR and EDSS progression in the two groups of patients similarly to the first year, whereas number of CELs decreased more significantly in natalizumab group (P = 0.008). After 12 and 24 months of therapy, natalizumab was more effective than IFN beta 1a SC on both disease activity and disability progression. Prospective head-to-head studies would be helpful to further evaluate the differences observed in the MRI outcomes.


Cephalometric evaluation of adenoids, upper airway, maxilla, velum length, need ratio for determining velopharyngeal incompetency in subjects with unilateral cleft lip and palate.
Children with cleft lip and palate (CLP) are seen to have reduced airway size and large adenoids, which might lead to different characteristics in the upper airway and surrounding tissues from both morphological and functional perspectives. Decrease in adenoid size and increase in need ratio in cleft patients might lead to velopharyngeal incompetency (VPI) and development of nasality in adulthood. No studies have been conducted on the Indian population with variables contributing to VPI. So the aim was to evaluate the size and position of the adenoids, upper airway, maxilla, velum length and need ratio contributing to VPI in subjects with and without unilateral cleft lip and palate (UCLP) during juvenile and adolescent stages. Cephalograms of 120 subjects with 6-17 years were taken and various linear and angular measurements were measured and data was analyzed using the unpaired t test. Adenoids were significantly larger and the upper airway smaller in the juvenile and adolescent cleft group than in the non-cleft group. In the adolescent cleft group, airway was larger than that in the adolescent non-cleft group. The maxilla was small and retropositioned in juvenile and adolescent subjects as compared to non cleft cases. Length of velum was smaller and need ratio was larger in both juvenile and adolescent groups as compared to the non-cleft group, suggestive of velopharyngeal incompetence. Decreased Adenoids, restricted airway, small, retruded maxilla, smaller velum length and larger need ratio larger were seen in the cleft group as compared to the non-cleft group, which was suggestive of VPI.


Synthesis of naturally occurring iminosugars from D-fructose by the use of a zinc-mediated fragmentation reaction.
A short synthesis of 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) and a formal synthesis of australine are described. In both cases, D-fructose is employed as the starting material and converted into a protected methyl 6-deoxy-6-iodo-furanoside. Zinc-mediated fragmentation produces an unsaturated ketone which serves as a key building block for both syntheses. Ozonolysis, reductive amination with benzylamine and deprotection affords 1,4-dideoxy-1,4-imino-D-arabinitol in only 7 steps and 11% overall yield from D-fructose. Alternatively, reductive amination with homoallylamine, ring-closing metathesis and protecting group manipulations give rise to an intermediate which can be converted into australine in 3 steps. The intermediate is prepared by two different strategies both of which use a total of 9 steps. The first strategy utilizes benzyl ethers for protection of fructose while the second and more effective strategy employs an isopropylidene acetal.


Gender-specific responses to climate variability in a semi-arid ecosystem in northern Benin.
Highly erratic rainfall patterns in northern Benin complicate the ability of rural farmers to engage in subsistence agriculture. This research explores gender-specific responses to climate variability in the context of agrarian Benin through a household survey (n = 260) and an experimental gaming exercise among a subset of the survey respondents. Although men and women from the sample population are equally aware of climate variability and share similar coping strategies, their specific land-use strategies, preferences, and motivations are distinct. Over the long term, these differences would likely lead to dissimilar coping strategies and vulnerability to the effects of climate change. Examination of gender-specific land-use responses to climate change and anticipatory learning can enhance efforts to improve adaptability and resilience among rural subsistence farmers.


Self-organised criticality in the evolution of a thermodynamic model of rodent thermoregulatory huddling.
A thermodynamic model of thermoregulatory huddling interactions between endotherms is developed. The model is presented as a Monte Carlo algorithm in which animals are iteratively exchanged between groups, with a probability of exchanging groups defined in terms of the temperature of the environment and the body temperatures of the animals. The temperature-dependent exchange of animals between groups is shown to reproduce a second-order critical phase transition, i.e., a smooth switch to huddling when the environment gets colder, as measured in recent experiments. A peak in the rate at which group sizes change, referred to as pup flow, is predicted at the critical temperature of the phase transition, consistent with a thermodynamic description of huddling, and with a description of the huddle as a self-organising system. The model was subjected to a simple evolutionary procedure, by iteratively substituting the physiologies of individuals that fail to balance the costs of thermoregulation (by huddling in groups) with the costs of thermogenesis (by contributing heat). The resulting tension between cooperative and competitive interactions was found to generate a phenomenon called self-organised criticality, as evidenced by the emergence of avalanches in fitness that propagate across many generations. The emergence of avalanches reveals how huddling can introduce correlations in fitness between individuals and thereby constrain evolutionary dynamics. Finally, a full agent-based model of huddling interactions is also shown to generate criticality when subjected to the same evolutionary pressures. The agent-based model is related to the Monte Carlo model in the way that a Vicsek model is related to an Ising model in statistical physics. Huddling therefore presents an opportunity to use thermodynamic theory to study an emergent adaptive animal behaviour. In more general terms, huddling is proposed as an ideal system for investigating the interaction between self-organisation and natural selection empirically.


Antiangiogenic therapy using bevacizumab in recurrent high-grade glioma: impact on local control and patient survival.
Antiangiogenic agents have recently shown impressive radiological responses in high-grade glioma. However, it is not clear if the responses are related to vascular changes or due to antitumoral effects. The authors report the mature results of a clinical study of bevacizumab-based treatment of recurrent high-grade gliomas. Sixty-one patients with recurrent high-grade gliomas received treatment with bevacizumab at 10 mg/ kg every 2 weeks for 4 doses in an 8-week cycle along with either irinotecan or carboplatin. The choice of concomitant chemotherapeutic agent was based on the number of recurrences and prior chemotherapy. At a median follow-up of 7.5 months (range 1-19 months), 50 (82%) of 61 patients relapsed and 42 patients (70%) died of the disease. The median number of administered bevacizumab cycles was 2 (range 1-7 cycles). The median progression-free survival (PFS) and overall survival (OS) were 5 (95% confidence interval [CI] 2.3-7.7) and 9 (95% CI 7.6-10.4) months, respectively, as calculated from the initiation of the bevacizumab-based therapy. Radiologically demonstrated responses following therapy were noted in 73.6% of cases. Neither the choice of chemotherapeutic agent nor the performance of a resection prior to therapy had an impact on patient survival. Although the predominant pattern of relapse was local, 15 patients (30%) had diffuse disease. Antiangiogenic therapy using bevacizumab appears to improve survival in patients with recurrent high-grade glioma. A possible change in the invasiveness of the tumor following therapy is worrisome and must be closely monitored.


The Value of Phenotypes in Knee Osteoarthritis Research.
Over the past decade, phenotypes have been used to help categorize knee osteoarthritis patients relative to being subject to disease, disease progression, and treatment response. A review of potential phenotype selection is now appropriate. The appeal of using phenotypes is that they most rely on simple physical examination, clinically routine imaging, and demographics. The purpose of this review is to describe the panoply of phenotypes that can be potentially used in osteoarthritis research. A search of PubMed was used singularly to review the literature on knee osteoarthritis phenotypes. Four phenotype assembly groups were based on physical features and noninvasive imaging. Demographics included metabolic syndrome (dyslipidemia, hypertension, obesity, and diabetes). Mechanical characteristics included joint morphology, alignment, the effect of injury, and past and present history. Associated musculoskeletal disorder characteristics included multiple joint involvement, spine disorders, neuromuscular diseases, and osteoporosis. With the knee as an organ, tissue characteristics were used to focus on synovium, meniscus, articular cartilage, patella fat pad, bone sclerosis, bone cysts, and location of pain. Many of these phenotype clusters require further validation studies. There is special emphasis on knee osteoarthritis phenotypes due to its predominance in osteoarthritic disorders and the variety of tissues in that joint. More research will be required to determine the most productive phenotypes for future studies. The selection and assignment of phenotypes will take on an increasing role in osteoarthritis research in the future.


Adenoidectomy with or without grommets for children with otitis media: an individual patient data meta-analysis.
Otitis media (OM) is a leading cause of medical consultations, antibiotic prescription and surgery in children. The surgical procedures offered to children with recurrent or persistent OM are insertion of grommets, adenoidectomy or a combination of the two. There is clear National Institute for Health and Care Excellence guidance for the use of grommets in subgroups of children with persistent OM with effusion (OME), but similar guidance is not available for adenoidectomy, either in persistent OME or in recurrent acute OM (AOM). (1) To develop a model to predict the risk of children referred for adenoidectomy having a prolonged duration of their OM. Then, (2a) to evaluate the overall effect of adenoidectomy, with or without grommets, on OM using individual patient data (IPD) and (2b) to identify those subgroups of children who are most likely to benefit from adenoidectomy with or without grommets. A number of electronic databases were searched from their inception including the Cochrane Ear, Nose and Throat Disorders Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), metaRegister of Current Controlled Trials (mRCT), ClinicalTrials.gov, International Clinical Trials Registry Platform (ICTRP), ClinicalStudyResults.org and Google. Studies eligible for inclusion in this IPD meta-analysis were randomised controlled trials (RCTs) in children up to 12 years of age diagnosed with recurrent AOM and/or persistent OME in which adenoidectomy (with or without grommets) was compared with non-surgical treatment or grommets alone. The final selection of eligible studies and the quality assessment were carried out according to standard methods and disagreement was resolved by discussion. A total of 503 articles were identified of which 10 trials were included in the meta-analysis; eight of these were at a low risk of bias and two were at moderate risk. The primary outcome was failure at 12 months, defined by a set of persisting symptoms and signs. In the prognostic analysis 56% of those children referred for adenoidectomy (but randomised to the non-surgical group) failed to improve (38% of the children with recurrent AOM and 89% of the children with persistent OME). Children who had adenoidectomy had a greater chance of clinical improvement. The size of that effect is, in general, small but persists for at least 2 years. Two subgroups of children are most likely to benefit from adenoidectomy: first, children aged < 2 years with recurrent AOM - 16% of those who had adenoidectomy failed at 12 months whereas 27% of those who did not have adenoidectomy failed [rate difference (RD) 12%, 95% confidence interval (Cl) 6% to 18%; number needed to treat (NNT) = 9]; second, children aged ≥ 4 years with persistent OME - 51% of those who had adenoidectomy failed at 12 months whereas 70% of those who did not have adenoidectomy failed (RD 19%, 95% Cl 12% to 26%; NNT = 6). No significant benefit of adenoidectomy was found in children aged ≥ 2 years with recurrent AOM and children aged < 4 years with persistent OME. The need to use a composite end point and the limited number of subgroup variables that could be studied are factors that reduce the robustness of these results; however, we do not believe that this reduces the validity of the conclusions. Adenoidectomy is most beneficial in children with persistent OME aged ≥ 4 years. A smaller beneficial effect was found in children with recurrent AOM aged < 2 years. Consideration must be given to the balance between benefits and harms. Future research is required in a number of key areas, including defining the best methods of selecting, developing and administering patient-reported outcome measures to assess the value of treatments for children with persistent OME and recurrent AOM and upper respiratory infections; investigating the clinical effectiveness and cost-effectiveness of hearing aids (air or bone conduction) and the use of interventions to improve classroom acoustics for children with different degrees of persistence and severity of hearing loss associated with OME; and investigating why professionals' and parents'/carers' treatment preferences vary so much both nationally and internationally. We do not understand why adenoidectomy works in different subgroups at different ages, nor its effects in special populations, such as children with Down syndrome. We also need further research on the impact and optimal management of otitis media in these special situations and others, such as in children with a cleft palate or developmental problems. The study is registered as PROSPERO CRD42011001549. The National Institute for Health Research Health Technology Assessment programme.


