When and where do hip fractures occur? A population-based study.
We investigated the effects of socio-demographic and health factors on timing and location of hip fracture among 484 subjects. Time of fracture varied between community dwellers and residential care facility dwellers, and in relation to subjects' psychotropic drug status. Indoor hip fracture incidence increased on snow-covered days. This paper aims to describe the timing and whereabouts of hip fracture cases in a population-based setting and to relate these factors with residential and health status, seasonal variation, and snow-covered ground. We consecutively included 484 incident hip fracture events (age ≥50 years) admitted to a Swedish orthopedic department during a 1-year period. Data concerning socio-demographic details, fall location, time of fracture, comorbidity, and medications were collected from in-patient medical records and through patient or caregiver interviews. The expected peak in fracture occurrence during daytime was observed among community dwellers but not among subjects living in residential care. Hip fracture was twice as likely to occur during nighttime hours among psychotropic drug users (adjusted odds ratio (Adj. OR), 2.20; 95% confidence interval (CI), 1.12-4.30) compared to those not receiving these medications. Subjects without dementia, taking psychotropic drugs, were also more likely to fracture during nighttime hours (Adj. OR, 2.91; 95% CI, 1.40-6.0). We observed an increase in indoor hip fracture incidence on snow-covered days among community dwellers (incidence rate ratio, 1.34; 95% CI, 1.02-1.74). We observed only a weak seasonal trend in hip fracture incidence, based on month, among community dwellers who fractured indoors. Special attention and possibly fall-preventive efforts should be directed not only toward those living in residential care facilities but also toward community-dwelling subjects taking psychotropic drugs since these groups have a higher incidence of nighttime hip fracture. Further research aiming to explain the seasonal variation of indoor fracture incidence among community dwellers is warranted.


Substrate-induced shifts and screening in the fluorescence spectra of supramolecular adsorbed organic monolayers.
We have investigated the influence of the substrate on the fluorescence of adsorbed organic molecules. Monolayer films of perylene-3,4,9,10-tetracarboxylic-3,4,9,10-diimide (PTCDI), a supramolecular network formed from PTCDI and melamine, and perylene-3,4,9,10-tetracarboxylic-3,4,9,10-dianhydride have been deposited on hexagonal boron nitride (hBN). The principal peaks in the fluorescence spectra of these films were red-shifted by up to 0.37 eV relative to published measurements for molecules in helium droplets. Smaller shifts (∼0.03 eV) arising from interactions between neighbouring molecules are investigated by comparing the fluorescence of distinct arrangements of PTCDI, which are templated by supramolecular self-assembly and determined with molecular resolution using atomic force microscopy under ambient conditions. We compare our experimental results with red-shifts calculated using a combination of a perturbative model and density functional theory which account for, respectively, resonant and non-resonant effects of a dielectric hBN substrate. We show that the substrate gives rise to a red-shift in the fluorescence of an adsorbed molecule and also screens the interactions between neighbouring transition dipole moments; both these effects depend on the refractive index of the substrate.


Stent supported angioplasty in Takayasu arteritis.
Eleven patients with Takayasu Arteritis (TA) underwent angioplasty and stent placement in aorta, renal, carotid, subclavian and coronary arteries. Five wall stents were deployed in aorta in four patients. Indications for angioplasty and stent placement in aorta included hypertension in four patients and claudication and erectile impotence in one patient each. Post-procedure the peak systolic pressure gradient across the stenotic segment in the aorta disappeared. Six patients underwent angioplasty and stent placement in carotid arteries. Indications were syncope in 6 patients, loss of vision, stroke, transient ischaemic attack and seizures in one patients each. There was a marked improvement in symptoms in the patients following the procedure. For chronic total occlusion of subclavian arteries, two stents were deployed in two patients. Following the stent placement pulses in upper limb reappeared. Stents were also deployed to treat near total occlusion of right coronary artery and flow limited dissection of renal artery in one patient each. Complications of the procedure included pain in the back, mild hypertension, transient bradycardia and conduction block in one patient each. In conclusion, the stenotic and obliterative vascular lesions in TA can be managed successfully with angioplasty and stent placement. A long term follow up is required to determine the re-stenosis rate.


An endoplasmic reticulum stress-regulated lncRNA hosting a microRNA megacluster induces early features of diabetic nephropathy.
It is important to find better treatments for diabetic nephropathy (DN), a debilitating renal complication. Targeting early features of DN, including renal extracellular matrix accumulation (ECM) and glomerular hypertrophy, can prevent disease progression. Here we show that a megacluster of nearly 40 microRNAs and their host long non-coding RNA transcript (lnc-MGC) are coordinately increased in the glomeruli of mouse models of DN, and mesangial cells treated with transforming growth factor-β1 (TGF- β1) or high glucose. Lnc-MGC is regulated by an endoplasmic reticulum (ER) stress-related transcription factor, CHOP. Cluster microRNAs and lnc-MGC are decreased in diabetic Chop-/- mice that showed protection from DN. Target genes of megacluster microRNAs have functions related to protein synthesis and ER stress. A chemically modified oligonucleotide targeting lnc-MGC inhibits cluster microRNAs, glomerular ECM and hypertrophy in diabetic mice. Relevance to human DN is also demonstrated. These results demonstrate the translational implications of targeting lnc-MGC for controlling DN progression.


Evaluation of disease modifying activity of Coriandrum sativum in experimental models.
Coriandrum sativum (CS), has been widely used in traditional systems of medicine for treatment of rheumatoid arthritis. However, the mechanism of action for its antiarthritic effects is not clearly known. Therefore, the present study was carried out to evaluate the antiarthritic activity of CS in rats in two experimental models. The antiarthritic activity of CS seed hydroalcoholic extract (CSHE) was evaluated in adult Wistar rats by using two experimental models, viz. formaldehyde and Complete Freund's adjuvant (CFA) induced arthritis. The expression of pro-inflammatory cytokines (predominantly contributed by macrophages) was also evaluated. TNF- α level was estimated in serum by ELISA method. TNF-R1, IL-1 β and IL-6 expression in the synovium was analysed by immunohistochemistry. CSHE produced a dose dependent inhibition of joint swelling as compared to control animals in both, formaldehyde and CFA induced arthritis. Although there was a dose dependent increase in serum TNF-α levels in the CSHE treated groups as compared to control, the synovial expression of macrophage derived pro-inflammatory cytokines/cytokine receptor was found to be lower in the CSHE treated groups as compared to control. Our results demonstrate that the antiarthritic activity of CSHE may be attributed to the modulation of pro-inflammatory cytokines in the synovium. In further studies CSHE could be explored to be developed as a disease modifying agent in the treatment of RA.


Evaluation of PROforma as a language for implementing medical guidelines in a practical context.
PROforma is one of several languages that allow clinical guidelines to be expressed in a computer-interpretable manner. How these languages should be compared, and what requirements they should meet, are questions that are being actively addressed by a community of interested researchers. We have developed a system to allow hypertensive patients to be monitored and assessed without visiting their GPs (except in the most urgent cases). Blood pressure measurements are performed at the patients' pharmacies and a web-based system, created using PROforma, makes recommendations for continued monitoring, and/or changes in medication. The recommendations and measurements are transmitted electronically to a practitioner with authority to issue and change prescriptions. We evaluated the use of PROforma during the knowledge acquisition, analysis, design and implementation of this system. The analysis focuses on the logical adequacy, heuristic power, notational convenience, and explanation support provided by the PROforma language. PROforma proved adequate as a language for the implementation of the clinical reasoning required by this project. However a lack of notational convenience led us to use UML activity diagrams, rather than PROforma process descriptions, to create the models that were used during the knowledge acquisition and analysis phases of the project. These UML diagrams were translated into PROforma during the implementation of the project. The experience accumulated during this study highlighted the importance of structure preserving design, that is to say that the models used in the design and implementation of a knowledge-based system should be structurally similar to those created during knowledge acquisition and analysis. Ideally the same language should be used for all of these models. This means that great importance has to be attached to the notational convenience of these languages, by which we mean the ease with which they can be read, written, and understood by human beings. The importance of notational convenience arises from the fact that a language used during knowledge acquisition and analysis must be intelligible to the potential users of a system, and to the domain experts who provide the knowledge that will be used in its construction.


Paeoniflorin Attenuates Dexamethasone-Induced Apoptosis of Osteoblast Cells and Promotes Bone Formation via Regulating AKT/mTOR/Autophagy Signaling Pathway.
Paeoniflorin, a natural product derived from Paeonia lactiflora, possesses diverse pharmacological activities such as anti-inflammatory, antitumor, and antidiabetic effects. It has been reported for promoting osteoblastogenesis and inhibiting osteoclastogenesis. This study investigates the therapeutic effects of paeoniflorin in glucocorticoid-induced osteoporosis (GIOP) in vitro and in vivo. MC3T3-E1 cells were incubated with dexamethasone (DEX; 200 μM) and/or paeoniflorin (10 μM), followed by the investigation of cell proliferation, differentiation, mineralization, apoptosis, and autophagy. The AKT activator SC79 was used for evaluating the involvement of the AKT/mTOR signaling pathway. After DEX pretreatments, paeoniflorin promoted osteoblast differentiation and mineralization characterized by increase in Runx2, ALP, beclin-1, and LC3-II/LC3-I ratio levels and a decrease in apoptosis. The autophagy-promoting effects of paeoniflorin were reversed by SC79. C57BL/6 mice were given DEX (1 mg/kg) once daily and paeoniflorin (15 mg/kg) 48 hours for a total of 8 weeks followed by the investigation of histological changes, the trabecular bone microarchitecture, and the levels of bone turnover markers. The results showed that paeoniflorin increased alkaline phosphatase (ALP) activity and upregulated the expression of osteocalcin and beclin-1 but reduced the levels of Bax and C-terminal telopeptide of type I collagen (CTX-1). Thus, paeoniflorin may alleviate DEX-induced osteoporosis by promoting osteogenic differentiation and autophagy via inhibition of the AKT/mTOR signaling pathway.


Adiposity suppression effect in mice due to black pepper and its main pungent component, piperine.
We investigated energy metabolism enhancement by pepper by examining suppression of body fat accumulation in mice due to piperine (PIP) and black pepper (BP) intake. To induce adiposity, mice were fed a high-fat, high-sucrose (HFS) diet as a control diet for 4 weeks. Visceral fat weights decreased significantly in the mice fed diets of 0.03% and of 0.05% PIP. Body weight in the 0.05% PIP group also decreased significantly. In the mice fed a diet of 1.0% BP, body weight and visceral fat weights decreased significantly. For all parameters tested, the 1.0% BP group tended to show values slightly lower than those of the 0.03% PIP group. Expression of thermogenic protein uncoupling protein 1 tended to increase in the mice on the 1.0% BP diet. These results indicate that BP suppresses the effect of body fat accumulation mainly through the action of PIP.


