Naloxane enhanced inhibitory effect of verapamil on seizure induced by pentylenetetrazol in male rats.
The role of opioid receptor and voltage dependent calcium channels on the kindling induced by the convulsant pentylenetetrazole (PTZ) were investigated in the rats. Experiment involved 24 rats which were divided into four groups. Kindling was established with PTZ in subconvulsive dose (37.5 mg/kg i.p.) every 48 h and effects were observed within 20 min using five-point scoring system. All animals were kindled to three consecutive-stage five seizures and their stability was tested. Saline, verapamil (calcium channel blocker), naloxone (opioid antagonist) or both of them were then administrated 20 min before PTZ application. Convulsant parameters were significantly (P<0.05) reduced by verapamil. Naloxone had no significant effect on the seizure expression of fully kindled animals, whereas simultaneous application of naloxone and verapamil had profound inhibitory effect on all seizure parameters. The results of the present study suggest that naloxane increased the inhibitory effect of verapamil on the seizure induced by PTZ kindling.


Cervicovestibular rehabilitation in sport-related concussion: a randomised controlled trial.
Concussion is a common injury in sport. Most individuals recover in 7-10 days but some have persistent symptoms. The objective of this study was to determine if a combination of vestibular rehabilitation and cervical spine physiotherapy decreased the time until medical clearance in individuals with prolonged postconcussion symptoms. This study was a randomised controlled trial. Consecutive patients with persistent symptoms of dizziness, neck pain and/or headaches following a sport-related concussion (12-30 years, 18 male and 13 female) were randomised to the control or intervention group. Both groups received weekly sessions with a physiotherapist for 8 weeks or until the time of medical clearance. Both groups received postural education, range of motion exercises and cognitive and physical rest until asymptomatic followed by a protocol of graded exertion. The intervention group also received cervical spine and vestibular rehabilitation. The primary outcome of interest was medical clearance to return to sport, which was evaluated by a study sport medicine physician who was blinded to the treatment group. In the treatment group, 73% (11/15) of the participants were medically cleared within 8 weeks of initiation of treatment, compared with 7% (1/14) in the control group. Using an intention to treat analysis, individuals in the treatment group were 3.91 (95% CI 1.34 to 11.34) times more likely to be medically cleared by 8 weeks. A combination of cervical and vestibular physiotherapy decreased time to medical clearance to return to sport in youth and young adults with persistent symptoms of dizziness, neck pain and/or headaches following a sport-related concussion. NCT01860755.


[Indirect hemagglutination inhibition reactions as a method of titrating immune serums. V. Application of the reaction to the quantitative determination of immunoglobulins A, M and G in human blood sera].
The authors present the results of using the indirect hemagglutination inhibition test (IHIT) for quantitative determination of A, M and G immunoglobulins in the blood sera of humans in comparison with the method of radial immunodiffusion in agar (RID) after Mancini. The results of IHIT were no less precise and reproducible than those of RID. The significance of the correlation coefficient of grades after Spirman constituted greater than 99.9% for both tests. On this basis a conclusion was made that, having a number of advantages over RID, IHIT could be recommended for quantitative titration of immunoglobulins of various classes.


Functional characterization of NIPBL physiological splice variants and eight splicing mutations in patients with Cornelia de Lange syndrome.
Cornelia de Lange syndrome (CdLS) is a congenital developmental disorder characterized by distinctive craniofacial features, growth retardation, cognitive impairment, limb defects, hirsutism, and multisystem involvement. Mutations in five genes encoding structural components (SMC1A, SMC3, RAD21) or functionally associated factors (NIPBL, HDAC8) of the cohesin complex have been found in patients with CdLS. In about 60% of the patients, mutations in NIPBL could be identified. Interestingly, 17% of them are predicted to change normal splicing, however, detailed molecular investigations are often missing. Here, we report the first systematic study of the physiological splicing of the NIPBL gene, that would reveal the identification of four new splicing isoforms ΔE10, ΔE12, ΔE33,34, and B'. Furthermore, we have investigated nine mutations affecting splice-sites in the NIPBL gene identified in twelve CdLS patients. All mutations have been examined on the DNA and RNA level, as well as by in silico analyses. Although patients with mutations affecting NIPBL splicing show a broad clinical variability, the more severe phenotypes seem to be associated with aberrant transcripts resulting in a shift of the reading frame.


Frameless stereotactic placement of depth electrodes in epilepsy surgery.
Depth electrodes are useful in the identification of deep epileptogenic foci. Computerized tomography-magnetic resonance (CT/MR)- and angiography-guided frame-based techniques are safe and accurate but require four-point skull fixation that limits cranial access for the placement of additional grids and strips. The authors investigated the viability and accuracy of placing depth electrodes by using a commercially available frameless system. A slotted, custom-designed adapter was built to interface with the StealthStation Guide Frame-DT and 960-525 StealthFighter. The Cranial Navigation software was used to plan the trajectory and entry site based on preoperative spoiled gradient MR imaging studies. Forty-one depth electrodes were placed in 51 targets in 20 patients. Thirty-one of these electrodes were inserted through the temporal neocortex following craniotomy and placement of subdural grids, whereas 10 were placed through burr holes. All electrodes had contact either within (71%) or touching (29%) the target, 50 of which (98%) provided adequate recordings. Although the mean distance of the distal electrode contact from the intended target was 3.1 +/- 0.5 mm, the mean distance to the edge of the anatomical structure was 0.4 +/- 0.9 mm. Placement via the laterotemporal approach was significantly (p < 0.001) more accurate than that via the occipitotemporal approach. No complication occurred. Depth electrodes can be placed safely and accurately by using a commercially available frameless stereotactic navigation system and a custom-made adapter. Depth electrode placement to record ictal onsets during epilepsy surgery only requires the contacts to touch rather than to reside within the intended structure. The laterotemporal approach is a more accurate method of placing electrodes than is the occipitotemporal one, likely due to the increased distance from the entry point to the target.