Note onset deviations as musical piece signatures.
A competent interpretation of a musical composition presents several non-explicit departures from the written score. Timing variations are perhaps the most important ones: they are fundamental for expressive performance and a key ingredient for conferring a human-like quality to machine-based music renditions. However, the nature of such variations is still an open research question, with diverse theories that indicate a multi-dimensional phenomenon. In the present study, we consider event-shift timing variations and show that sequences of note onset deviations are robust and reliable predictors of the musical piece being played, irrespective of the performer. In fact, our results suggest that only a few consecutive onset deviations are already enough to identify a musical composition with statistically significant accuracy. We consider a mid-size collection of commercial recordings of classical guitar pieces and follow a quantitative approach based on the combination of standard statistical tools and machine learning techniques with the semi-automatic estimation of onset deviations. Besides the reported results, we believe that the considered materials and the methodology followed widen the testing ground for studying musical timing and could open new perspectives in related research fields.


Variation in periodontal diagnosis and treatment planning among clinical instructors.
Consistency in clinical decision making may be necessary for reliable assessment of student performance and teaching effectiveness, yet little has been done to examine variation in periodontal diagnosis and treatment planning among dental school faculty. The purpose of this investigation was to examine variation among faculty in diagnosis and management of common periodontal diseases. Twenty-seven clinical instructors (periodontists, general dentists, dental hygienists, and first- and second-year periodontal graduate students) reviewed three web-based cases and answered a brief questionnaire focusing on radiographic interpretation, periodontal diagnosis, and treatment planning. Response rates for the three cases ranged from 62 percent to 70 percent. Clinical instructors' rating of percent bone loss in the majority of cases varied between three descriptive categories for the same tooth. Greater consistency in periodontal diagnosis was noted within the graduate student group as compared to periodontal and dental hygiene faculty groups. Diagnoses offered for one of the three patients varied between gingivitis and chronic and aggressive periodontitis. Six to nineteen different treatment plans (many with subtle differences) were submitted for each of the three cases. Inter-rater variation was qualitatively more prevalent than intra-rater variation. To our knowledge, this is the first study to document substantial variation among instructors in radiographic interpretation, diagnosis, and treatment planning for common periodontal diseases. Qualitative judgments speculating on the impact of variability among dental school faculty on student performance and patient care can be made but as yet remain unknown. Consistent use of accepted practice guidelines and greater consensus-building opportunities may decrease variation among faculty and enhance dental education.


Prophylaxis of postoperative leg vine thrombosis by low dose subcutaneous heparin or peroperative calf muscle stimulation: a controlled clinical trial.
In a randomized, controlled clinical trial of two methods of preventing postoperative leg vein thrombosis patients undergoing major surgery were divided into three groups. One received intermittent electrical calf muscle stimulation during surgery, the second subcutaneous heparin calcium 5000 IU every eight hours for six days, and the third no specific prophylaxis. Leg vein thrombosis was detected by the 125-I-fibrinogen uptake test. Neither method was effective in patients undergoing open bladder or prostatic surgery. Stimulation did not reduce the incidence of leg vein thrombosis in patients with malignant disease undergoing laparotomy, but heparin calcium was highly successful in this group (P smaller than 0-001). When the laparotomy was for a benign condition, however, both heparin calcium (P smaller than 0-001) and stimulation (P smaller than 0-01) were effective.


"If the Big Fish are Doing It Then Why Not Me Down Here?": Informal Fee Payments and Reproductive Health Care Provider Motivation in Kenya.
Informal fees are payments made by patients to their health care provider that are over and above the official cost of services. Payments may be motivated by a combination of factors such as low supervision, weak sanctions, and inadequate provider salaries. The practice of soliciting informal fees from patients may result in restricted access to medical care and reduced care-seeking behavior among vulnerable populations. The objective of this study is to examine nuanced health care provider perspectives on informal fee payments solicited from reproductive health patients in Kenya. We conducted in-depth semistructured interviews in 2015-2016 among a sample of 20 public and private-sector Kenyan health care workers. Interviews were coded and analyzed using an iterative thematic approach. More than half of participants reported that solicitation of informal fees is common practice in health care facilities. Providers reported low public-sector wages were a primary driver of informal fee solicitation coupled with collusion among senior staff. Additionally, patients may be unaware that they are being asked to pay more than the official cost of services. Strategies for reducing this behavior include more adequate and timely remuneration within the public sector, educating patient populations of free or low-cost services, and evidence-based methods to increase provider motivation.


Motor fatigue measurement by distance-induced slow down of walking speed in multiple sclerosis.
Motor fatigue and ambulation impairment are prominent clinical features of people with multiple sclerosis (pMS). We hypothesized that a multimodal and comparative assessment of walking speed on short and long distance would allow a better delineation and quantification of gait fatigability in pMS. Our objectives were to compare 4 walking paradigms: the timed 25-foot walk (T25FW), a corrected version of the T25FW with dynamic start (T25FW(+)), the timed 100-meter walk (T100MW) and the timed 500-meter walk (T500MW). Thirty controls and 81 pMS performed the 4 walking tests in a single study visit. The 4 walking tests were performed with a slower WS in pMS compared to controls even in subgroups with minimal disability. The finishing speed of the last 100-meter of the T500MW was the slowest measurable WS whereas the T25FW(+) provided the fastest measurable WS. The ratio between such slowest and fastest WS (Deceleration Index, DI) was significantly lower only in pMS with EDSS 4.0-6.0, a pyramidal or cerebellar functional system score reaching 3 or a maximum reported walking distance ≤ 4000 m. The motor fatigue which triggers gait deceleration over a sustained effort in pMS can be measured by the WS ratio between performances on a very short distance and the finishing pace on a longer more demanding task. The absolute walking speed is abnormal early in MS whatever the distance of effort when patients are unaware of ambulation impairment. In contrast, the DI-measured ambulation fatigability appears to take place later in the disease course.


Influence of cataract surgery on macular thickness: a 6-month follow-up.
To determine long-term changes in macular thickness after cataract surgery. Research work included 27 patients (27 eyes) who underwent uneventful cataract surgery with phacoemulsification and IOL implantation on one eye. Optical coherence tomography was used to obtain data of macular thickness before surgery and for patients who attended scheduled control measurement 1 month (22 patients), 3 months (23 patients), and 6 months (20 patients) after the surgery. The greatest increase in average macular thickness was seen 1 month after cataract surgery, statistically significant in all areas except in fovea and superior quarter of macula. Statistically significant decrease in macular thickness was noticed 3 and 6 months after the surgery. Comparison of macular thickness 6 months after cataract surgery and values before surgery showed no statistically significant difference. Findings confirmed the reversibility of macular thickness changes 6 months after cataract surgery and its return to preoperative values.


Sequential one-pot multienzyme (OPME) synthesis of lacto-N-neotetraose and its sialyl and fucosyl derivatives.
Lacto-N-neotetraose and its sialyl and fucosyl derivatives including Lewis x (Le(x)) pentasaccharide, sialyl Lewis x (sLe(x)) hexasaccharide and internally sialylated derivatives were enzymatically synthesized from readily available lactoside, commercially available uridine 5'-diphosphate-glucose (UDP-Glc) and the corresponding monosaccharides using a highly efficient sequential one-pot multienzyme (OPME) strategy. The OPME strategy which combines bacterial glycosyltransferases and sugar nucleotide generation enzymes provides easy access to the biologically important complex oligosaccharides at preparative scale. Moreover, the same OPME strategy can be used for the regioselective introduction of sialic acid to the internal galactose unit of LNnT in a designed glycosylation route by simply changing the glycosylation sequence.


Microstructural and Mechanical Properties of the Anterolateral Ligament of the Knee.
The variable anatomy and controversy of the anterolateral ligament (ALL) reflect the complex relationship among the anterolateral knee structures. The purpose was to quantify the microstructural and mechanical properties of the ALL as compared with the anterolateral capsule (ALC) and lateral collateral ligament (LCL). The primary hypotheses were that (1) there is no difference in these properties between the ALL and ALC and (2) the LCL has significantly different properties from the ALL and ALC. Descriptive laboratory study. The LCL, ALL, and ALC were harvested from 25 cadaveric knees. Mechanical testing and microstructural analyses were performed using quantitative polarized light imaging. The average degree of linear polarization (AVG DoLP; mean strength of collagen alignment) and standard deviation of the angle of polarization (STD AoP; degree of variation in collagen angle orientation) were calculated. Linear region moduli were not different between the ALC and ALL (3.75 vs 3.66 MPa, respectively; P > .99). AVG DoLP values were not different between the ALC and ALL in the linear region (0.10 vs 0.10; P > .99). Similarly, STD AoP values were not different between the ALC and ALL (24.2 vs 21.7; P > .99). The LCL had larger modulus, larger AVG DoLP, and smaller STD AoP values than the ALL and ALC. Of 25 knee specimens, 3 were observed to have a distinct ALL, which exhibited larger modulus, larger AVG DoLP, and smaller STD AoP values as compared with nondistinct ALL samples. There were no differences in the mechanical and microstructural properties between the ALL and ALC. The ALC and ALL exhibited comparably weak and disperse collagen alignment. However, when a distinct ALL was present, the properties were suggestive of a ligamentous structure. The properties of the ALL are similar to those of a ligament only when a distinct ALL is present, but otherwise, for the majority of specimens, ALL properties are closer to those of the capsule. Variability in the ligamentous structure of the ALL suggests that it may be more important in some patients than others and reconstruction may be considered in selective patients. Further study is needed to better understand its selective role and optimal indications for reconstruction.