How adolescent subjective health and satisfaction with weight and body shape are related to participation in sports.
Physical exercise has positive effects on health. However, its associations with self-rated health and body image, which are important predictors for adolescents' wellbeing and later morbidity, are complex. Cross-sectional survey among 2527 Norwegian adolescents. We examined the relations between self-reported gender, body size, amount and type of exercise and measures of self-rated health, drive for thinness, and desire to change body, with binary logistic regression analyses. Girls and overweight students reported to a greater extent than their peers impaired self-rated health, weight concerns, and desire to change their body. Increasing amount of time spent on sports was related to improved self-rated health in a dose-response manner. Both girls and boys who engaged in individual sports with an advantage of leanness, but only girls engaged in team sports, reported an increased desire to change the body. However, weight concern was not related to amount or type of sports. Physical exercise is positively related to self-reported health but has negative associations with body image for many adolescents. Health promotion efforts should consider this paradox and stimulate physical activity and sports along with body acceptance.


[Kabuki syndrome, a congenital syndrome with multiple anomalies].
The characteristics of a 5-years old girl, referred to a multidisciplinary team for cleft lip and palate because of speaking problems, were diagnosed as Kabuki syndrome. The Kabuki syndrome is a congenital syndrome of unknown aetiology, diagnosed based on a combination of clinical findings. It is characterised by distinctive facial features, skeletal anomalies, dermatoglyphic abnormalities, developmental delay and mild to moderate mental retardation. Children with the syndrome often have oral manifestations such as cleft palate, missing permanent teeth and conic crowns of upper incisors. The Kabuki syndrome was first described regarding the Japanese population but it is now known to occur in many other races as well. In a recent publication, 20 Dutch patients with Kabuki syndrome were described.


Pathology reporting of malignant pleural mesothelioma first diagnosis: A population-based approach.
Accurate pathologic diagnosis and reporting in malignant pleural mesothelioma are essential for clinical care, and cancer registration. Practical guidelines for pathologists are provided in publications and textbooks but it is unclear how these recommendations are applied in routine practice. We investigated the characteristics of pathology reports, and the extent to which they meet guideline standards. We reviewed 819 pathology reports relating to a first diagnosis of malignant pleural mesothelioma. Data sources were a regional section of the Italian network of the Mesothelioma Registry (2001-2014) and a pathology archive (1990-2000). We evaluated tumor characteristics, the diagnosis field including terminology and immunohistochemistry (IHC) workup, and report completeness (the proportion of items recorded). We investigated also two IHC panels identified by the most used markers in current practical guidelines, one best suited for epithelioid mesotheliomas (combinations of at least 2 positive and at least 2 negative mesothelioma markers) and the other best suited for sarcomatoid mesotheliomas (positive mesothelioma markers plus cytokeratins). Reports (753 histology, 66 cytology, IHC-confirmed 86%) were 74% complete and always narrative. Missing data were related to clinical history (76%), tumor laterality (61%), specimen size (38%), and histological subtype (23%). The proportion of cases with IHC was higher for epithelioid (90%) than sarcomatoid mesothelioma (87%). Compliance to IHC recommendations was higher for epithelioid (59%) than sarcomatoid mesothelioma (11%). The mean number of stains was significantly higher for sarcomatoid than epithelioid mesothelioma (p<0.000; Kruskal-Wallis test). Our findings show that although guidelines are designed to improve actual reporting practices, there is ample room for improvement in their application to standardize the diagnosis of mesothelioma. Synoptic pathology reporting needs to be implemented to better utilize pathology information.


Deamidation Slows Curli Amyloid-Protein Aggregation.
Nonenzymatic deamidation of asparagine and glutamine in peptides and proteins is a frequent modification both in vivo and in vitro. The biological effect is not completely understood, but it is often associated with protein degradation and loss of biological function. Here we describe the deamidation of CsgA, the major protein subunit of curli, which are important proteinaceous components of biofilms. CsgA has a high content of Asn and Gln, a feature seen in a few proteins that self-aggregate. We have implemented an approach to monitor deamidation rapidly by following the globally centroid mass shift, providing guidance for studies at the residue level. From the global mass measurement, we identified, using LC-MS/MS, extensive deamidation of several Asn residues and discovered three "Asn-Gly" sites to be the hottest spots for deamidation. The fibrillization of deamidated CsgA was measured using thioflavin T (ThT) fluorescence, circular dichroism (CD), and a previously reported hydrogen-deuterium exchange (HDX) platform. Deamidated proteins exhibit a longer lag phase and lower final ThT fluorescence, strongly suggesting slower and less amyloid fibril formation. CD spectra show that extensively deamidated CsgA remains unstructured and loses its ability to form amyloids. Mass-spectrometry-based HDX also shows that deamidated CsgA aggregates more slowly than wild-type CsgA. Taken together, the results show that deamidation of CsgA slows its fibrillization and disrupts its function, suggesting an opportunity to modulate CsgA fibrillization and affect curli and biofilm formation.


The effects of endoscopic sinus surgery on level of fatigue in patients with chronic rhinosinusitis.
Fatigue is a common symptom of chronic rhinosinusitis (CRS), but the response of fatigue to endoscopic sinus surgery (ESS) is rarely studied. A prospective, open cohort of adult patients undergoing ESS for CRS was studied using 10-cm fatigue visual analog scales (VASs), Lund-MacKay computed tomography (CT), and Lund-Kennedy nasal endoscopy scoring. Two hundred seventy-two patients, followed for a mean (+/-SD) of 16.5 +/- 8.5 months after ESS, noted significant fatigue improvement with an effect size defined as large by Cohen (0.8 [95% CI, 0.5-1.3]). Neither preoperative CT scores nor preoperative endoscopy scores correlated with preoperative fatigue severity. Compared with the mean preoperative fatigue score (6.1 +/- 2.9 cm), preoperative fatigue was more severe in women (6.9 +/- 2.6 cm; p < 0.001) patients with depression (7.7 +/- 2.4 cm; p < 0.001) and patients with fibromyalgia (7.9 +/- 2.2 cm; p = 0.013), but less severe in patients with nasal polyposis (5.4 +/- 3.2 cm; p = 0.009). Significantly greater postoperative reduction in fatigue was noted in patients with fibromyalgia when compared with study patients without fibromyalgia (effect size = 1.8 [95% CI, 1.6-2.2]; p > 0.001) with final fatigue severity scores similar to the entire study group. Similarly, patients with severe fatigue (n = 112; mean VAS score, 8.8 +/- 0.8 cm) showed a more pronounced improvement than patients less severely fatigued (n = 160; mean VAS score 4.2 +/- 2.4 cm; effect size = 2.2 [95% CI, 2.0-2.9]; p > 0.001). Fatigue improves after ESS, with significantly greater improvement in patients with fibromyalgia and in patients that are more severely fatigued at presentation.


Involvement of Neutrophil Dynamics and Function in Exercise-Induced Muscle Damage and Delayed-Onset Muscle Soreness: Effect of Hydrogen Bath.
The purpose of this study was to investigate the involvement of neutrophil dynamics and function in exercise-induced muscle damage (EIMD) and delayed-onset muscle soreness (DOMS), and the effect of molecular hydrogen (H₂) intake on these parameters. Nine healthy and active young men performed H₂ and placebo bath trial in a crossover design. They carried out downhill running (-8% slope) for 30 min at a speed corresponding to 75~85% of peak oxygen uptake (VO₂peak). Subsequently, they repeated bathing for 20 min per day for one week. Degree of muscle soreness (visual analogue scale: VAS), peripheral leukocyte counts, neutrophil dynamics and function, muscle damage, and inflammation markers were measured. Plasma interleukin (IL)-6 concentration was significantly correlated with peripheral neutrophil count, VAS, and serum creatine kinase activity, respectively, after downhill running. Peripheral neutrophil count and serum myoglobin concentration were also significantly correlated. Conversely, there were no effects of H₂ bath. These results suggest that IL-6 may be involved in the mobilization of neutrophils into the peripheral blood and subsequent EIMD and DOMS after downhill running; however, it is not likely that H₂ bath is effective for the inflammatory process that was centered on neutrophils after downhill running.


Target-controlled infusion (Propofol) versus inhaled anaesthetic (Sevoflurane) in patients undergoing shoulder arthroscopic surgery.
One of the challenges of anaesthesia for shoulder arthroscopic procedures is the need for controlled hypotension to lessen intra-articular haemorrhage and thereby provide adequate visualisation to the surgeon. Achievement of optimal conditions necessitates several interventions and manipulations by the anaesthesiologist and the surgeon, most of which directly or indirectly involve maintaining intra-operative blood pressure (BP) control. This study aimed to compare the efficacy and convenience of target controlled infusion (TCI) of propofol and inhalational agent sevoflurane in patients undergoing shoulder arthroscopic surgery after preliminary inter-scalene blockade. Of thirty four patients studied, seventeen received TCI propofol (target plasma concentration of 3 μg/ml) and an equal number, sevoflurane (1.2-1.5 Minimum Alveolar Concentration). N2O was used in both groups. Systolic, diastolic, mean blood pressures and heart rate were recorded regularly throughout the procedure. All interventions to control BP by the anaesthesiologist and pump manipulation requested by the surgeon were recorded. The volume of saline irrigant used and the haemoglobin (Hb) content of the return fluid were measured. TCI propofol could achieve lower systolic, mean BP levels and the number of interventions required was also lower as compared to the sevoflurane group. The number of patients with measurable Hb was lower in the TCI propofol group and this translated into better visualisation of the joint space. A higher volume of saline irrigant was required in the sevoflurane group. No immediate peri-operative anaesthetic complications were noted in either category. TCI propofol appears to be superior to and more convenient than sevoflurane anaesthesia in inter-scalene blocked patients undergoing shoulder arthroscopy.