Ethnic differences in patient perceptions of heart failure and treatment: the West Birmingham heart failure project.
To investigate further the hypothesis that ethnic groups would have different levels of knowledge and perceptions of congestive heart failure (CHF) and treatments for this condition, a cross sectional survey was conducted of patients who were attending the heart failure clinics in two teaching hospitals of Birmingham, UK, that serve a multiethnic population. 103 patients with CHF (66 men, 37 women) were surveyed by standard questionnaire: 42 were white, 34 Indo-Asian, 22 Afro-Caribbean, and 5 Oriental. When asked about their beliefs about control of one's health, 22 (64.7%) of Indo-Asians felt that God/fate controlled their health. The majority of white patients tended to believe that the greatest factor influencing their health was the doctor (15 (35.7%)). Of the total study cohort, only 68 (66%) of patients were aware of their primary diagnosis of heart failure; the majority of Indo-Asians (21 (61.8%)) were not aware of their diagnosis. Half of Indo-Asians (17 (50%)) felt that heart failure was not severe, in contrast to 40.9% (n = 9) of Afro-Caribbeans and only 19.1% (n = 8) of white patients. Of the study cohort, 38 (36.9%) were taking their drugs because their doctor told them to, a response most common among the Indo-Asians. The majority of Indo-Asians (22 (64.7%)) and Afro-Caribbeans (14 (63.6%)) stated that they did not have, or did not know whether they had enough, information about their drug. The corresponding figure for white patients was 21.4% (n = 9). When asked whether they took their medication regularly as prescribed, 7 (31.8%) of Afro-Caribbeans reported that they did not take their drugs regularly. Our study has highlighted deficiencies in the knowledge of CHF among patients from ethnic minority groups, as well as deficiencies in the information being given to these patients. There is a clear need to invest more in patient education for CHF, with special emphasis on certain high risk subgroups.


Simulation of the landfall of the Deepwater Horizon oil on the shorelines of the Gulf of Mexico.
We conducted simulations of oil transport from the footprint of the Macondo Well on the water surface throughout the Gulf of Mexico, including deposition on the shorelines. We used the U.S. National Oceanic Atmospheric Administration (NOAA) model General NOAA Operational Modeling Environment (GNOME) and the same parameter values and input adopted by NOAA following the Deepwater Horizon (DWH) blowout. We found that the disappearance rate of oil off the water surface was most likely around 20% per day based on satellite-based observations of the disappearance rate of oil detected on the sea surface after the DWH wellhead was capped. The simulations and oil mass estimates suggest that the mass of oil that reached the shorelines was between 10,000 and 30,000 tons, with an expected value of 22,000 tons. More than 90% of the oil deposition occurred on the Louisiana shorelines, and it occurred in two batches. Simulations revealed that capping the well after 2 weeks would have resulted in only 30% of the total oil depositing on the shorelines, while capping after 3 weeks would have resulted in 60% deposition. Additional delay in capping after 3 weeks would have averted little additional shoreline oiling over the ensuing 4 weeks.


A clinical evaluation of the intubating laryngeal airway as a conduit for tracheal intubation in children.
The air-Q Intubating Laryngeal Airway (ILA) (Cookgas LLC, Mercury Medical, Clearwater, FL) is a supraglottic airway device available in pediatric sizes, with design features to facilitate passage of cuffed tracheal tubes when used to guide tracheal intubation. We designed this prospective observational study of the ILA to assess the ease of its placement in paralyzed pediatric patients, determine its position and alignment to the larynx using a fiberoptic bronchoscope, gauge its efficacy as a conduit for fiberoptic intubation with cuffed tracheal tubes, and evaluate the ability to remove the ILA without dislodgement of the tracheal tube after successful tracheal intubation. One hundred healthy children, aged 6 months to 8 years, ASA physical status I to II, and scheduled for elective surgery requiring general endotracheal anesthesia were enrolled in this prospective study. Based on the manufacturer's guidelines, each patient received either a size 1.5 or 2.0 ILA according to their weight. The number of attempts for successful insertion, leak pressures, fiberoptic grade of view, number of attempts and time for tracheal intubation, time for ILA removal, and complications were recorded. ILA placement, fiberoptic tracheal intubation, and ILA removal were successful in all patients. The size 1.5 ILA cohort had significantly higher rates of epiglottic downfolding compared with the size 2.0 ILA cohort (P < 0.001), despite adequate ventilation variables. When comparing fiberoptic grade of view to weight, a moderate negative correlation was found (r = -0.41, P < 0.001), indicating that larger patients tended to have better fiberoptic grades of view. The size 1.5 ILA cohort had a significantly longer time to intubation (P = 0.04) compared with the size 2.0 ILA cohort. However, this difference may not be clinically significant because there was a large overlap of confidence bounds in the average times of the size 1.5 ILA (27.0 ± 13.0 seconds) and size 2.0 ILA cohorts (22.7 ± 6.9 seconds). When comparing weight to time to tracheal intubation, a weak correlation that was not statistically significant was found (r = -0.17, P = 0.09), showing that time to intubation did not differ significantly according to weight, despite higher fiberoptic grades in smaller patients. The ILA was easy to place and provided an effective conduit for tracheal intubation with cuffed tracheal tubes in children with normal airways. Additionally, removal of the ILA after successful intubation could be achieved quickly and without dislodgement of the tracheal tube. Because of the higher incidence of epiglottic downfolding in smaller patients, the use of fiberoptic bronchoscopy is recommended to assist with tracheal intubation through this device.


Risks of Adverse Events Following Coprescription of Statins and Calcium Channel Blockers: A Nationwide Population-Based Study.
Some statins (simvastatin, lovastatin, and atorvastatin) are metabolized by cytochrome P450s 3A4 (CYP3A4). Inhibitors of CYP3A4 including some calcium channel blockers (CCBs) might increase statin blood concentration, owing to drug-drug interactions. Risk of adverse events such as acute kidney injury might occur following the coprescription of CYP3A4-metabolized statins and CCBs that inhibit CYP3A4.This was a population-based cohort study. The study analyzed data of patients treated between 1997 and 2011, retrieved from Taiwan's National Health Insurance database. We enrolled 32,801 patients who received coprescription of statins and CCBs that inhibit CYP3A4 (amlodipine, diltiazem, felodipine nicardipine, nifedipine, and verapamil). These patients were divided into 2 groups, according to whether they had received CYP3A4-metabolized statins (lovastatin, simvastatin, and atorvastatin) or non-CYP3A4-metabolized statins (fluvastatin, rosuvastatin, and pitavastatin). These 2 groups were 1:1 matched by age, gender, and Carlson comorbidity index. All outcomes were assessed within 90 days following drug coprescription.In this study, 5857 patients received coprescription of CYP3A4-metabolized statins and CCBs that inhibit CYP3A4. There were no differences in comorbidity or use of antihypertensive drugs between patients who received CYP3A4-metabolized statins and those who received non-CYP3A4-metabolized statins. Patients who received CYP3A4-metabolized statins had significantly higher risk of acute kidney injury (adjusted odds ratio [OR] = 2.12; 95% CI = 1.35-3.35), hyperkalemia (adjusted OR = 2.94; 95% CI = 1.36-6.35), acute myocardial infarction (adjusted OR = 1.55; 95% CI = 1.16-2.07), and acute ischemic stroke (adjusted OR = 1.35; 95% CI = 1.08-1.68) than those who received non-CYP3A4-metabolized statins.This nationwide cohort study demonstrated the increased risk of adverse events following the coprescription of CYP3A4-metabolized statins and CCBs that inhibit CYP3A4. Therefore, it is important to take into account the potential adverse events while coprescribing CYP3A4-metabolized statins and CCBs that inhibit CYP3A4.


P2-substituted N-acylprolylpyrrolidine inhibitors of prolyl oligopeptidase: biochemical evaluation, binding mode determination, and assessment in a cellular model of synucleinopathy.
We have investigated the effect of regiospecifically introducing substituents in the P2 part of the typical dipeptide derived basic structure of PREP inhibitors. This hitherto unexplored modification type can be used to improve target affinity, selectivity, and physicochemical parameters in drug discovery programs focusing on PREP inhibitors. Biochemical evaluation of the produced inhibitors identified several substituent types that significantly increase target affinity, thereby reducing the need for an electrophilic "warhead" functionality. Pronounced PREP specificity within the group of Clan SC proteases was generally observed. Omission of the P1 electrophilic function did not affect the overall binding mode of three representative compounds, as studied by X-ray crystallography, while the P2 substituents were demonstrated to be accommodated in a cavity of PREP that, to date, has not been probed by inhibitors. Finally, we report on results of selected inhibitors in a SH-SY5Y cellular model of synucleinopathy and demonstrate a significant antiaggregation effect on α-synuclein.


A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples.
The role of enhancers, a key class of non-coding regulatory DNA elements, in cancer development has increasingly been appreciated. Here, we present the detection and characterization of a large number of expressed enhancers in a genome-wide analysis of 8928 tumor samples across 33 cancer types using TCGA RNA-seq data. Compared with matched normal tissues, global enhancer activation was observed in most cancers. Across cancer types, global enhancer activity was positively associated with aneuploidy, but not mutation load, suggesting a hypothesis centered on "chromatin-state" to explain their interplay. Integrating eQTL, mRNA co-expression, and Hi-C data analysis, we developed a computational method to infer causal enhancer-gene interactions, revealing enhancers of clinically actionable genes. Having identified an enhancer ∼140 kb downstream of PD-L1, a major immunotherapy target, we validated it experimentally. This study provides a systematic view of enhancer activity in diverse tumor contexts and suggests the clinical implications of enhancers.


Purinergic Receptors in Thrombosis and Inflammation.
Under various pathological conditions, including thrombosis and inflammation, extracellular nucleotide levels may increase because of both active release and passive leakage from damaged or dying cells. Once in the extracellular compartment, nucleotides interact with plasma membrane receptors belonging to the P2 purinergic family, which are expressed by virtually all circulating blood cells and in most blood vessels. In this review, we focus on the specific role of the 3 platelet P2 receptors P2Y1, P2Y12, and P2X1 in hemostasis and arterial thrombosis. Beyond platelets, these 3 receptors, along with the P2Y2, P2Y6, and P2X7 receptors, constitute the main P2 receptors mediating the proinflammatory effects of nucleotides, which play important roles in various functions of circulating blood cells and cells of the vessel wall. Each of these P2 receptor subtypes specifically contributes to chronic or acute vascular inflammation and related diseases, such as atherosclerosis, restenosis, endotoxemia, and sepsis. The potential for therapeutic targeting of these P2 receptor subtypes is also discussed.


A Total Offloading Foot Brace for Treatment of Diabetic Foot Ulcers: Results From a Halted Randomized Controlled Trial.
Foot offloading is the mainstay treatment for plantar diabetic foot ulcers (DFUs). This multicenter, single-blinded, randomized controlled trial evaluates the efficacy of a total offloading foot brace for healing plantar DFUs. Seventeen patients were randomized to standard therapy (ie, reducing stress and pressure via mechanical offloading) or offloading foot brace. Comparison of plantar pressures was performed using digital pressure sensing films. The ulcers were assessed by physical inspection and digital planimetry of photographs. Reductions in peak plantar pressures ranged from 67.3% to 89.4% (P = .09). Healing at weeks 12 to 15 had minimal differences (brace vs. control: 71.7% vs. 80.3%, respectively). Although not significant, earlier periods of the brace versus the control demonstrated faster wound healing in weeks 2 to 5 (36.0% vs. 6.8%, respectively) and weeks 6 to 9 (50.7% vs. 17.0%, respectively). The total offloading foot brace minimizes plantar pressure, allowing for early healing of DFUs, and optimizations in brace design may enhance healing of plantar DFUs.


Oxidized low-density lipoprotein (Ox-LDL) but not LDL aggravates the manifestations of experimental antiphospholipid syndrome (APS).
Ox-LDL is thought to play a major role in atherogenesis. The mechanisms mediating the deleterious influences of Ox-LDL include foam cell formation and cell cytotoxicity. The production of anti-Ox-LDL antibodies results in the formation of immune complexes which are taken up at enhanced rate by macrophages, leading to foam cell formation. APS is characterized by repeated venous and arterial thromboembolic phenomena, recurrent fetal loss and thrombocytopenia, associated with the presence of antibodies to negatively charged phospholipids (aPL) (i.e. cardiolipin, phosphatidylserine). Phospholipids bear structural resemblance to LDL, and several studies have indeed proved that aPL display cross-reactivity with anti-Ox-LDL antibodies. In this study we assessed the capacity of oxidized and native forms of LDL to aggravate the clinical picture of experimentally induced APS in naive mice. Mice were actively immunized intradermally with anticardiolipin antibodies and developed a clinical picture resembling APS in humans. Subsequently, the mice were infused with either Ox-LDL, native LDL or PBS, and similar regimens were applied to controls. APS mice infused with Ox-LDL were found to exhibit a significantly more severe form of the disease in comparison with native LDL- and PBS-infused mice, expressed by lower platelet counts (261,000/mm3, 535,000/mm3 and 455,000/mm3, respectively), longer activated partial thromboplastin time (aPTT) (99 +/- 12 s, 63 +/- 8 s and 74 +/- 8 s, respectively) and higher fetal resorption rates (72.7%, 34.4% and 32.6%, respectively). The results of this study show that Ox-LDL, compared with native LDL, aggravates the clinical manifestations of experimental APS and suggest that cross-reactivity of Ox-LDL with phospholipids may provide a pathogenic explanation for this effect.


HPSE2 mutations in urofacial syndrome, non-neurogenic neurogenic bladder and lower urinary tract dysfunction.
Urofacial syndrome (UFS) is characterised by congenital bladder dysfunction accompanied by a characteristic abnormal grimace upon smiling and crying. In recent years, biallelic mutations of HPSE2 and LRIG2 have been reported in UFS patients. Non-neurogenic neurogenic bladder (NNNB) has a bladder identical to UFS without typical facial features. The aim of this study was to analyse HPSE2 mutations in patients with UFS and NNNB or severe lower urinary tract dysfunction (LUTD) without abnormal facial expression. Patients with UFS, NNNB and severe LUTD were enrolled in the study. We examined a total of 35 patients from 33 families. There were seven UFS patients from five different families, 21 patients with NNNB and seven with LUTD. HPSE2 gene mutation analysis was performed using the polymerase chain reaction protocol followed by Sanger sequencing in these patients. A twin pair with UFS was found to be homozygous for c.457C>T (p.Arg153*) mutation. No other pathogenetic variant was detected. HPSE2 mutations were found in one UFS family but not detected in patients with NNNB and severe LUTD. Considering the increasingly recognised cases of NNNB that were diagnosed in early childhood period, genetic factors appear to be responsible. Thus, further genetic studies are needed to discover novel associated gene variants in these bladder anomalies.


Serenoa repens extracts: In vitro study of the 5α-reductase activity in a co-culture model for Benign Prostatic Hyperplasia.
Benign Prostatic Hyperplasia (BPH) is a form of benign tumor that occurs in humans mainly with ageing. It affects more than 50% of over 50 years old males and it is characterized by an increased synthesis of dihydrotestosterone (DHT), due to the 5α-reductase activity. The BPH therapeutic approach mainly uses 5α-reductase inhibitors, such as the active compounds present in the extracts deriving from species Serenoa repens. Many lipidosterolic extracts are available on the market, which are obtained with different solvents, among them ethanol is recognized as non-toxic and has less handling risks than hexane. The purpose of the present experimental study was to investigate in-vitro the potency of an ethanol extract of S. repens comparing it with an n-hexane one. Two different lipido-sterolic extracts of S. repens have been tested: ethanol extract and n-hexane extract, two batches for each one. The inhibitory action of the extract was evaluated estimating in-vitro the activity of enzyme 5α-reductase type I (5α-RI), which was mainly active under the experimental condition of pH 7.5. DHT amount, synthesized from testosterone (1 μM), was evaluated in a co-culture model of epithelial cells and fibroblasts resulting from prostatic biopsy of a patient with BPH. The analysis of the resulting dose-response curves showed that the entire S. repens extracts inhibited the 5α-RI showing no difference between the two kinds of extract or between the batches. The resulting IC50 values were the following: 8.809 (95% CI = 5.133-15.56) and 9.464 (95% CI = 5.094- 18.27) for ethanol extracts; 11.08 (95% CI = 6.389-19.98) and 12.72 (95% CI = 7.758-21.53) for n-hexane extracts. The potency of ethanol extracts of S. repens was comparable with the one of n-hexane extracts.


Differential DNA methylation in experienced meditators after an intensive day of mindfulness-based practice: Implications for immune-related pathways.
The human methylome is dynamically influenced by psychological stress. However, its responsiveness to stress management remains underexplored. Meditation practice has been shown to significantly reduce stress level, among other beneficial neurophysiological outcomes. Here, we evaluated the impact of a day of intensive meditation practice (t2-t1 = 8 h) on the methylome of peripheral blood mononuclear cells in experienced meditators (n = 17). In parallel, we assessed the influence of a day of leisure activities in the same environment on the methylome of matched control subjects with no meditation experience (n = 17). DNA methylation profiles were analyzed using the Illumina 450 K beadchip array. We fitted for each methylation site a linear model for multi-level experiments which adjusts the variation between t1 and t2 for baseline differences. No significant baseline differences in methylation profiles was detected between groups. In the meditation group, we identified 61 differentially methylated sites (DMS) after the intervention. These DMS were enriched in genes mostly associated with immune cell metabolism and ageing and in binding sites for several transcription factors involved in immune response and inflammation, among other functions. In the control group, no significant change in methylation level was observed after the day of leisure activities. These results suggest that a short meditation intervention in trained subjects may rapidly influence the epigenome at sites of potential relevance for immune function and provide a better understanding of the dynamics of the human methylome over short time windows.


Plastic and evolutionary responses to climate change in fish.
The physical and ecological 'fingerprints' of anthropogenic climate change over the past century are now well documented in many environments and taxa. We reviewed the evidence for phenotypic responses to recent climate change in fish. Changes in the timing of migration and reproduction, age at maturity, age at juvenile migration, growth, survival and fecundity were associated primarily with changes in temperature. Although these traits can evolve rapidly, only two studies attributed phenotypic changes formally to evolutionary mechanisms. The correlation-based methods most frequently employed point largely to 'fine-grained' population responses to environmental variability (i.e. rapid phenotypic changes relative to generation time), consistent with plastic mechanisms. Ultimately, many species will likely adapt to long-term warming trends overlaid on natural climate oscillations. Considering the strong plasticity in all traits studied, we recommend development and expanded use of methods capable of detecting evolutionary change, such as the long term study of selection coefficients and temporal shifts in reaction norms, and increased attention to forecasting adaptive change in response to the synergistic interactions of the multiple selection pressures likely to be associated with climate change.