Pomalidomide Plus Low-Dose Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma and Renal Impairment: Results From a Phase II Trial.
Purpose Renal impairment (RI) limits treatment options in patients with relapsed/refractory multiple myeloma (RRMM). Here, we prospectively studied pomalidomide plus low-dose dexamethasone (LoDEX) in patients with RRMM and moderate or severe RI, including those receiving hemodialysis. Patients and Methods MM-013, a noncomparative, European phase II trial, enrolled three patient cohorts: moderate RI (cohort A; estimated glomerular filtration rate, 30 to < 45 mL/min/1.73 m2); severe RI (cohort B; estimated glomerular filtration rate, < 30 mL/min/1.73 m2); and severe RI that requires hemodialysis (cohort C). Patients received pomalidomide 4 mg/d on days 1 to 21 and LoDEX 20 or 40 mg once per week in 28-day cycles. The primary end point was overall response rate. Results Of 81 enrolled patients (33, 34, and 14 patients in cohorts A, B, and C, respectively), 13 were still receiving treatment at data cutoff (January 28, 2017). Overall response rates were 39.4%, 32.4%, and 14.3%, with a median duration of response of 14.7 months, 4.6 months, and not estimable, respectively. Of importance, 100%, 79.4%, and 78.6% of patients, respectively, achieved disease control. With a median follow-up of 8.6 months, median overall survival was 16.4 months, 11.8 months, and 5.2 months, respectively. Complete renal responses were observed only in cohort A (18.2%), and no patients in cohort C became hemodialysis independent. Grade 3 and 4 hematologic treatment-emergent adverse events and pomalidomide discontinuations as a result of treatment-emergent adverse events occurred more frequently in cohort C. Pomalidomide pharmacokinetics were comparable among the three renal cohorts. Conclusion Pomalidomide 4 mg/d plus LoDEX is efficacious in patients with RRMM with moderate or severe RI, including those who had more advanced disease and required hemodialysis. The safety profile was acceptable among the three groups, and no new safety signals were observed.


Hyperlipidaemia in general practice: three year follow up of an opportunistic screening project.
As part of the national lipid screening project 927 people with a plasma cholesterol level greater than 6.5 mM were detected by screening 4006 men and women aged 25-59 years. Three years later 801 of the 878 patients eligible for a follow-up study (91%) had been followed up at least once. The median number of follow-up visits was two. The bulk of the workload fell on the nursing staff. The mean decrease in cholesterol level was 8-14% in those receiving dietary advice only, 15-25% in those receiving additional drug treatment and 12% for all patients. A proportion of this decrease must be attributable to regression to the mean, loss to follow up when patients were doing well, and the patients' knowledge of their follow-up date. Data on a group of patients not attending for regular follow up suggest that regression to the mean could account for up to 7% of the cholesterol reduction observed. Screening for hyperlipidaemia in general practice is feasible when the necessary infrastructure is provided, but even with a fairly conservative protocol 3% of those screened received drug treatment.


Carbohydrate binding activities of Bradyrhizobium japonicum. III. Lectin expression, bacterial binding, and nodulation efficiency.
In previous studies, evidence that the Bradyrhizobium japonicum lectin, designated BJ38, mediated the observed carbohydrate-specific binding activities of the bacteria, including the saccharide-specific adhesion to soybean root cells was presented. In the present study, it is found that both B. japonicum, as well as the purified BJ38, bind predominantly to young emergent root hairs of soybean roots and, to a much lesser extent, to the root cap, mature root hairs, epicotyl or hypocotyl regions. Thus, the region of preferential binding for both the bacteria and the isolated lectin coincide with the region of the soybean root most susceptible to B. japonicum infection. The importance of bacterial binding for the nodulation process was studied by comparing the nodulation efficiency of binding-deficient mutants N4 and N6 to the wild-type. These mutants had been shown to be defective in carbohydrate recognition, as represented by their diminished ability to bind to soybean roots. BJ38 was immunolocalized to one pole of the cell surface of wild-type B. japonicum, but no surface labeling could be detected on either mutant. Moreover, both N4 and N6 showed a substantial decrease in nodulation activity, relative to the wild-type. These results provide additional evidence that the carbohydrate binding activity of B. japonicum, most probably mediated by BJ38, may play an important role(s) in the initial phases of the infection process.


The ED-AWARENESS Study: A Prospective, Observational Cohort Study of Awareness With Paralysis in Mechanically Ventilated Patients Admitted From the Emergency Department.
Awareness with paralysis is a devastating complication for patients receiving mechanical ventilation and risks long-term psychological morbidity. Data from the emergency department (ED) demonstrate a high rate of longer-acting neuromuscular blocking agent use, delayed analgosedation, and a lack of sedation depth monitoring. These practices are discordant with recommendations for preventing awareness with paralysis. Despite this, awareness with paralysis has not been rigorously studied in the ED population. Our objective is to assess the prevalence of awareness with paralysis in ED patients receiving mechanical ventilation. This was a single-center, prospective, observational cohort study on 383 mechanically ventilated ED patients. After extubation, we assessed patients for awareness with paralysis by using the modified Brice questionnaire. Three expert reviewers independently adjudicated awareness with paralysis. We report the prevalence of awareness with paralysis (primary outcome); the secondary outcome was perceived threat, a mediator for development of posttraumatic stress disorder. The prevalence of awareness with paralysis was 2.6% (10/383). Exposure to rocuronium at any point in the ED was significantly different between patients who experienced awareness with paralysis (70%) versus the rest of the cohort (31.4%) (unadjusted odds ratio 5.1; 95% confidence interval 1.30 to 20.1). Patients experiencing awareness with paralysis had higher mean values on the threat perception scale, denoting a higher degree of perceived threat, compared with patients who did not experience awareness with paralysis (13.4 [SD 7.7] versus 8.5 [SD 6.2]; mean difference 4.9; 95% confidence interval 0.94 to 8.8). Awareness with paralysis occurs in a significant minority of ED patients who receive mechanical ventilation. Potential associations of awareness with paralysis with ED care and increased perceived threat warrant further evaluation.


Human Replay Spontaneously Reorganizes Experience.
Knowledge abstracted from previous experiences can be transferred to aid new learning. Here, we asked whether such abstract knowledge immediately guides the replay of new experiences. We first trained participants on a rule defining an ordering of objects and then presented a novel set of objects in a scrambled order. Across two studies, we observed that representations of these novel objects were reactivated during a subsequent rest. As in rodents, human "replay" events occurred in sequences accelerated in time, compared to actual experience, and reversed their direction after a reward. Notably, replay did not simply recapitulate visual experience, but followed instead a sequence implied by learned abstract knowledge. Furthermore, each replay contained more than sensory representations of the relevant objects. A sensory code of object representations was preceded 50 ms by a code factorized into sequence position and sequence identity. We argue that this factorized representation facilitates the generalization of a previously learned structure to new objects.


Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society.
To update the 2004 American Academy of Neurology (AAN) guideline for treating new-onset focal or generalized epilepsy with second- and third-generation antiepileptic drugs (AEDs). The 2004 AAN criteria were used to systematically review literature (January 2003-November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength. Several second-generation AEDs are effective for new-onset focal epilepsy. Data are lacking on efficacy in new-onset generalized tonic-clonic seizures, juvenile myoclonic epilepsy, or juvenile absence epilepsy, and on efficacy of third-generation AEDs in new-onset epilepsy. Lamotrigine (LTG) should (Level B) and levetiracetam (LEV) and zonisamide (ZNS) may (Level C) be considered in decreasing seizure frequency in adults with new-onset focal epilepsy. LTG should (Level B) and gabapentin (GBP) may (Level C) be considered in decreasing seizure frequency in patients ≥60 years of age with new-onset focal epilepsy. Unless there are compelling adverse effect-related concerns, ethosuximide or valproic acid should be considered before LTG to decrease seizure frequency in treating absence seizures in childhood absence epilepsy (level B). No high-quality studies suggest clobazam, eslicarbazepine, ezogabine, felbamate, GBP, lacosamide, LEV, LTG, oxcarbazepine, perampanel, pregabalin, rufinamide, tiagabine, topiramate, vigabatrin, or ZNS is effective in treating new-onset epilepsy because no high-quality studies exist in adults of various ages. A recent Food and Drug Administration (FDA) strategy allows extrapolation of efficacy across populations; therefore, for focal epilepsy, eslicarbazepine and lacosamide (oral only for pediatric use) as add-on or monotherapy in persons ≥4 years old and perampanel as monotherapy received FDA approval.


The Evaluation Imperative.
With the advent of wide scale adoption and use of clinical information systems and other technologies to support the delivery of healthcare services, the inclusion of iterative evaluation is an often overlooked but important component of project management. In this paper, it is proffered that the evaluation process should be an imperative and initiated at the outset of the design and implementation of clinical information systems including any single component of hardware or software. Ideally, methods of evaluation should be multi-faceted, include formative and summative evaluation approaches and include a range of metrics that will provide organizations with insight to process and technology efficiency and effectiveness as well as human and financial impacts.


Metal-induced malformations in early Palaeozoic plankton are harbingers of mass extinction.
Glacial episodes have been linked to Ordovician-Silurian extinction events, but cooling itself may not be solely responsible for these extinctions. Teratological (malformed) assemblages of fossil plankton that correlate precisely with the extinction events can help identify alternate drivers of extinction. Here we show that metal poisoning may have caused these aberrant morphologies during a late Silurian (Pridoli) event. Malformations coincide with a dramatic increase of metals (Fe, Mo, Pb, Mn and As) in the fossils and their host rocks. Metallic toxins are known to cause a teratological response in modern organisms, which is now routinely used as a proxy to assess oceanic metal contamination. Similarly, our study identifies metal-induced teratology as a deep-time, palaeobiological monitor of palaeo-ocean chemistry. The redox-sensitive character of enriched metals supports emerging 'oceanic anoxic event' models. Our data suggest that spreading anoxia and redox cycling of harmful metals was a contributing kill mechanism during these devastating Ordovician-Silurian palaeobiological events.


Transcriptional profiling reveals barcode-like toxicogenomic responses in the zebrafish embryo.
Early life stages are generally most sensitive to toxic effects. Our knowledge on the action of manmade chemicals on the developing vertebrate embryo is, however, rather limited. We addressed the toxicogenomic response of the zebrafish embryo in a systematic manner by asking whether distinct chemicals would induce specific transcriptional profiles. We exposed zebrafish embryos to a range of environmental toxicants and measured the changes in gene-expression profiles by hybridizing cDNA to an oligonucleotide microarray. Several hundred genes responded significantly to at least one of the 11 toxicants tested. We obtained specific expression profiles for each of the chemicals and could predict the identity of the toxicant from the expression profiles with high probability. Changes in gene expression were observed at toxicant concentrations that did not cause morphological effects. The toxicogenomic profiles were highly stage specific and we detected tissue-specific gene responses, underscoring the sensitivity of the assay system. Our results show that the genome of the zebrafish embryo responds to toxicant exposure in a highly sensitive and specific manner. Our work provides proof-of-principle for the use of the zebrafish embryo as a toxicogenomic model and highlights its potential for systematic, large-scale analysis of the effects of chemicals on the developing vertebrate embryo.


Clinicopathologic characteristics of colonic carcinoid tumors.
Extra-appendiceal colonic carcinoids are uncommon neuroendocrine tumors with a poor prognosis compared with carcinoids of other gastrointestinal origins. Few studies have examined the clinicopathologic profile and behavior of this rare tumor. A retrospective analysis was performed on patients with colonic carcinoid tumors evaluated at a single tertiary care center between 1996 and 2012. Collected data included patient and tumor characteristics, presentation, treatment, recurrence, and survival. Results were integrated into a comprehensive review of the colonic carcinoid literature. In total, 114 patients with colorectal carcinoid tumors were identified, and 15 patients with extra-appendiceal tumors were analyzed. The mean age was 58.6 ± 3.0 y, and subjects were predominantly male (73.3%). The most common presenting problem was abdominal pain (33.3%), although 26.7% of patients were asymptomatic. Cecal tumors were the most prevalent (73.3%), and most patients underwent right hemicolectomy. Three patients with lesions < 1 cm were treated endoscopically. The mean tumor diameter was 2.9 ± 0.5 cm, with lymph node or distant metastasis present in 53.3% and 26.7%, respectively. All but two patients underwent a presumed curative resection. During a mean follow-up of 4.2 ± 1.0 y, there was only one death (non-carcinoid specific). Eleven patients were alive without evidence of disease at last follow-up and three patients were alive with disease, one of whom initially had a presumed curative resection that recurred. This case series further elucidates the clinicopathologic characteristics of colonic carcinoid tumors, which aids physicians in guiding the diagnosis and management of these rare tumors.


Polycystic ovaries and adrenal insufficiency in a young pubescent female with lipoid congenital adrenal hyperplasia due to splice mutation of the StAR gene: a case report and review of the literature.
We report a case of Lipoid Congenital Adrenal Hyperplasia (LCAH) secondary to Steroidogenic Acute Regulatory (StAR) gene mutation in an adolescent female with bilateral ovarian cysts. StAR gene defects follow an autosomal recessive mode of inheritance and typically present with severe adrenal insufficiency during infancy. Both sexes can be affected equally. XY males often present with sex reversal, while XX females may develop gonadal failure later in life due to premature loss of ovarian follicles. Recently there have been reported cases of successful fertility outcomes in women with LCAH. In our case report, we describe the clinical, biochemical and molecular analysis of a 16 year-old XX adolescent female who was suspected of having LCAH upon discovery of bilateral ovarian cysts in the context of adrenal insufficiency. Examination of the StAR gene revealed a homozygous splice site mutation. The patient is currently undergoing estradiol therapy to suppress ovarian cyst formation.


Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium.
At least 75% of head and neck cancers are attributable to a combination of cigarette smoking and alcohol drinking. A precise understanding of the independent association of each of these factors in the absence of the other with the risk of head and neck cancer is needed to elucidate mechanisms of head and neck carcinogenesis and to assess the efficacy of interventions aimed at controlling either risk factor. We examined the extent to which head and neck cancer is associated with cigarette smoking among never drinkers and with alcohol drinking among never users of tobacco. We pooled individual-level data from 15 case-control studies that included 10,244 head and neck cancer case subjects and 15,227 control subjects, of whom 1072 case subjects and 5775 control subjects were never users of tobacco and 1598 case subjects and 4051 control subjects were never drinkers of alcohol. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models. All statistical tests were two-sided. Among never drinkers, cigarette smoking was associated with an increased risk of head and neck cancer (OR for ever versus never smoking = 2.13, 95% CI = 1.52 to 2.98), and there were clear dose-response relationships for the frequency, duration, and number of pack-years of cigarette smoking. Approximately 24% (95% CI = 16% to 31%) of head and neck cancer cases among nondrinkers in this study would have been prevented if these individuals had not smoked cigarettes. Among never users of tobacco, alcohol consumption was associated with an increased risk of head and neck cancer only when alcohol was consumed at high frequency (OR for three or more drinks per day versus never drinking = 2.04, 95% CI = 1.29 to 3.21). The association with high-frequency alcohol intake was limited to cancers of the oropharynx/hypopharynx and larynx. Our results represent the most precise estimates available of the independent association of each of the two main risk factors of head and neck cancer, and they exemplify the strengths of large-scale consortia in cancer epidemiology.


Strategies to sustain a quality improvement initiative in neonatal resuscitation.
Many neonatal deaths can be prevented globally through effective resuscitation. South Africa (SA) committed towards attaining the Millennium Development Goal 4 (MDG4) set by the World Health Organization (WHO). However, SA's district hospitals have the highest early neonatal mortality rates. Modifiable and avoidable causes associated with patient-related, administrative and health care provider factors contribute to neonatal mortality. A quality improvement initiative in neonatal resuscitation could contribute towards decreasing neonatal mortality, thereby contributing towards the attainment of the MDG4. The aim of this study was, (1) to explore and describe the existing situation regarding neonatal resuscitation in a district hospital, (2) to develop strategies to sustain a neonatal resuscitation quality improvement initiative and (3) to decrease neonatal mortality. Changes that occurred and the sustainability of strategies were evaluated. A maternity section of a district hospital in South Africa. The National Health Service (NHS) Sustainability Model formed the theoretical framework for the study. The Problem Resolving Action Research model was applied and the study was conducted in three cycles. Purposive sampling was used for the quantitative and qualitative aspects of data collection. Data was analysed accordingly. The findings indicated that the strategies formulated and implemented to address factors related to neonatal resuscitation (training, equipment and stock, staff shortages, staff attitude, neonatal transport and protocols) had probable sustainability and contributed towards a reduction in neonatal mortality in the setting. These strategies had the probability of sustainability and could potentially improve neonatal outcomes and reduce neonatal mortality to contribute toward South Africa's drive to attain the MDG4.


Cooling and alpha 1- and alpha 2-adrenergic responses in cutaneous veins: role of receptor reserve.
Experiments were designed to determine the effects of cooling on alpha 1- and alpha 2-adrenergic responses in isolated canine cutaneous veins. Rings of saphenous veins were suspended for isometric tension recording in physiological salt solution. Cooling (from 37 to 24 degrees C) augmented contractions to norepinephrine under control conditions and after alpha 1-adrenergic blockade (prazosin) but not following alpha 2-adrenergic blockade (rauwolscine). Cooling augmented contractions evoked by the alpha 2-adrenergic agonists B-HT 920 and UK 14304 but did not affect responses to the full alpha 1-adrenergic agonist phenylephrine. These experiments suggest that cooling augments alpha 2-adrenergic responsiveness without affecting alpha 1-adrenergic responsiveness. However, the contractions evoked by the partial alpha 1-adrenergic agonist St 587 were virtually abolished by cooling. Moreover, following partial irreversible blockade of the alpha 1-adrenoceptors with phenoxybenzamine, cooling also reduced the contractions evoked by phenylephrine. Therefore, cooling reduces alpha 1-adrenergic responsiveness in canine cutaneous veins, but in the case of full alpha 1-adrenergic agonists such as norepinephrine and phenylephrine the inhibitory effect of cooling is buffered by an alpha 1-adrenoceptor reserve. With norepinephrine, this permits the potentiating effect of cooling on the alpha 2-adrenergic component of the response to predominate.


Acute neurocognitive effects of epigallocatechin gallate (EGCG).
Green tea is reported to have wide ranging beneficial health outcomes across epidemiological studies, which have been attributed to its flavonoid content. We investigated whether the flavonoid epigallocatechin gallate (EGCG) modulates brain activity and self-reported mood in a double-blind, placebo controlled crossover study. Participants completed baseline assessments of cognitive and cardiovascular functioning, mood and a resting state electroencephalogram (EEG) before and then 120 min following administration of 300 mg EGCG or matched placebo. EGCG administration was associated with a significant overall increase in alpha, beta and theta activity, also reflected in overall EEG activity, more dominant in midline frontal and central regions, specifically in the frontal gyrus and medial frontal gyrus. In comparison to placebo the EGCG treatment also increased self-rated calmness and reduced self rated stress. This pattern of results suggests that participants in the EGCG condition may have been in a more relaxed and attentive state after consuming EGCG. This is in keeping with the widespread consumption of green tea for its purported relaxing/refreshing properties. The modulation of brain function due to EGCG is deserving of further controlled human studies.


Adult and fetal haemoglobin J-Sardegna [alpha50(CE8)His-->Asp]: functional and molecular modelling studies.
Haemoglobin (Hb) J-Sardegna [alpha50(CE8)His-->Asp] is a haemoglobin variant characteristic of subjects from the island of Sardinia. Here we report a study of the functional properties of both fetal and adult Hb J-Sardegna. The results indicate that adult Hb J-Sardegna displays an oxygen affinity that is higher than that of adult Hb only in the presence of 2,3-diphosphoglycerate (2,3-DPG). On the contrary, at 20 degrees C, the oxygen affinity of fetal Hb J-Sardegna is identical to that of normal fetal haemoglobin, both in the presence and in the absence of 2,3-DPG. A significant difference between these two systems (i.e. a higher oxygen affinity of fetal Hb J-Sardegna) shows up very clearly only when temperature is increased to 37 degrees C. Hence in fetal Hb, the main effect of the amino acid substitution is a decrease in the overall enthalpy change of oxygenation. The results outline the role of the alpha(1)-beta(1) interface in assessing the thermodynamics of oxygen binding. The functional properties of both adult and fetal Hb J-Sardegna have been interpreted at the structural level in light of the results obtained by a computational modelling approach performed in comparison with HbA and Hb Aichi, a variant characterized by a different mutation [alpha50(CE8)His-->Arg] at the same position.