Sonochemical reduction of Cr(VI) in air in the presence of organic additives: What are the involved mechanistic pathways?
The sonochemical (850 kHz) reduction of Cr(VI) (0.3 mM, pH 2, reactor open to air) was analyzed in the presence of different additives. The effects on Cr(VI) reduction efficiency of added formic acid (FA, 10 mM), citric acid (Cit, 2 mM), ethylenediaminetetraacetic acid (EDTA, 1 mM), methanol (MeOH, 0.1 M), ethanol (EtOH, 0.1 M), 2-propanol (2-PrOH, 0.1 M), tert-butanol (t-BuOH, 0.1 M), phenol (PhOH, 2 mM) and sodium lauryl sulfate (SLS, 1 mM) have been evaluated in comparison with the system in the absence of additives. Complete Cr(VI) reduction was obtained only when using EDTA (at 120 min) and Cit (at 180 min). Cr(III) complexes with these compounds or with their degradation products were detected as final products. For EDTA, Cit, t-BuOH, FA and SLS, the Cr(VI) decay could be adjusted to a zero-order kinetics; in the cases of MeOH, EtOH and 2-PrOH, there was a deviation from the zero-order kinetics. The Cr(VI) conversion increased in the order SLS (very low) < no additive ≅ MeOH ≅ EtOH ≅ 2-PrOH < FA < t-BuOH < PhOH < Cit < EDTA. The role of EDTA and Cit in stabilizing intermediate Cr(V) peroxo compounds and enhancing their direct transformation into different Cr(III) species is considered a major factor in the acceleration of Cr(VI) reduction processes. Mechanistic pathways are proposed.


Human cationic trypsinogen (PRSS1) variants and chronic pancreatitis.
Variations in the serine protease 1 (PRSS1) gene encoding human cationic trypsinogen have been conclusively associated with autosomal dominant hereditary pancreatitis and sporadic nonalcoholic chronic pancreatitis. Most high-penetrance PRSS1 variants increase intrapancreatic trypsin activity by stimulating trypsinogen autoactivation and/or by inhibiting chymotrypsin C-dependent trypsinogen degradation. Alternatively, some PRSS1 variants can cause trypsinogen misfolding, which results in intracellular retention and degradation with consequent endoplasmic reticulum stress. However, not all PRSS1 variants are pathogenic, and clinical relevance of rare variants is often difficult to ascertain. Here we review the PRSS1 variants published since 1996 and discuss their functional properties and role in chronic pancreatitis.


The aryl hydrocarbon receptor directly regulates expression of the potent mitogen epiregulin.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is known to cause a large number of adverse effects, mediated largely by its binding to the aryl-hydrocarbon receptor (AhR) and subsequent modulation of gene expression. It is thought that AhR mediates these effects through the untimely and disproportionate expression of specific genes. However, the exact mechanism, or the genes involved, through which TCDD leads to these effects is still unknown. This study reports the discovery of a novel target gene, epiregulin, which is regulated by TCDD-activated AhR. Epiregulin is a growth regulator which belongs to the epidermal growth factor (EGF) family. Using real time quantitative PCR (qPCR), it was established that TCDD upregulates epiregulin gene expression. The promoter region of epiregulin has a dioxin responsive element (DRE) 56 nucleotides upstream of the transcription start site, along with three potential Sp1 binding sites. Chromatin immunoprecipitation (ChIP) assays with an anti-AhR antibody showed promoter occupancy upon TCDD treatment. Luciferase reporter assays using a vector harboring the first 125 base pairs of the epiregulin rat promoter revealed an increase in signal on TCDD treatment, which was lost upon mutation of the DRE. Epiregulin and TCDD treatment mediated a dose-dependent increase in primary mouse keratinocyte growth. These results demonstrate that AhR directly increases epiregulin expression, which could play an important role in TCDD mediated tumor promotion observed in rodent models.


Sodium current in ventricular myocardial fibers.
Membrane currents were measured in thin bundles of dog ventricular myocardium under voltage-clamp conditions. A rather large initial inward current which had an equilibrium potential at about + 55 millivolts could be recorded. When the external sodium concentration was reduced, the equilibrium potential for this current was shifted by the amount predicted theoretically for a current carried solely by sodium ions. The size of the sodium inward current (I(Na)) was largely dependent on the preceding membrane potential. The I(Na) was completely inactivated if the membrane potential was as low as -45 millivolts. Sodium ions are the main carrier of charge during the rapid depolarization phase of the action potential.


The hypothalamic-pituitary-thyroid axis and melatonin in humans: possible interactions in the control of body temperature.
Melatonin plays a role in the regulation of biological rhythms, body temperature presents circadian variations with lower levels during nighttime, when melatonin levels are very high, and thyroid hormones influence shiver independent thermogenesis. We have investigated on possible interactions between the hypothalamic-pituitary-thyroid axis and melatonin in the control of body temperature in humans. Peripheral blood samples for thyrotropin-releasing hormone (TRH), thyroid-stimulating hormone (TSH), free-thyroxine (FT4), melatonin levels determination and body temperature measurements were obtained every four hours for 24-hours starting at 0600 h in a controlled temperature and light-dark environment from ten healthy males, aged 38-65 (mean age +/-s.e. 57.4+/-3.03, mean body mass index +/-s.e. 25.5+/-0.75). We calculated fractional variation and correlation on single time point hormone serum levels and tested whether the time-qualified data series showed consistent pattern of circadian variation. A statistically significant difference was evidenced for the fractional variation of daytime TSH serum levels (0600 h-1000 h vs. 1000 h-1400 h, p=0.01, 1000 h-1400 h vs. 1400 h-1800 h, p=0.0001, 1400 h-1800 h vs. 1800 h-2200 h, p=0.001) and for the fractional variation of FT4 serum levels at 1800 h-2200 h vs. 2200 h-0200 h (p=0.02). FT4 serum levels correlated positively with TRH serum levels at 1000 h (r=0.67, P=0.03) and at 1400 h (r=0.63, p=0.04), negatively with TSH serum levels at 2200 h (r=-0.67, p=0.03), negatively with melatonin serum levels at 2200 h (r=-0.64, p=0.04) and at 0200 h (r=-0.73, p=0.01). TRH serum levels correlated positively with TSH serum levels at 0200 h (r=0.65, p=0.04) and at 0600 h (r=0.64, p=0.04). Body temperature correlated positively with FT4 serum levels at 1000 h (r=0.63, p=0.04) and negatively with melatonin serum levels at 0200 h (r=-0.64, p=0.04). A clear circadian rhythm was validated for body temperature (with acrophase in the morning) and melatonin, TRH and TSH secretion (with acrophase at night), while FT4 serum level changes presented ultradian periodicity (with acrophase in the morning). Changes of TSH serum levels are smaller and those of FT4 are greater at night, when melatonin levels are higher, so that the response of anterior pituitary to hypothalamic TRH and of thyroid to hypophyseal TSH may be influenced by the pineal hormone that may modulate the hypothalamic-pituitary-thyroid axis function and influence the circadian rhythm of body temperature.


Clinical experience with atovaquone on a treatment investigational new drug protocol for Pneumocystis carinii pneumonia.
The clinical experience of human immunodeficiency virus (HIV) + patients treated with oral atovaquone for acute Pneumocytstis carinii pneumonia (PCP) under a Treatment Investigational New Drug (IND) protocol (mild or moderate PCP) and an Open-Label Study protocol (severe PCP) was evaluated. A total of 940 patients intolerant of or unresponsive to trimethoprimsulfamethoxazole were enrolled from private practices, clinics, and institutional HIV treatment centers in the United States. Demographics data and the history and severity of PCP were collected at enrollment. The number of therapy days, adverse experiences, clinical response to therapy, and mortality were collected at day 21. Reporting of serious, unexpected adverse experiences attributable to therapy was required. Of the 760 (96%) patients with mild to moderate disease for whom follow-up observation was complete, 591 (78%) responded clinically to treatment, 177 patients (23%) discontinued treatment prematurely, and 50 patients (7%) died. Of the 140 patients (95%) with severe PCP with follow-up data, 79 (56%) responded to treatment, 45 (32%) discontinued treatment early, and 53 patients (38%) died. Adverse events that resulted in temporary or permanent discontinuation of therapy included diarrhea, vomiting, elevated liver enzyme levels, nausea, and fever. No serious unexpected adverse events attributable to the drug were reported. The treatment IND mechanism enabled a large number of patients with acute PCP to be treated with this experimental therapy while the drug was under regulatory view.


Biochemical and molecular characterization of Cronobacter spp. (formerly Enterobacter sakazakii) isolated from foods.
The aim of this study was to identify and characterize Cronobacter spp. isolated from a range of foods. A total of 71 Cronobacter strains were isolated from 602 foods in our laboratory. The highest contamination was observed in foods of plant origin, e.g. spices, teas, chocolate, nuts, pastries and vegetables. On the basis of genus and species identification performed using genus-specific PCR, 16S rRNA sequencing and AFLP genotyping, most of the strains belonged to Cronobacter sakazakii. Biochemical profiling by the tests included in API 20E, complemented with relevant additional tests, classified the strains into 13 biogroups. AFLP genotyping facilitated discrimination of six main groups at the 70% similarity level and strain grouping correlated clearly with species identification. Our results indicate that molecular typing by AFLP may be applied as a useful tool not only for direct comparison of Cronobacter isolates, providing traceability, but also for the reliable species classification. Moreover, tracing of these bacteria in a wider variety of foods should be important to enhance the knowledge of their transmission.


Treatment of Refractory Filamentary Keratitis With Autologous Serum Tears.
To report a case of filamentary keratitis (FK) successfully treated with autologous serum tears and to review the pathogenesis and management of FK. Case report including high-resolution anterior segment optical coherence tomography and filament histopathology. A 61-year-old Hispanic man presented with pain and photophobia of the right eye. He was found to have a corneal epithelial defect and a small peripheral infiltrate 4 months after Laser Assisted in situ Keratomileusis. After resolution of the epithelial defect, he developed FK. Over a 4-month period, conservative management with aggressive lubrication, lid hygiene, topical corticosteroids, topical cyclosporine, bandage contact lenses, and oral doxycycline failed to resolve the corneal filaments. Notably, treatment with 20% autologous serum tears, four times daily, led to a sustained resolution of the FK within 1 week. This case demonstrates the complexity of FK management and introduces autologous serum tears as a viable management option when conservative approaches to this condition fail.