Teledermatologic consultation and reduction in referrals to dermatologists: a cluster randomized controlled trial.
To determine whether teledermatologic consultations can reduce referrals to a dermatologist by general practitioners (GPs). Multicenter cluster randomized controlled trial. We recruited 85 GPs from 35 general practices in 2 regions in the Netherlands (Almere and Zeist); 5 dermatologists from 2 nonacademic hospitals were also included in the study. Interventions The GPs randomized to the intervention used a teledermatologic consultation system to confer with a dermatologist, whereas those in the control group referred their patients according to usual practice. All patients, regardless of their condition, were seen in the office by a dermatologist after approximately 1 month. The main outcome measure was the proportion of office visits prevented by teledermatologic consultation, as determined by dermatologists at approximately the 1-month office visit. The secondary outcome measure was patient satisfaction, measured using the Patient Satisfaction Questionnaire III developed by Ware et al. The 85 study GPs enrolled 631 patients (46 intervention GPs, 327 patients; 39 control GPs, 304 patients). The 5 dermatologists considered a consultation preventable for 39.0% of patients who received teledermatologic consultation and 18.3% of 169 control patients, a difference of 20.7% (95% confidence interval, 8.5%-32.9%). At the 1-month dermatologist visit, 20.0% of patients who received teledermatologic consultation had recovered compared with 4.1% of control patients. No significant differences in patient satisfaction were found between groups. Teledermatologic consultation offers the promise of reducing referrals to a dermatologist by 20.7%. Providing teledermatologic consultation by GPs with more extended knowledge of dermatology may further reduce the need for dermatologist referrals. Trial Registration Current Controlled Trials No. ISRCTN57478950.


Can laypersons be trained to effectively deliver osteopathic manual therapy to patients with HIV?: a pilot study.
Osteopathic manipulative treatment (OMT) may provide added benefits to standard human immunodeficiency virus (HIV) and AIDS treatments. However, lack of access to trained OMT providers is a potential barrier to the widespread use of OMT in the management of HIV and AIDS. To determine the best time to measure the short-term impact of a brief OMT protocol on white blood cell counts in individuals with HIV and AIDS. Also, to explore recruiting and training laypersons to administer select osteopathic manual techniques. Participants were HIV-positive men aged between 18 and 65 years who had not undergone antiretroviral therapy in the past 12 months, had CD4(+) lymphocyte counts of 200 to 700 cells/mm(3), and had viral load levels of less than 100,000 copies/mL. Participants were randomly assigned to an OMT group or a control group; those in the OMT group recruited a layperson for training in osteopathic manual therapy. Participants in the OMT group received a 15-minute OMT protocol consisting of myofascial release of the thoracic inlet, pectoral traction, rib raising, thoracic pump, and abdominal pump. Participants in the control group engaged in conversation with the researcher for 15 minutes. Between-group differences for each white blood cell type were examined at varying time intervals after the protocols. Laypersons were trained to administer thoracic and abdominal pump techniques. They were tested by multiple choice examinations and by an independent rater for fidelity of administration. Twenty-one participants met the eligibility criteria. Of those, 18 returned for their study visit (OMT group, n=9; control group, n=9). An optimal time interval for measurement of white blood cell changes across the 5 cell types was not determined. However, P values for the 30-minute interval were consistently below 0.18 for neutrophils, eosinophils, and monocytes. Nine laypersons were trained in osteopathic manual therapy, 5 of whom scored 100% on initial completion of the multiple-choice examination; the remaining 4 laypersons scored 80% on the first try and 100% on the second try. All laypersons appropriately administered the manual therapy protocol. It is feasible to recruit and train laypersons to administer selected osteopathic manual therapy techniques with fidelity. Longitudinal studies on this concept are needed to examine patient outcomes and to evaluate the retention and fidelity of laypersons over time.


Bacterial sampling by absorbent paper points. An in vitro study.
This in vitro study was designed to test the hypothesis that sampling of bacterial suspensions by absorbent paper points would accurately reflect the proportion of the bacterial species whether they are homogeneously or non-homogeneously distributed in the sample site. The non-homogeneously distributed populations consisted of equal numbers of colony forming units (CFU) of two periodontal bacterial species present as separate cultures, one layered on top of the other. The species in the top layer accounted for greater than 90% of the total number of CFU detected by paper point sampling, regardless of which species formed the top layer. In contrast, when the layers were mixed prior to sampling to give a homogeneous bacterial distribution, the paper points detected equal numbers of CFU of each species. Thus the hypothesis was not supported and the proportions yielded by paper point sampling are not the same when the bacteria are non-homogeneously distributed as when they are homogeneously distributed. Ultrastructural observations have documented a non-homogeneous distribution of bacterial species in periodontal pockets. If the specific microbiota in the apical portion of deep periodontal pockets are important to the periodontal disease process, these data suggest that bacterial samples obtained by absorbent paper points misrepresent the presence of such bacterial species.


One size does not fit all: older adults benefit from redundant text in multimedia instruction.
The multimedia design of presentations typically ignores that younger and older adults have varying cognitive strengths and weaknesses. We examined whether differential instructional design may enhance learning in these populations. Younger and older participants viewed one of three computer-based presentations: Audio only (narration), Redundant (audio narration with redundant text), or Complementary (audio narration with non-redundant text and images). Younger participants learned better when audio narration was paired with relevant images compared to when audio narration was paired with redundant text. However, older participants learned best when audio narration was paired with redundant text. Younger adults, who presumably have a higher working memory capacity (WMC), appear to benefit more from complementary information that may drive deeper conceptual processing. In contrast, older adults learn better from presentations that support redundant coding across modalities, which may help mitigate the effects of age-related decline in WMC. Additionally, several misconceptions of design quality appeared across age groups: both younger and older participants positively rated less effective designs. Findings suggest that one-size does not fit all, with older adults requiring unique multimedia design tailored to their cognitive abilities for effective learning.


P2Y1 Receptor Activation of the TRPV4 Ion Channel Enhances Purinergic Signaling in Satellite Glial Cells.
Transient receptor potential (TRP) ion channels of peripheral sensory pathways are important mediators of pain, itch, and neurogenic inflammation. They are expressed by primary sensory neurons and by glial cells in the central nervous system, but their expression and function in satellite glial cells (SGCs) of sensory ganglia have not been explored. SGCs tightly ensheath neurons of sensory ganglia and can regulate neuronal excitability in pain and inflammatory states. Using a modified dissociation protocol, we isolated neurons with attached SGCs from dorsal root ganglia of mice. SGCs, which were identified by expression of immunoreactive Kir4.1 and glutamine synthetase, were closely associated with neurons, identified using the pan-neuronal marker NeuN. A subpopulation of SGCs expressed immunoreactive TRP vanilloid 4 (TRPV4) and responded to the TRPV4-selective agonist GSK1016790A by an influx of Ca(2+) ions. SGCs did not express functional TRPV1, TRPV3, or TRP ankyrin 1 channels. Responses to GSK1016790A were abolished by the TRPV4 antagonist HC067047 and were absent in SGCs from Trpv4(-/-) mice. The P2Y1-selective agonist 2-methylthio-ADP increased [Ca(2+)]i in SGCs, and responses were prevented by the P2Y1-selective antagonist MRS2500. P2Y1 receptor-mediated responses were enhanced in TRPV4-expressing SGCs and HEK293 cells, suggesting that P2Y1 couples to and activates TRPV4. PKC inhibitors prevented P2Y1 receptor activation of TRPV4. Our results provide the first evidence for expression of TRPV4 in SGCs and demonstrate that TRPV4 is a purinergic receptor-operated channel in SGCs of sensory ganglia.


Cervical vertebral motions and biomechanical responses to direct loading of human head.
There is little known data characterizing the biomechanical responses of the human head and neck under direct head loading conditions. However, the evaluation of the appropriateness of current crash test dummy head-neck systems is easily accomplished. Such an effort, using experimental means, generates and provides characterizations of human head-neck response to several direct head loading conditions. Low-level impact loads were applied to the head and face of volunteers and dummies. The resultant forces and moments at the occipital condyle were calculated. For the volunteers, activation of the neck musculature was determined using electromyography (EMG). In addition, cervical vertebral motions of the volunteers have been taken by means of X-ray cineradiography. The Ethics Committee of Tsukuba University approved the protocol of the experiments in advance. External force of about 210 N was applied to the head and face of five volunteers with an average age of 25 for the duration of 100 msec or so, via a strap at one of four locations in various directions: (1) an upward load applied to the chin, (2) a rearward load applied to the chin without facial mask, (3) a rearward load applied to the chin with the facial mask, and (4) a rearward load applied to the forehead. The same impact force as those for the human volunteers was also applied to HY-III, THOR, and BioRID. We found that cervical vertebral motions differ markedly according to the difference in impact loading condition. Some particular characteristics are also found, such as the flexion or extension of the upper cervical vertebrae (C0, C1, and C2) or middle cervical vertebrae (C3-C4), showing that the modes of cervical vertebral motions are markedly different among the different loading conditions. We also found that the biofidelity of dummies to neck response characteristics of the volunteers at the low-level impact loads is in the order of BioRID, THOR, and HY-III. It is relevant in this regard that the BioRID dummy was designed for a low-severity impact environment, whereas THOR and HY-III were optimized for higher-severity impacts.


A Randomized Study Comparing Digital Imaging to Traditional Glass Slide Microscopy for Breast Biopsy and Cancer Diagnosis.
Digital whole slide imaging may be useful for obtaining second opinions and is used in many countries. However, the U.S. Food and Drug Administration requires verification studies. Pathologists were randomized to interpret one of four sets of breast biopsy cases during two phases, separated by ≥9 months, using glass slides or digital format (sixty cases per set, one slide per case, n = 240 cases). Accuracy was assessed by comparing interpretations to a consensus reference standard. Intraobserver reproducibility was assessed by comparing the agreement of interpretations on the same cases between two phases. Estimated probabilities of confirmation by a reference panel (i.e., predictive values) were obtained by incorporating data on the population prevalence of diagnoses. Sixty-five percent of responding pathologists were eligible, and 252 consented to randomization; 208 completed Phase I (115 glass, 93 digital); and 172 completed Phase II (86 glass, 86 digital). Accuracy was slightly higher using glass compared to digital format and varied by category: invasive carcinoma, 96% versus 93% (P = 0.04); ductal carcinoma in situ (DCIS), 84% versus 79% (P < 0.01); atypia, 48% versus 43% (P = 0.08); and benign without atypia, 87% versus 82% (P < 0.01). There was a small decrease in intraobserver agreement when the format changed compared to when glass slides were used in both phases (P = 0.08). Predictive values for confirmation by a reference panel using glass versus digital were: invasive carcinoma, 98% and 97% (not significant [NS]); DCIS, 70% and 57% (P = 0.007); atypia, 38% and 28% (P = 0.002); and benign without atypia, 97% and 96% (NS). In this large randomized study, digital format interpretations were similar to glass slide interpretations of benign and invasive cancer cases. However, cases in the middle of the spectrum, where more inherent variability exists, may be more problematic in digital format. Future studies evaluating the effect these findings exert on clinical practice and patient outcomes are required.


Bi(x)La(1-x)VO4 solid solutions: tuning of electronic properties via stoichiometry modifications.
BixLa1-xVO4 solid solutions were obtained in the form of fine powder via a microwave-assisted hydrothermal route. The presence of a solid solution in the studied system was confirmed using X-ray diffraction (XRD) and optical spectroscopy techniques. Pure BiVO4 and LaVO4 were obtained in the monoclinic form, whereas solid solutions in the tetragonal, zircon-type structure. The optical band gap dependence on the composition of the solid solution is parabolic, thus there is a possibility to tune this parameter in a wide concentration range, from 2.4 to 4.0 eV. An absorption coefficient maximum is also concentration-dependent, possibly, due to the structural disorder of the samples. Solid solutions with Bi(3+) concentration between 11.94 and 32.57 at.% exhibit intense, green luminescence. This indicates the presence of Bi-originated electronic states within the band gap. The value of the conduction band edge potential, measured by both electrochemical impedance spectroscopy and work function measurements, is concentration-independent. Moreover, solid solutions exhibit a photoelectrochemical photocurrent switching effect, thus they may be promising materials for molecular electronics and as dioxygen activators.


Future prospects for vaccines to control fertility.
Vaccination is used routinely to protect against infectious disease and is being explored increasingly as a method of protection against tumors. Also, it has been established that vaccination using antigens associated with reproduction can protect against undesired pregnancy. Substantial progress over the past decade suggests that, if the remaining immunological and socioeconomic issues can be resolved, antifertility vaccines could be a valuable, additional method of family planning.


Sexually transmitted infections in adolescent girls.
Two hundred and ten adolescent girls in residential care with an age range of 12 to 16 years were screened for sexually transmitted infections. The incidences of infection with Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis were 13.7%, 16.2%, and 16.0% respectively. Pelvic inflammatory disease was identified in 16.4% of those with C trachomatis or gonococcal infection. The high morbidity from sexually transmitted disease in these adolescent girls reinforces the need for screening similar at risk teenagers.


Plasma levels of soluble intercellular adhesion molecule-1 as a biomarker for disease severity of patients with community-acquired pneumonia.
Community-acquired pneumonia (CAP) is characterized as an acute inflammation of the lung associated with the activation of macrophages and neutrophils. Intercellular adhesion molecule-1 (ICAM-1) is an essential adhesion molecule involved in immune cell recruitment in lung inflammation. We investigated whether ICAM-1 is a useful biomarker for assessing the disease severity of hospitalized adult patients with CAP. Plasma soluble ICAM-1 (sICAM-1) levels were measured in 78 patients with CAP and 69 healthy controls by using a commercial enzyme-linked immunosorbent assay. The pneumonia severity index scores were used to determine CAP severity in patients upon initial hospitalization. The sICAM-1 and C-reactive protein (CRP) levels decreased significantly in patients with CAP after antibiotic treatment. The plasma concentration of sICAM-1 alone, but not CRP, was correlated with CAP severity according to the pneumonia severity index scores (r=0.431, p<0.001). The sICAM-1 levels in patients with CAP with high mortality risk were significantly higher than those in patients with CAP with medium or low mortality risk. Moreover, the sICAM-1 level showed a significant correlation with the length of hospital stay (r=0.488, p<0.001). Mechanistic investigations found that bacterial lipopolysaccharide induced upregulation of ICAM-1 expression through the c-Jun N-terminal kinase pathway in RAW264.7 macrophages. Plasma sICAM-1 levels may play a role in the diagnosis and clinical assessment of CAP severity.


C1 inhibitor, a multi-functional serine protease inhibitor.
C1 inhibitor (C1INH) is a serpin that regulates both complement and contact (kallikrein-kinin) system activation. It consists of a serpin domain that is highly homologous to other serpins and an amino terminal non-serpin mucin-like domain. Deficiency of C1INH results in hereditary angioedema, a disease characterised by episodes of angioedema of the skin or the mucosa of the gastrointestinal tract or the oropharynx. Although early data suggested that angioedema was mediated via complement system activation, the preponderance of the data indicate that bradykinin is the mediator. In the past few years, it has become apparent that C1INH has additional anti-inflammatory functions independent of protease inhibition. These include interactions with leukocytes that may result in enhanced phagocytosis, with endothelial cells via E- and P-selectins that interfere with leukocyte rolling and in turn results in suppression of transmigration of leukocytes across the endothelium, and interactions with extracellular matrix components that may serve to concentrate C1INH at sites of inflammation. In addition, C1INH suppresses gram negative sepsis and endotoxin shock, partly via direct interaction with endotoxin that interferes with its interaction with macrophages, thereby suppressing tumour necrosis factor-a and other inflammatory mediators. C1INH treatment improves outcome in a number of disease models, including sepsis and other bacterial infections, possibly malaria, ischaemia-reperfusion injury (intestinal, hepatic, muscle, cardiac, brain), hyper-acute transplant rejection, and other inflammatory disease models. Recent data suggest that this effectiveness is the result of mechanisms that do not require protease inhibition, in addition to both complement and contact system activation.


Reliability of clinical tests to evaluate nerve function and mechanosensitivity of the upper limb peripheral nervous system.
Clinical tests to assess peripheral nerve disorders can be classified into two categories: tests for afferent/efferent nerve function such as nerve conduction (bedside neurological examination) and tests for increased mechanosensitivity (e.g. upper limb neurodynamic tests (ULNTs) and nerve palpation). Reliability reports of nerve palpation and the interpretation of neurodynamic tests are scarce. This study therefore investigated the intertester reliability of nerve palpation and ULNTs. ULNTs were interpreted based on symptom reproduction and structural differentiation. To put the reliability of these tests in perspective, a comparison with the reliability of clinical tests for nerve function was made. Two experienced clinicians examined 31 patients with unilateral arm and/or neck pain. The examination included clinical tests for nerve function (sensory testing, reflexes and manual muscle testing (MMT)) and mechanosensitivity (ULNTs and palpation of the median, radial and ulnar nerve). Kappa statistics were calculated to evaluate intertester reliability. A meta-analysis determined an overall kappa for the domains with multiple kappa values (MMT, ULNT, palpation). We then compared the difference in reliability between the tests of mechanosensitivity and nerve function using a one-sample t-test. We observed moderate to substantial reliability for the tests for afferent/efferent nerve function (sensory testing: kappa = 0.53; MMT: kappa = 0.68; no kappa was calculated for reflexes due to a lack of variation). Tests to investigate mechanosensitivity demonstrated moderate reliability (ULNT: kappa = 0.45; palpation: kappa = 0.59). When compared statistically, there was no difference in reliability for tests for nerve function and mechanosensitivity (p = 0.06). This study demonstrates that clinical tests which evaluate increased nerve mechanosensitivity and afferent/efferent nerve function have comparable moderate to substantial reliability. To further investigate the clinometric properties of these tests, more studies are needed to evaluate their validity.


Effects of weekly low-frequency rTMS on autonomic measures in children with autism spectrum disorder.
The term autism spectrum disorder (ASD) describes a range of conditions characterized by impairments in social interactions, communication, and by restricted and repetitive behaviors. Autism spectrum disorder may also present with symptoms suggestive of autonomic nervous system (ANS) dysfunction. The objective of this study was to determine the effect of 18 sessions of low frequency (LF) repetitive transcranial magnetic stimulation (rTMS) on autonomic function in children with ASD by recording electrocardiogram (ECG) and electrodermal activity (EDA) pre- post- and during each rTMS session. The autonomic measures of interest in this study were R-R cardiointervals in EKG (R-R), time and frequency domain measures of heart rate variability (HRV) and skin conductance level (SCL). Heart rate variability measures such as R-R intervals, standard deviation of cardiac intervals, pNN50 (percentage of cardiointervals >50 ms different from preceding interval), power of high frequency (HF) and LF components of HRV spectrum, LF/HF ratio, were then derived from the recorded EKG. We expected that the course of 18 weekly inhibitory LF rTMS applied to the dorsolateral prefrontal cortex (DLPFC) would enhance autonomic balance by facilitating frontal inhibition of limbic activity thus resulting in decreased overall heart rate (HR), increased HRV (in a form of increased HF power), decreased LF power (resulting in decreased LF/HF ratio), and decreased SCL. Behavioral evaluations post-18 TMS showed decreased irritability, hyperactivity, stereotype behavior and compulsive behavior ratings while autonomic measures indicated a significant increase in cardiac interval variability and a decrease of tonic SCL. The results suggest that 18 sessions of LF rTMS in ASD results in increased cardiac vagal control and reduced sympathetic arousal.


Effect of 4-quinolones and novobiocin on calf thymus DNA polymerase alpha primase complex, topoisomerases I and II, and growth of mammalian lymphoblasts.
The influence of ciprofloxacin, nalidixic acid, norfloxacin, novobiocin, and ofloxacin on elements of eucaryotic DNA replication was investigated in vitro. Each of the 4-quinolones, when present in amounts of more than 100 micrograms/ml, reversibly inhibited the DNA synthesis performed by the 95 DNA polymerase alpha primase complex from calf thymus. Novobiocin at 500 micrograms/ml or at higher concentrations irreversibly inactivated DNA polymerase alpha primase complex. The accuracy of in vitro DNA synthesis in the absence of repair mechanisms was determined from amber-revertant assays with phi X174am16(+) DNA as template. The antimicrobial agents did not significantly increase the frequencies of base pairing mismatches during the course of replication, indicating that the basal mutation rate is not affected by novobiocin and the 4-quinolones. The Ki values of 50% inhibition of DNA topoisomerases from calf thymus by ciprofloxacin, norfloxacin, novobiocin, nalidixic acid, and ofloxacin were 300, 400, 1,000 or more, 1,000 or more, and 1,500 or more micrograms/ml, respectively, in the case of topoisomerase I, and the Ki values were 150, 300, 500, 1,000, and 1,300 micrograms/ml, respectively, in the case of topoisomerase II. The procaryotic topoisomerase II is approximately 100-fold more sensitive to inhibition by ciprofloxacin, norfloxacin, and ofloxacin than is its eucaryotic counterpart. Growth curves of lymphoblasts were recorded in the presence of ofloxacin and ciprofloxacin. Neither 1 nor 10 micrograms of ciprofloxacin or of ofloxacin per ml affected cell proliferation. Ofloxacin and ciprofloxacin at 100 micrograms/ml inhibited cell growth; 1,000 micrograms/ml led to cell death. No correlation exists between the antimicrobial and cytotoxic activities of the 4-quinolones.