Socio-demographic and Household-Level Risk Factors for Severe Acute Malnutrition in Pre-school Children in North-Western Nigeria.
Severe acute malnutrition (SAM) is associated with significant morbidity and mortality and is disproportionately distributed mainly in developing countries. In Nigeria, the prevalence of SAM in the North-Western region of the country is significantly higher than the national average. In this study, we identified risk factors for SAM in North-Western Nigeria. Identifying such risk factors would be helpful in developing local preventive strategies and providing insights for broader SAM control programs in other high-burden country settings. We performed post hoc data analysis, comparing baseline socio-demographic and household-level risk factors in a cohort of 1011 children aged between 6 and 59 months who either had SAM or were well-nourished children. We defined nutritional status using the World Health Organization (WHO) reference standards and investigated the association between SAM and our identified risk factors using multivariable logistic regression model. Children aged between 12 and 23 months [adjusted odds ratio (AOR) 2.95, 95% confidence interval (CI) 1.99-4.38], household who reared domestic animals (AOR 1.94, 95% CI 1.40-2.69) and those from polygamous households (AOR 1.91, 95% CI 1.33-2.74) had significantly increased odds of developing SAM. Parental education and being on the household diet reduced the odds of having SAM. Our findings suggest the need to develop optimal complementary feeding nutrition programs and promote adult and general education in our community. Cultural and feeding practices in local polygamous households also need further investigation to understand the association between polygamy with SAM.


Identification of snails infected with schistosomes by ELISA employing monoclonal antibodies: Schistosoma mansoni in laboratory snails (Biomphalaria glabrata) and in field snails (Biomphalaria pfeifferi) from Kenya.
An enzyme-linked immunosorbent assay (ELISA) employing monoclonal antibodies was used for detecting Schistosoma mansoni antigens in hemolymph of laboratory snails (Biomphalaria glabrata) in Kenya. Infected laboratory snails shedding cercariae were differentially identified by ELISA from uninfected snails with 100% sensitivity and specificity. Prepatent infections were detected by ELISA from 2 weeks after exposure to miracidia. Thus, ELISA revealed infection 3 weeks before maximal patency was reached (5-6 weeks post-exposure). Infected field snails (B. pfeifferi) shedding cercariae were differentially identified by ELISA, with 100% sensitivity and specificity, from uninfected field snails and from snails naturally infected with other trematodes (echinostomes and strigeids). Prepatent infections with S. mansoni were readily identified by ELISA in field snails. A case is demonstrated where infection rate, as determined by shedding test alone, was 9.8%, whereas the combined figure of prepatent and patent infection rates was 22.9%


An evaluation of exact matching and propensity score methods as applied in a comparative effectiveness study of inhaled corticosteroids in asthma.
Cohort matching and regression modeling are used in observational studies to control for confounding factors when estimating treatment effects. Our objective was to evaluate exact matching and propensity score methods by applying them in a 1-year pre-post historical database study to investigate asthma-related outcomes by treatment. We drew on longitudinal medical record data in the PHARMO database for asthma patients prescribed the treatments to be compared (ciclesonide and fine-particle inhaled corticosteroid [ICS]). Propensity score methods that we evaluated were propensity score matching (PSM) using two different algorithms, the inverse probability of treatment weighting (IPTW), covariate adjustment using the propensity score, and propensity score stratification. We defined balance, using standardized differences, as differences of <10% between cohorts. Of 4064 eligible patients, 1382 (34%) were prescribed ciclesonide and 2682 (66%) fine-particle ICS. The IPTW and propensity score-based methods retained more patients (96%-100%) than exact matching (90%); exact matching selected less severe patients. Standardized differences were >10% for four variables in the exact-matched dataset and <10% for both PSM algorithms and the weighted pseudo-dataset used in the IPTW method. With all methods, ciclesonide was associated with better 1-year asthma-related outcomes, at one-third the prescribed dose, than fine-particle ICS; results varied slightly by method, but direction and statistical significance remained the same. We found that each method has its particular strengths, and we recommend at least two methods be applied for each matched cohort study to evaluate the robustness of the findings. Balance diagnostics should be applied with all methods to check the balance of confounders between treatment cohorts. If exact matching is used, the calculation of a propensity score could be useful to identify variables that require balancing, thereby informing the choice of matching criteria together with clinical considerations.


Quantifying the economic cost of antibiotic resistance and the impact of related interventions: rapid methodological review, conceptual framework and recommendations for future studies.
Antibiotic resistance (ABR) poses a major threat to health and economic wellbeing worldwide. Reducing ABR will require government interventions to incentivise antibiotic development, prudent antibiotic use, infection control and deployment of partial substitutes such as rapid diagnostics and vaccines. The scale of such interventions needs to be calibrated to accurate and comprehensive estimates of the economic cost of ABR. A conceptual framework for estimating costs attributable to ABR was developed based on previous literature highlighting methodological shortcomings in the field and additional deductive epidemiological and economic reasoning. The framework was supplemented by a rapid methodological review. The review identified 110 articles quantifying ABR costs. Most were based in high-income countries only (91/110), set in hospitals (95/110), used a healthcare provider or payer perspective (97/110), and used matched cohort approaches to compare costs of patients with antibiotic-resistant infections and antibiotic-susceptible infections (or no infection) (87/110). Better use of methods to correct biases and confounding when making this comparison is needed. Findings also need to be extended beyond their limitations in (1) time (projecting present costs into the future), (2) perspective (from the healthcare sector to entire societies and economies), (3) scope (from individuals to communities and ecosystems), and (4) space (from single sites to countries and the world). Analyses of the impact of interventions need to be extended to examine the impact of the intervention on ABR, rather than considering ABR as an exogeneous factor. Quantifying the economic cost of resistance will require greater rigour and innovation in the use of existing methods to design studies that accurately collect relevant outcomes and further research into new techniques for capturing broader economic outcomes.


Folic acid protected silver nanocarriers for targeted drug delivery.
A one-step approach towards the synthesis of folic acid (FA) coated silver nanoparticles (AgNPs) and doxorubicin (DOX) for drug delivery is proposed. The FA-AgNPs were 23 +/- 2 nm in diameter and showed good monodispersity with a characteristic surface plasmon peak at 409 nm. Taking advantage of the enhanced Raman signal of FA on AgNPs and targeting specificity of FA to folate-receptor expressing cancer cells, the as-prepared FA-AgNPs showed excellent receptor-mediated cellular uptake, as demonstrated both by surface enhanced raman scattering (SERS) imaging and fluorescent lifetime imaging (FLIM). Next, a chemotherapeutic drug, DOX was attached to the FA-AgNPs surface through electrostatic bonding and the release of DOX from FA-AgNPs was monitored by FLIM. The release of DOX into the cytoplasm after 4 hours of incubation was clearly seen by FLIM. After 8 hours, the cells underwent cell death due to the release of DOX from nanoparticles. However, in control cell lines with low-expression levels of the FA receptor, no scattering signal from AgNPs could be observed from within the cells even after an incubation period of 24 hours. Our study shows that nanocarriers can be designed with various chemistries to study targeting and release of disease-specific drugs.


Engineered microstructure granules for tailored drug release rate.
Biomaterials developed for controlled drug delivery have demonstrated excellent results in the present study. A biomaterial prepared using hydroxyapatite (HAp) was shown to have a hollow structure with the presence of interconnected pores to house drug carriers. The poly(lactic-co-glycolic acid) particles were used as drug carriers loaded with dexamethasone, a corticosteroid that is known to promote osteoinduction. The surface of the drug carriers was modified using polyethyleneimine, and then conjugated to the surface of HAp granules. The hollow HAp granules had drug carriers on both their inner and outer surfaces and showed a controlled drug release rate that was comparable to that of granules containing drug carriers on their outer surface alone. The pores were designed for insertion of drug carriers and preosteoblasts. Consequently, the biomaterials influenced cellular behavior by first promoting cell proliferation and then inducing early stage osteogenic differentiation. The effects of controlled release rate were evidenced for up to two weeks after cell seeding, resulting in an increase of osteogenic differentiation. In summary, drug carriers loaded onto hollow HAp granules were shown to be suitable for patients who require replacement of missing bone for repair of bone fractures that are extremely complex, pose a significant health risk to the patient, or fail to heal properly.


Physiological evidence that pyramidal neurons lack functional water channels.
The physiological conditions that swell mammalian neurons are clinically important but contentious. Distinguishing the neuronal component of brain swelling requires viewing intact neuronal cell bodies, dendrites, and axons and measuring their changing volume in real time. Cultured or dissociated neuronal somata swell within minutes under acutely overhydrated conditions and shrink when strongly dehydrated. But paradoxically, most central nervous system (CNS) neurons do not express aquaporins, the membrane channels that conduct osmotically driven water. Using 2-photon laser scanning microscopy (2PLSM), we monitored neuronal volume under osmotic stress in real time. Specifically, the volume of pyramidal neurons in cerebral cortex and axon terminals comprising cerebellar mossy fibers was measured deep within live brain slices. The expected swelling or shrinking of the gray matter was confirmed by recording altered light transmittance and by indirectly measuring extracellular resistance over a wide osmotic range of -80 to +80 milliOsmoles (mOsm). Neurons expressing green fluorescent protein were then imaged with 2PLSM between -40 and +80 mOsm over 20 min. Surprisingly, pyramidal somata, dendrites, and spines steadfastly maintained their volume, as did the cerebellar axon terminals. This precluded a need for the neurons to acutely regulate volume, preserved their intrinsic electrophysiological stability, and confirmed that these CNS nerve cells lack functional aquaporins. Thus, whereas water easily permeates the aquaporin-rich endothelia and glia driving osmotic brain swelling, neurons tenatiously maintain their volume. However, these same neurons then swell dramatically upon oxygen/glucose deprivation or [K+]0 elevation, so prolonged depolarization (as during stroke or seizure) apparently swells neurons by opening nonaquaporin channels to water.