Genetic Variants in the Vitamin D Pathway, 25(OH)D Levels, and Mortality in a Large Population-Based Cohort Study.
Low 25-hydroxyvitamin D [25(OH)D] concentrations have been consistently associated with excess mortality in epidemiological studies, but this association could be due to confounding by health impairments associated with low 25(OH)D levels. An association of vitamin D-related genetic variants with all-cause mortality could strengthen the claims of causality, because this association is assumed to be unaffected by confounding. To assess the associations of low 25(OH)D with mortality in the presence or absence of genetic variants in the vitamin D pathway. The study consisted of a population-based cohort of 8417 German older adults in whom genetic variants were genotyped. The primary outcome measure was all-cause mortality. Two single nucleotide polymorphisms (SNPs), rs3755967 (GC) and rs11603330 (DHCR7), were associated with higher risk of low vitamin D status [odds ratio (95% confidence interval) per minor allele, 1.27 (1.18 to 1.36) and 1.16 (1.08 to 1.25), respectively]. Low 25(OH)D (less than the season-specific 33rd percentile) was associated with increased mortality. However, none of the SNPs was associated with increased mortality. Furthermore, the increase in mortality for those with low 25(OH)D was generally smaller in the presence of the risk alleles for low 25(OH)D ["genetically low 25(OH)D"] than in the absence of those risk alleles ["otherwise low 25(OH)D"]. Although we may have been limited by a low statistical power to detect small associations, our study showed that the strong relationship between low 25(OH)D and increased mortality may be at least partly due to other factors related to low 25(OH)D levels.


Preserved cardiac synchrony and function with single-site left ventricular epicardial pacing during mid-term follow-up in paediatric patients.
Right ventricular (RV) pacing may cause dyssynchronous left ventricular (LV) contraction and systolic dysfunction. Left ventricular-based pacing may prevent such deterioration. The aim of this study was to evaluate ventricular synchrony and function with permanent LV pacing (LVP) vs. RV pacing (RVP) in paediatric patients with normal cardiac anatomy. Twenty-five paediatric patients with normal cardiac anatomy and single-site epicardial RV apex pacing (RVP, n=10, pacing duration: 7.9+/-2.9 years) or LV free wall pacing (LVP, n=15, pacing duration: 4.3+/-2.6 years) for complete heart block were enrolled. A total of 15 healthy children served as a control group. Conventional echocardiography, myocardial circumferential (LV), and longitudinal (RV) 2D strain (2Ds) analysis were obtained. Paced QRS duration did not differ between groups (P=0.915). Interventricular mechanical delay (LVP: 17+/-10, RVP: 62+/-15 ms; P<0.0001), septal-to-posterior wall motion delay (LVP: 59+/-23, RVP: 294+/-84 ms; P<0.0001), septal-to-lateral wall motion delay (LVP: 40+/-19, RVP: 59+/-12 ms; P=0.009), and LV mechanical delay (LVP: 35+/-9, RVP: 63+/-17 ms; P<0.0001) were preserved for LVP but not for RVP. Right ventricular mechanical delay was similar among paced groups (P=0.639). Left ventricular ejection fraction was normal for LVP but not for RVP (LVP: 60+/-6%, RVP: 45+/-6%; P=0.012). Left ventricular pacing did not differ from controls for synchrony or function. Conventional and 2Ds echocardiographic measurements indicate preserved LV synchrony and function in paediatric patients with LVP compared with RVP. Permanent LVP has no impact on RV synchrony.


Effect of Charcoal in Cigarette Filters on Free Radicals in Mainstream Smoke.
The addition of charcoal in cigarette filters may be an effective means of reducing many toxicants from tobacco smoke. Free radicals are a highly reactive class of oxidants abundant in cigarette smoke, and here we evaluated the effectiveness of charcoal to reduce free radical delivery by comparing radical yields from commercially available cigarettes with charcoal-infused filters to those without and by examining the effects of incorporating charcoal into conventional cigarette filters on radical production. Commercial cigarettes containing charcoal filters produced 40% fewer gas-phase radicals than did regular cellulose acetate filter cigarettes when smoked using the International Organization of Standardization (ISO, p = 0.07) and Canadian Intense (CI, p < 0.01) smoking protocols. While mean-particulate-phase radicals were 25-27% lower in charcoal cigarettes, differences from noncharcoal products were not significant ( p = 0.06-0.22). When cellulose acetate cigarette filters were modified to incorporate different types and amounts of activated charcoal, reductions in gas-phase (>70%), but not particulate-phase, radicals were observed. The reductions in gas-phase radicals were similar for the three types of charcoal. Decreases in radical production were dose-responsive with increasing amounts of charcoal (25-300 mg) with as little as 25 mg of activated charcoal reducing gas-phase radicals by 41%. In all studies, charcoal had less of an effect on nicotine delivery, which was decreased 33% at the maximal amount of charcoal tested (300 mg). Overall, these results support the potential consideration of charcoal in cigarette filters as a means to reduce exposure to toxic free radicals from cigarettes and other combustible tobacco products.


A convex lateral tibial plateau for knee replacement.
Unicompartmental knee replacements have not performed as well in the lateral compartment as in the medial. This may be because the tibial components have flat or slightly concave surfaces which match the medial plateau but not the convex lateral plateau. The aim of this study was to find the optimal radius for a convex lateral tibial component. Twelve normal lateral tibial plateau were retrieved at knee replacement, and their surface contour in their mid sagittal plane was determined. The optimal circle was fitted and its radius measured. A series of different shaped tibial components were superimposed. From published information about the position of the femoral condyle relative to the tibia in different degrees of flexion, the flexion gap at these angles was determined. The average radius of the lateral tibial plateau was 40 mm. However, as the surface was polyradial it was not clear if this average radius would be optimal. In full flexion, a flat tibial plateau distracted the knee by 8 mm (p<0.001). A 75 mm radius spherical tibial plateau did not alter the knee kinematics significantly and gave rise to a change in joint distraction of 1.5 mm. Spherical tibial plateau of 50 mm and 25 mm radii significantly altered knee kinematics (p<0.001) and resulted in changes in distraction of 3 mm and 4 mm respectively. The optimal shape for a unicompartmental lateral tibial plateau is likely to be a spherical dome with radius of about 75 mm. The incorporation of this shape in the lateral side of a total knee replacement might improve its flexion.


Expression and/or activity of the SVCT2 ascorbate transporter may be decreased in many aggressive cancers, suggesting potential utility for sodium bicarbonate and dehydroascorbic acid in cancer therapy.
Hypoxia-inducible factor-1 (HIF-1) is a heterodimer transcription factor whose elevated activity in many cancers helps them to survive under hypoxic conditions and enhances their capacity to grow invasively, establish metastases, and survive chemo- or radiotherapy. Optimal intracellular levels of ascorbate suppress the level and transcriptional activity of HIF-1under normoxic or mildly hypoxic conditions by supporting the activity of proly and asparagyl hydroxylases that target HIF-1alpha. High intracellular ascorbate can also work in various ways to down-regulate activation of NF-kappaB which, like HIF-1 is constitutively active in many cancers and promotes aggressive behavior - in part by promoting transcription of HIF-1alpha. Yet recent evidence suggests that, even in the context of adequate ascorbate nutrition, the intracellular ascorbate content of many aggressive cancers may be supoptimal for effective HIF-1 control. This likely reflects low expression or activity of the SVCT2 ascorbate transporter. The expression of SVCT2 in cancers has so far received little study; but the extracellular acidity characteristic of many tumors would be expected to reduce the activity of this transporter, which has a mildly alkaline pH optimum. Unfortunately, since SVCT2 has a high affinity for ascorbate, and its activity is nearly saturated at normal healthy serum levels of this vitamin, increased oral administration of ascorbate would be unlikely to have much impact on the intracellular ascorbate content of tumors. However, cancers in which HIF-1 is active express high levels of glucose transporters such as GLUT-1, and these transporters can promote influx of dehydroascorbic acid (DHA) via facilitated diffusion; once inside the cell, DHA is rapidly reduced to ascorbate, which effectively is "trapped" within the cell. Hence, episodic intravenous infusions of modest doses of DHA may have potential for optimizing the intracellular ascorbate content of cancers, potentially rendering them less aggressive. Indeed, several published studies have concluded that parenteral DHA--sometimes in quite modest doses--can retard the growth of transplanted tumors in rodents. As an alternative or adjunctive strategy, oral administration of sodium bicarbonate, by normalizing the extracellular pH of tumors, has the potential to boost the activity of SCTV2 in tumor cells, thereby promoting increased ascorbate uptake. Indeed, the utility of oral sodium bicarbonate for suppressing metastasis formation in nude mice xenografted with a human breast cancer has been reported. Hence, oral sodium bicarbonate and intravenous DHA may have the potential to blunt the aggressiveness of certain cancers in which suboptimal intracellular ascorbate levels contribute to elevated HIF-1 activity.


Strong influence of regional species pools on continent-wide structuring of local communities.
There is a long tradition in ecology of evaluating the relative contribution of the regional species pool and local interactions on the structure of local communities. Similarly, a growing number of studies assess the phylogenetic structure of communities, relative to that in the regional species pool, to examine the interplay between broad-scale evolutionary and fine-scale ecological processes. Finally, a renewed interest in the influence of species source pools on communities has shown that the definition of the source pool influences interpretations of patterns of community structure. We use a continent-wide dataset of local ant communities and implement ecologically explicit source pool definitions to examine the relative importance of regional species pools and local interactions for shaping community structure. Then we assess which factors underlie systematic variation in the structure of communities along climatic gradients. We find that the average phylogenetic relatedness of species in ant communities decreases from tropical to temperate regions, but the strength of this relationship depends on the level of ecological realism in the definition of source pools. We conclude that the evolution of climatic niches influences the phylogenetic structure of regional source pools and that the influence of regional source pools on local community structure is strong.


Genomic structure of and genome-wide recombination in the Saccharomyces cerevisiae S288C progenitor isolate EM93.
The diploid isolate EM93 is the main ancestor to the widely used Saccharomyces cerevisiae haploid laboratory strain, S288C. In this study, we generate a high-resolution overview of the genetic differences between EM93 and S288C. We show that EM93 is heterozygous for >45,000 polymorphisms, including large sequence polymorphisms, such as deletions and a Saccharomyces paradoxus introgression. We also find that many large sequence polymorphisms (LSPs) are associated with Ty-elements and sub-telomeric regions. We identified 2,965 genetic markers, which we then used to genotype 120 EM93 tetrads. In addition to deducing the structures of all EM93 chromosomes, we estimate that the average EM93 meiosis produces 144 detectable recombination events, consisting of 87 crossover and 31 non-crossover gene conversion events. Of the 50 polymorphisms showing the highest levels of non-crossover gene conversions, only three deviated from parity, all of which were near heterozygous LSPs. We find that non-telomeric heterozygous LSPs significantly reduce meiotic recombination in adjacent intervals, while sub-telomeric LSPs have no discernable effect on recombination. We identified 203 recombination hotspots, relatively few of which are hot for both non-crossover gene conversions and crossovers. Strikingly, we find that recombination hotspots show limited conservation. Some novel hotspots are found adjacent to heterozygous LSPs that eliminate other hotspots, suggesting that hotspots may appear and disappear relatively rapidly.


A gene dosage map of Chromosome 18: a map with clinical utility.
Microarray technology has revolutionized the field of clinical genetics with the ability to detect very small copy number changes. However, challenges remain in linking genotype with phenotype. Our goal is to enable a clinical geneticist to align the molecular karyotype information from an individual patient with the annotated genomic content, so as to provide a clinical prognosis. We have combined data regarding copy number variations, microdeletion syndromes, and classical chromosome abnormalities, with the sparse but growing knowledge about the biological role of specific genes to create a genomic map of Chromosome 18 with clinical utility. We have created a draft model of such a map, drawing from our long-standing interest in and data regarding the abnormalities of Chromosome 18. We have taken the first step toward creating a genomic map that can be used by the clinician in counseling and directing preventive or symptomatic care of individuals with Chromosome 18 abnormalities.


Peripheral refraction profiles in subjects with low foveal refractive errors.
To study the variability of peripheral refraction in a population of 43 subjects with low foveal refractive errors. A scan of the refractive error in the vertical pupil meridian of the right eye of 43 subjects (age range, 18 to 80 years, foveal spherical equivalent, < ± 2.5 diopter) over the central ± 45° of the visual field was performed using a recently developed angular scanning photorefractor. Refraction profiles across the visual field were fitted with four different models: (1) "flat model" (refractions about constant across the visual field), (2) "parabolic model" (refractions follow about a parabolic function), (3) "bi-linear model" (linear change of refractions with eccentricity from the fovea to the periphery), and (4) "box model" ("flat" central area with a linear change in refraction from a certain peripheral angle). Based on the minimal residuals of each fit, the subjects were classified into one of the four models. The "box model" accurately described the peripheral refractions in about 50% of the subjects. Peripheral refractions in six subjects were better characterized by a "linear model," in eight subjects by a "flat model," and in eight by the "parabolic model." Even after assignment to one of the models, the variability remained strikingly large, ranging from -0.75 to 6 diopter in the temporal retina at 45° eccentricity. The most common peripheral refraction profile (observed in nearly 50% of our population) was best described by the "box model." The high variability among subjects may limit attempts to reduce myopia progression with a uniform lens design and may rather call for a customized approach.


The chemistry of thiosulfate and vascular calcification.
Thiosulfate has been shown to inhibit vascular calcification in uremic rats and may inhibit calcification in humans with end-stage renal disease but whether this is due to a systemic or local action is unknown. The underlying mechanism is also unclear but complexation of calcium ions has been proposed. In vitro assays were used to determine the effect of thiosulfate on vascular calcification and hydroxyapatite formation. Thiosulfate (EC50: 1-2 mM) prevented calcification of injured or devitalized aortas but not uninjured aortas, and similar results were obtained with sulfate. There was no effect on reversal of calcification. Measurements with an ion-sensitive electrode (corrected for changes in ionic strength) revealed a very weak interaction between thiosulfate and Ca(2+) (K(a) = 10.9 ± 1.0 × 10(-6) M(-1)) that resulted in a 4% decrease in ionized Ca(2+) in culture medium at 5 mM thiosulfate and a corresponding 5% increase in the solubility product for calcium-phosphate. Adjustment of the total Ca(2+) concentration to account for this did not prevent the inhibition of aortic calcification by thiosulfate. Thiosulfate did not inhibit hydroxyapatite formation from seed crystals or the calcification of purified elastin and did not alter medium pH. Thiosulfate inhibits vascular calcification at millimolar concentrations through a direct extracellular effect that does not require intact smooth muscle cells but is related to cellular injury. This effect is not specific for thiosulfate since sulfate has similar properties. Inhibition cannot be explained by effects on ionized calcium, calcium-phosphate solubility, pH, oxidative stress or hydroxyapatite formation.


Morphometry of the kidneys of fresh water percoid and ostariophysian teleosts.
Kidneys of four fresh water teleost species representing percormorpha (Oreochromis niloticus and Micropterus salmoides) and Ostariophysi (Cyprinus carpio and Clarias mossambicus) were studied for quantitative structural characteristics using tissues fixed by perfusion. The renosomatic index (weight of kidney/weight of fish) was higher in the ostariophysian than percoid fish (p < 0.05) but values of volume of nephronic tissue/body weight were not significantly different. Results obtained by point counting morphometry showed that the kidneys of the percoid species were made up of 56.85-64.4% nephronic tissue, 30.45-32.47% blood vessels, 2.84-8.20% ureter and ureteral ducts and 2.07-2.48% connective tissue. The kidneys of the osariophysian species comprised of 35.27-36.71% nephronic tissue, 27.86-29.29% blood vessels, 1.59-4.20% ureter and its ducts, 29.07-29.51% interstitial cells and 2.70-3.60% connective tissue. The mean values for the volume proportions of the components of nephronic tissue were not significantly different in the percoids and ostariophysians and they were; renal corpuscles 3.84-6.54%, neck segments 0.50-1.11%, proximal segments 67.17-69.72%, distal segments 18.16-20.55%, and collecting tubule-collecting duct (CT-CD) system 5.66-7.41%. These results show that the quantitative structural characteristics of the kidneys of fresh water species from different orders are quite similar and emphasise the all persuasive influence of the environment on renal structure and function in teleosts.


Does Kinesiophobia Modify the Effects of Physical Therapy on Outcomes in Patients With Sciatica in Primary Care? Subgroup Analysis From a Randomized Controlled Trial.
A higher level of kinesiophobia appears to be associated with poor recovery in patients with sciatica. The aim of this study was to investigate whether kinesiophobia modifies the effect of physical therapy on outcomes in patients with sciatica. This was a subgroup analysis from a randomized controlled trial. The study was conducted in a primary care setting. A total of 135 patients with acute sciatica participated. Patients were randomly assigned to groups that received (1) physical therapy plus general practitioners' care (intervention group) or (2) general practitioners' care alone (control group). Kinesiophobia at baseline was measured with the Tampa Scale for Kinesiophobia (TSK) and a single substitute question for kinesiophobia (SQK). Pain and recovery were assessed at 3- and 12-month follow-ups. Regression analysis was used to test for interaction between the level of kinesiophobia at baseline and treatment allocation. Subgroup results were calculated for patients classified with high fear of movement and for those classified with low fear of movement. Kinesiophobia at baseline interacted with physical therapy in the analysis with leg pain intensity at 12-month follow-up. Kinesiophobia at baseline did not interact with physical therapy regarding any outcome at 3-month follow-up or recovery at 12-month follow-up. When comparing both treatment groups in the subgroup of patients with high fear of movement (n=73), the only significant result was found for leg pain intensity difference from baseline at 12-month follow-up (intervention group: X̅=-5.0, SD=2.6; control group: X̅=-3.6, SD=2.7). The post hoc study design and relatively small sample size were limitations of the study. In 135 patients with sciatica, evidence shows that patients with a higher level of kinesiophobia at baseline may particularly benefit from physical therapy with regard to decreasing leg pain intensity at 12-month follow-up.


Mediterranean diet pyramid today. Science and cultural updates.
To present the Mediterranean diet (MD) pyramid: a lifestyle for today. A new graphic representation has been conceived as a simplified main frame to be adapted to the different nutritional and socio-economic contexts of the Mediterranean region. This review gathers updated recommendations considering the lifestyle, dietary, sociocultural, environmental and health challenges that the current Mediterranean populations are facing. Mediterranean region and its populations. Many innovations have arisen since previous graphical representations of the MD. First, the concept of composition of the 'main meals' is introduced to reinforce the plant-based core of the dietary pattern. Second, frugality and moderation is emphasised because of the major public health challenge of obesity. Third, qualitative cultural and lifestyle elements are taken into account, such as conviviality, culinary activities, physical activity and adequate rest, along with proportion and frequency recommendations of food consumption. These innovations are made without omitting other items associated with the production, selection, processing and consumption of foods, such as seasonality, biodiversity, and traditional, local and eco-friendly products. Adopting a healthy lifestyle and preserving cultural elements should be considered in order to acquire all the benefits from the MD and preserve this cultural heritage. Considering the acknowledgment of the MD as an Intangible Cultural Heritage of Humanity by UNESCO (2010), and taking into account its contribution to health and general well-being, we hope to contribute to a much better adherence to this healthy dietary pattern and its way of life with this new graphic representation.


Cold-induced heat production preceding shivering.
Individual changes in heat production and body temperature were studied in response to cold exposure, prior to shivering. The subjects ten women (seven men) were of normal weight, had a mean age of 23 (SD 3) years and average BMI 22.2 (SD 1.6) Kg/m2. They were lying supine under thermoneutral conditions for 30 min and were subsequently exposed to air of 15 degrees C until shivering occurred. Heat production was measured with a ventilated hood. Body composition was measured with underwater weighing and 2H dilution. Body temperatures were measured with thermistors. Heat production during cold exposure prior to shivering increased and reached a plateau. Skin temperature decreased and did not reach a plateau during the test period. The non-shivering interval (NSI) ranged from 20 to 148 min, was not related to body composition and was not significantly different between women (81 (sd 15) min) and men (84 (sd 34) min). NSI was negatively related to skin temperature (r2 0.44, P=0.004), and skin temperature was related to heat production (r2 0.39, P=0.007). In conclusion, subjects with a relatively large heat production during cold exposure maintained a relatively high skin temperature but showed a short NSI, independent of differences in body composition.