CFTR as a cAMP-dependent regulator of sodium channels.
Cystic fibrosis transmembrane regulator (CFTR), the gene product that is mutated in cystic fibrosis (CF) patients, has a well-recognized function as a cyclic adenosine 3',5'-monophosphate (cAMP)-regulated chloride channel, but this property does not account for the abnormally high basal rate and cAMP sensitivity of sodium ion absorption in CF airway epithelia. Expression of complementary DNAs for rat epithelial Na+ channel (rENaC) alone in Madin Darby canine kidney (MDCK) epithelial cells generated large amiloride-sensitive sodium currents that were stimulated by cAMP, whereas coexpression of human CFTR with rENaC generated smaller basal sodium currents that were inhibited by cAMP. Parallel studies that measured regulation of sodium permeability in fibroblasts showed similar results. In CF airway epithelia, the absence of this second function of CFTR as a cAMP-dependent regulator likely accounts for abnormal sodium transport.


Postexercise motor evoked potentials in depressed patients, recovered depressed patients, and controls.
We hypothesized that impaired postexercise motor evoked potential (MEP) facilitation in depressed patients would reverse with recovery from depression. Transcranial magnetic stimulation and exercise of the thenar muscles were used to examine the 10 controls, 10 medicated depressed patients, and 10 medicated recovered patients. Depressed patients showed reduced mean postexercise facilitation compared to both controls (p = 0.005) and recovered patients (p = 0.012). Controls and recovered patients had similar mean postexercise MEPs (p = 0.45). This is consistent with other evidence of reversibility of abnormal findings following recovery from depression.


Multiscale Modelling Tool: Mathematical modelling of collective behaviour without the maths.
Collective behaviour is of fundamental importance in the life sciences, where it appears at levels of biological complexity from single cells to superorganisms, in demography and the social sciences, where it describes the behaviour of populations, and in the physical and engineering sciences, where it describes physical phenomena and can be used to design distributed systems. Reasoning about collective behaviour is inherently difficult, as the non-linear interactions between individuals give rise to complex emergent dynamics. Mathematical techniques have been developed to analyse systematically collective behaviour in such systems, yet these frequently require extensive formal training and technical ability to apply. Even for those with the requisite training and ability, analysis using these techniques can be laborious, time-consuming and error-prone. Together these difficulties raise a barrier-to-entry for practitioners wishing to analyse models of collective behaviour. However, rigorous modelling of collective behaviour is required to make progress in understanding and applying it. Here we present an accessible tool which aims to automate the process of modelling and analysing collective behaviour, as far as possible. We focus our attention on the general class of systems described by reaction kinetics, involving interactions between components that change state as a result, as these are easily understood and extracted from data by natural, physical and social scientists, and correspond to algorithms for component-level controllers in engineering applications. By providing simple automated access to advanced mathematical techniques from statistical physics, nonlinear dynamical systems analysis, and computational simulation, we hope to advance standards in modelling collective behaviour. At the same time, by providing expert users with access to the results of automated analyses, sophisticated investigations that could take significant effort are substantially facilitated. Our tool can be accessed online without installing software, uses a simple programmatic interface, and provides interactive graphical plots for users to develop understanding of their models.


Competition between folding and glycosylation in the endoplasmic reticulum.
Using carboxypeptidase Y in Saccharomyces cerevisiae as a model system, the in vivo relationship between protein folding and N-glycosylation was studied. Seven new sites for N-glycosylation were introduced at positions buried in the folded protein structure. The level of glycosylation of such new acceptor sites was analysed by pulse-labelling under two sets of conditions that are known to reduce the rate of folding: (i) addition of dithiothreitol to the growth medium and (ii) introduction of deletions in the propeptide. A variety of effects was observed, depending on the position of the new acceptor sites. In some cases, all the newly synthesized mutant protein was modified at the novel site while in others no modification took place. In the most interesting category of mutants, the level of glycosylation was dependent on the conditions for folding. This shows that folding and glycosylation reactions can compete in vivo and that glycosylation does not necessarily precede folding. The approach described may be generally applicable for the analysis of protein folding in vivo.


Bayesian relaxed clock estimation of divergence times in foraminifera.
Accurate and precise estimation of divergence times during the Neo-Proterozoic is necessary to understand the speciation dynamic of early Eukaryotes. However such deep divergences are difficult to date, as the molecular clock is seriously violated. Recent improvements in Bayesian molecular dating techniques allow the relaxation of the molecular clock hypothesis as well as incorporation of multiple and flexible fossil calibrations. Divergence times can then be estimated even when the evolutionary rate varies among lineages and even when the fossil calibrations involve substantial uncertainties. In this paper, we used a Bayesian method to estimate divergence times in Foraminifera, a group of unicellular eukaryotes, known for their excellent fossil record but also for the high evolutionary rates of their genomes. Based on multigene data we reconstructed the phylogeny of Foraminifera and dated their origin and the major radiation events. Our estimates suggest that Foraminifera emerged during the Cryogenian (650-920 Ma, Neo-Proterozoic), with a mean time around 770 Ma, about 220 Myr before the first appearance of reliable foraminiferal fossils in sediments (545 Ma). Most dates are in agreement with the fossil record, but in general our results suggest earlier origins of foraminiferal orders. We found that the posterior time estimates were robust to specifications of the prior. Our results highlight inter-species variations of evolutionary rates in Foraminifera. Their effect was partially overcome by using the partitioned Bayesian analysis to accommodate rate heterogeneity among data partitions and using the relaxed molecular clock to account for changing evolutionary rates. However, more coding genes appear necessary to obtain more precise estimates of divergence times and to resolve the conflicts between fossil and molecular date estimates.


How Should We Lower Blood Pressure after Cerebral Hemorrhage? A Systematic Review and Meta-Analysis.
The optimal treatment of high blood pressure (BP) after acute intra-cerebral hemorrhage (ICH) is controversial. The aim of the study was to evaluate the safety and efficacy of early intensive vs. conservative BP lowering treatment in patients with ICH. Randomized controlled trials with active and control groups receiving intensive and conservative BP lowering treatments were identified. The following outcomes were assessed: 3-month mortality and combined death or major disability, 24-h hematoma growth, early neurological deterioration, occurrence of hypotension, severe hypotension, and serious treatment-emergent adverse events. Five trials were included involving 4,350 participants, 2,162 and 2,188 for intensive and conservative treatment groups, respectively. The pooled risk ratio of 3-month death or major disability was 0.96 (0.91-1.01) and the weighted mean difference in absolute hematoma growth was -1.53 (95% CI -2.94 to -0.12) mL in the intensive compared to conservative BP-lowering. There were no differences across the treatments in the incidence rates of 3-month mortality, early neurological deterioration, hypotension, and treatment-related adverse effects other than renal events. Key Messages: The early intensive anti-hypertensive treatment was overall safe and reduced the hematoma expansion in patients presenting with acute-onset spontaneous ICH and high BP levels.


Pulmonary Zygomycosis caused by Cunninghamella bertholletiae in a child with acute lymphoblastic leukemia.
Zygomycosis is an invasive mycotic disease caused by fungi of the class Zygomycetes. Infections caused by zygomycetes, are known for their difficulty of diagnosis and treatment. Cunninghamella bertholletiae (Cb), is a saprobic fungus commonly found in the soil of temperate climates. Pulmonary infections caused by Cb are being identified with increasing frequency among patients on immunosuppressive therapy, and these infections usually have a fatal outcome. We present a rare case of pulmonary zygomycosis caused by Cb in a 10 year old male child with acute lymphoblastic leukemia. In spite of intensive antifungal chemotherapy (iv liposomal amphotericin B 7 mg/Kg once daily) following clinical diagnosis, he died of pulmonary failure.


Alzheimer's disease is associated with decreased risk of cancer-specific mortality: a prospective study (NEDICES).
Previous studies have shown that Alzheimer's disease (AD) is associated with a reduced risk of cancer. However, most studies exclude those with undiagnosed dementia. The only way to overcome this methodological issue is to examine all the participants or to screen the population for symptoms of dementia with a validated instrument and confirm any suspected dementia patients with a clinical examination (i.e., a two-phase investigation method). We used this methodology to estimate whether cancer-specific mortality is associated with AD and other types of dementia in a prospective population-based study (NEDICES) involving 5,278 elderly people. Community-dwelling subjects with and without dementia were identified and followed for a median of 12.5 years, after which the death certificates of those who deceased were examined. A total of 1,976 (47.1%) died, including 277 who had possible or probable AD and 126 with non-AD dementia. Cancer was reported significantly less often in those with possible or probable AD (5.8%) or non-AD dementia (6.3%) than in those without dementia (26.5%). In an unadjusted Cox model, hazard ratio (HR) of cancer-specific mortality in participants with AD = 0.45 (p = 0.002) and HR in participants with non-AD dementia = 0.62 (p = 0.179) when compared to the non-demented group. In a Cox model that adjusted for a variety of demographic factors and co-morbidities, HRs of cancer-specific mortality in participants with AD = 0.50 (p = 0.028) and 0.97 (p = 0.942) in non-AD dementia. This study provides further evidence of an inverse association between cancer and AD.


Modulation and compensation of the mRNA expression of energy related transporters in the brain of glucose transporter 1-deficient mice.
Facilitative glucose transporter 1 (GLUT1) is the molecule responsible for the entry of glucose into the brain, and its mutation is known as GLUT1 deficiency syndrome (GLUT1DS) in humans. To clarify the effect of GLUT1 gene deficiency, we have produced GLUT1-deficient mice, and investigated the developmental expression of GLUT1, monocarboxylate transporter 1 (MCT1) and MCT2 in the brains of these mice. Since the homozygotes were found to be embryonically lethal and the heterozygotes exhibited no abnormalities, GLUT1deficiency was examined using heterozygote mice. GLUT1 deficiency did not significantly affect the mRNA levels of GLUT1 at P0, P7 and in adults, or the levels of MCTs at P7, P14 and in adults. The GLUT1 level at P14 was reduced by 46.9%, although this was not statistically significant. The MCTs levels at P0 were increased about 2.0-fold in the deficient mice compared with the wild type. Furthermore, at P0, GLUT1 mRNA levels in wild type females were 1.91-fold higher than in wild type males. These results suggest that GLUT1 deficiency affects GLUT1 mRNA expression in the infant brain, and that of MCT1 and MCT2 in the neonatal brain. Furthermore, a compensatory effect of GLUT1 expression was observed in the brain of adult deficient mice. These effects of GLUT1 deficiency in the brain provide a molecular basis to assist in our understanding of the symptoms of GLUT1DS.


Two-year outcomes of a pilot glaucoma suspect telemedicine monitoring program.
The purpose of this study was to characterize a pilot program using e-health to monitor glaucoma suspects in a large integrated health system. A retrospective chart review of patients enrolled in the first 2 years of a new glaucoma suspect telemedicine monitoring program was conducted. Patients were enrolled in the program after being diagnosed as glaucoma suspects in the regular clinic setting and were eligible for the program if they had better than 20/40 vision, intraocular pressure (IOP) <25 mmHg, a normal baseline visual field, and an optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) without clear evidence of glaucomatous optic nerve damage. Patients were followed annually thereafter with measurements of vision, IOP, and OCT RNFL, which were reviewed at a centralized telemedicine reading center. Patients were retained within the program unless there was evidence of disease progression, in which case they were referred to an ophthalmologist for further evaluation. The first 100 patients received a survey assessing their satisfaction with the program after their first visit. The number of patients who adhered to follow-up recommendations, who were referred to an ophthalmologist for additional evaluation, and who began on IOP-lowering medications was evaluated. A total of 225 patients were enrolled in this program. Of eligible patients, 97.3% attended their 1-year follow-up visit and 92.5% attended their 2-year follow-up visit. Over the course of 2 years, five patients were referred for further clinic evaluation due to concern for progressive RNFL loss, of which two were started on IOP-lowering medications. No patients were referred to the clinic for vision loss or elevated IOP. In all, 87% of patients said that they would be extremely or quite likely to recommend the program to a friend. More than 80% of patients said that the program was extremely or very helpful, convenient, and professional. This novel telemedicine program for monitoring low-risk glaucoma suspects achieved high patient retention. Significant disease progression was rare with a few patients requiring referrals back to the clinic setting or initiation of IOP-lowering therapy. Telemedicine is a promising method to follow patients who are glaucoma suspects.


Assessing the Level and Determinants of COVID-19 Vaccine Confidence in Kenya.
The government of Kenya has launched a phased rollout of COVID-19 vaccination. A major barrier is vaccine hesitancy; the refusal or delay of accepting vaccination. This study evaluated the level and determinants of vaccine hesitancy in Kenya. We conducted a cross-sectional study administered through a phone-based survey in February 2021 in four counties of Kenya. Multilevel logistic regression was used to identify individual perceived risks and influences, context-specific factors and vaccine-specific issues associated with COVID-19 vaccine hesitancy. COVID-19 vaccine hesitancy in Kenya was high: 36.5%. Factors associated with vaccine hesitancy included: Rural regions, perceived difficulty in adhering to government regulations on COVID-19 prevention, no perceived COVID-19 infection risk, concerns regarding vaccine safety and effectiveness, and religious and cultural reasons. There is a need for the prioritization of interventions to address vaccine hesitancy and improve vaccine confidence as part of the vaccine roll-out plan. These messaging and/or interventions should be holistic to include the value of other public health measures, be focused and targeted to specific groups, raise awareness on the risks of COVID-19 and effectively communicate the benefits and risks of vaccines.


Comparison of the tick repellent efficacy of chemical and biological products originating from Europe and the USA.
The present paper investigates the efficacy of common anti-tick repellents in Europe and in the USA. There were tested Ixodes ricinus, Dermacentor reticulatus, and Rhipcephalus sanguineus when they are placed onto hands and clothes of male and female humans being treated with common tick repellents. It was seen that DEET needed high concentrations to repel ticks, while essential oils are mostly inefficient. On the other hand saltidin=icaridin, p-menthan-diol and IR 3535 showed long-lasting effects, which in the case of combinations of saltidin and Vitex extracts were even increased.


Idiopathic inflammatory myopathies, signified by distinctive peripheral cytokines, chemokines and the TNF family members B-cell activating factor and a proliferation inducing ligand.
Serum cytokines play an important role in the pathogenesis of myositis by initiating and perpetuating various cellular and humoral autoimmune processes. The aim of the present study was to describe a broad spectrum of T- and B-cell cytokines, growth factors and chemokines in patients with idiopathic inflammatory myopathies (IIMs) and healthy individuals. A protein array system, denoted as multiplex cytokine assay was utilized to measure simultaneously the levels of 24 circulating cytokines, including B-cell activating factor (BAFF) and a proliferation inducing ligand (APRIL) of patients with IIMs and healthy individuals. Additionally, correlational clustering and discriminant function analysis (DFA), two multivariate, supervised analysis methods were employed to identify a subset of biomarkers in order to describe potential functional interrelationships among these pathological cytokines. Univariate analysis demonstrated that a complex set of immune and inflammatory modulating cytokines are significantly up-regulated in patients with IIMs relative to unaffected controls including IL-10, IL-13, IFN-α, epidermal growth factor (EGF), VEGF, fibroblast growth factor (FGF), CCL3 [macrophage inflammatory protein (MIP-1α)], CCL4 (MIP-1β) and CCL11 (eotaxin), whereas G-CSF was significantly reduced in IIM patients. Correlational clustering was able to discriminate between, and hence sub-classify patients with IIMs. DFA identified EGF, IFN-α, VEGF, CCL3 (MIP-1α) and IL-12p40, as analytes with the strongest discriminatory power among various myositis patients and controls. Our findings suggest that these factors modulate myositis pathology and help to identify differences between subsets of the disease.


Differential effect of phosphodiesterase-3 inhibitors on sympathetic hyperinnervation in healed rat infarcts.
The effect of phosphodiesterase-3 (PDE-3) inhibitors on arrhythmia remains controversial, so the purpose of this study was to determine their differential effects on sympathetic hyperinnervation and the involved mechanisms in a rat model of myocardial infarction. After ligating the coronary artery, male Wistar rats were randomized to cilostazol or milrinone, chemically unrelated inhibitors of PDE-3, or vehicle for 4 weeks. The postinfarction period was associated with increased myocardial norepinephrine levels and oxidant release, as measured by myocardial superoxide level and dihydroethidine fluorescence staining. Infarcted rats in the milrinone- and cilostazol-treated groups had favorable ventricular remodeling with similar potency. Compared with milrinone, cilostazol significantly increased interstitial adenosine levels and reduced the production of myocardial cAMP and superoxide. Cilostazol significantly blunted sympathetic hyperinnervation, as assessed by immunofluorescent analysis of sympathetic innervation, and western blotting and real-time quantitative RT-PCR of nerve growth factor. Furthermore, the inhibitory effect of cilostazol on nerve growth factor was reversed by 8-cyclopentyl-1,3-dipropylxanthine, a selective A1 receptor antagonist, and enhanced by tempol administration. In spite of similar arrhythmic vulnerability during programmed stimulation in both the vehicle-and cilostazol-treated groups, cilostazol did not have proarrhythmic effects compared with milrinone. Unlike milrinone, cilostazol has therapeutic neutrality in arrhythmias because of adenosine uptake inhibition, which antagonizes the PDE-3-induced increase of sympathetic reinnervation via mediation of an adenosine A1 receptor-mediated antioxidation.


Effect of cardiac resynchronization therapy in patients with diabetes randomized in EchoCRT.
As patients with heart failure (HF) and concomitant diabetes carry a poor prognosis, this post-hoc subgroup analysis aimed to compare the outcomes of patients with and without diabetes randomized in the Echocardiography Guided Cardiac Resynchronization Therapy (EchoCRT) study. EchoCRT randomized patients with a QRS duration <130 ms and echocardiographic evidence of left ventricular dyssynchrony to CRT turned on (CRT=ON) vs. off (CRT=OFF) following device implantation. At study entry, 328 patients (40.5%) had diabetes. The primary outcome (all-cause death or first hospitalization for worsening HF) occurred more frequently in patients with than without diabetes (32.6% vs. 23%, P = 0.003). A significant treatment interaction was observed for the primary outcome indicating a higher risk for CRT=ON vs. CRT-OFF in patients without [26.5% vs. 19.8%, hazard ratio (HR) 1.58, 95% confidence interval (CI) 1.08-2.31] vs. with diabetes (31.4% vs. 34%; HR 0.86, 95% CI 0.58-1.27; P for interaction 0.041). This effect was mainly driven by a lower rate in HF hospitalizations, but was only of borderline significance after multivariate adjustment (P = 0.063). The most pronounced effect was observed in patients with non-ischaemic cardiomyopathy, where a significantly reduced risk of reaching the primary endpoint for CRT=ON vs. CRT-OFF was observed in patients with (HR 0.27, P = 0.003) vs. patients without diabetes (HR 1.79, P = 0.038; P for interaction 0.005). No treatment interaction by diabetes diagnosis was found for mortality endpoints. In EchoCRT, HF patients with a narrow QRS complex and coexisting diabetes demonstrated a signal for less harm caused by CRT compared with patients without diabetes, which was driven by differences in hospitalizations owing to HF.


Impact of Injection Speed, Volume, and Site on Pain Sensation.
Painful subcutaneous insulin injections may decrease treatment compliance. Improving injection comfort therefore represents a particular area of technological research in which steady progress has been made since the introduction of the insulin pen in 1985. Injection pain can be influenced by many variables, but relatively little is known about their impact. This study investigated the impact of injection volume (range 0-2250 µL), speed (range 0-800 µL/sec), and site (abdomen vs thigh) on pain sensation. In random order, patients (n = 80) with type 1 or type 2 diabetes received 24 saline injections subcutaneously through a 27G ultra-thin-wall needle. Injections were performed in the abdomen (n = 19) and thigh (n = 5) with predefined speed-volume combinations. For each injected speed-volume combination, patients scored their pain sensation on a 100 mm visual analog scale (VAS). The mean pain scores for speed-volume combinations were all in the lower part (<20 mm) of the VAS, indicating zero to mild pain. Pain sensation was statistically higher ( P < .05) with the 2250 µL volume compared to other injection volumes (range 4.3-5.1 mm) and with thigh compared to abdomen injections (2.1 mm). Pain sensation did not change with increasing injection speed. Patient acceptance of the injection pain was high for all injections (range 93.7-98.7%). In summary, large volume and thigh injections are rated more painful, but the clinical impact of these findings is likely marginal considering the low absolute pain levels and high patient acceptance rates. Injection speed does not influence pain sensation.