[Peter Plett and other discoverers of cowpox vaccination before Edward Jenner].
Before Edward Jenner tested the possibility of using the cowpox vaccine as an immunisation for smallpox in humans in 1796, at least six people had done the same several years earlier. However, the findings of these six people regarding the cowpox vaccination are either hardly known or have even been forgotten. For the first time, the originally scattered information on the procedures used by these six people has been gathered and will be presented in this article. Detailed attention will be given to the works of the teacher Peter Plett (1766-1823), the only one to recognize the importance of his discovery for mankind. In 1790 and 1791/92, Plett reported his findings to the Medical Faculty of the University of Kiel. The faculty disregarded Plett's reports by neither responding to them nor changing their methods of immunisation, as the faculty at that time was still in favour of variolation. This article contains the available information and references concerning Plett's discovery, including the entire sources from 1802 and 1815 describing his findings.


Effectiveness of diode laser trans-scleral cyclophotocoagulation in patients following silicone oil-induced ocular hypertension in Chinese eyes.
We evaluated the effectiveness of diode laser trans-scleral cyclophotocoagulation (TSCPC) on intraocular pressure (IOP) in nine patients having raised IOP following use of silicone oil (SO) for retinal detachment (RD) surgery in a retrospective observational case series. Diode laser TSCPC was applied at a power setting of 1.75 to 2.5 watts, for two sec with a maximum of 30 applications. The patients were followed up for 40 to 312 weeks. The mean pre-laser IOP was 32.06 mm Hg (SD 7.32). The mean post-laser IOP at one month, three months and six months was 17.89 mm Hg (SD 8.23), 21.89 mm Hg (SD 8.16) and 21.67 mm Hg (SD 7.55) respectively. The final IOP (at the last follow-up) was 19.56 mm Hg (SD 7.85) (P=0.021). Seven of them had undergone SO removal. In our observation, effectiveness of TSCPC in long-term control of SO-induced ocular hypertension was limited as compared to short-term control of IOP.


Protective Effect of Naringin on DSS-Induced Ulcerative Colitis in Mice.
Peroxisome proliferator-activated receptor γ (PPARγ) is an important member of the nuclear receptor superfamily. Previous studies have shown the satisfactory anti-inflammatory role of PPARγ in experimental colitis models, mainly through negatively regulating several transcription factors such as nuclear factor-κB (NF-κB). Therefore, regulating PPARγ and PPARγ-related pathways has great promise for treating ulcerative colitis (UC). In the present study, our objective was to explore the potential effect of naringin on dextran sulfate sodium (DSS) induced UC in mice and its involved potential mechanism. We found that naringin significantly relieved DSS-induced disease activities index (DAI), colon length shortening, and colonic pathological damage. Exploration of the potential mechanisms demonstrated that naringin significantly activated DSS-induced PPARγ and subsequently suppressed NF-κB activation. PPARγ inhibitor GW9662 largely abrogated the roles of naringin in vitro. Moreover, DSS induced the activation of mitogen-activated protein kinase (MAPK) and (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome was inhibited by naringin. Tight junction (TJ) architecture in naringin groups was also maintained by regulating zonula occludens-1 (ZO-1) expression. These results suggested that naringin may be a potential natural agent for protecting mice from DSS-induced UC.


Angiotensin-converting enzyme activity in sarcoidosis and other disorders.
A review is given on S-angiotensin-converting enzyme (SACE) and its clinical value, based upon 327 sarcoidosis patients and 1,274 patients with various disorders. SACE was elevated in 55% of the sarcoidosis patients, although with a higher frequency in those with active disease. Erythema nodosum was associated with normal initial SACE, subsequently rising, and sarcoid hypercalcaemia was consistently followed by elevated SACE. In non-sarcoid patients, elevated SACE was observed in only 10 cases. The sensitivity and specificity were 0.55 and 0.99, respectively, and the positive and negative predictive values were 0.95 and 0.90, respectively. Elevated SACE pointed strongly towards the presence of sarcoidosis, although reservations must be made in patients with liver disorders, diabetes mellitus, hyperthyroidism, asbestosis or silicosis which are rather common disorders also associated with elevated SACE. Normal SACE does not exclude sarcoidosis.


Stormwater outlets: A source of microplastics in coastal zones of Cape Town, South Africa.
The runoff from stormwater outlets are potential sources of microplastics (MPs) in coastal zones. The characteristics and concentrations of MPs in coastal water, sediment and biota (mussels, whelks and sea urchins) were measured in summer (2020/2021) (dry season) and winter (2021) (wet season) from three sites (Camps Bay, Mouille Point and Three Anchor Bay) in Cape Town. MPs were characterised visually using a stereo microscope and chemically using spectroscopy. MP concentrations were higher in water and sediment during winter, and higher in biota in summer. Compared to control sites, MPs were higher at all impact sites sampled. MPs extracted were mainly black polyester (PEST) fibres, 1000 to 2000 μm in length averaging 0.15 MPs/L in water, 52.11 MPs/kg dry weight in sediment and 1.35 MPs/g soft tissue wet weight in biota. The results indicate that coastal stormwater systems are potential sources of MPs in the coastal environment of Cape Town.


[Status of the adrenal medulla in various forms of cardiomyopathy].
Adrenal medulla was studied quantitatively by a histofluorescent method and by that of Wood in 20 persons who had died at the age 35-50 years. The autopsy material was obtained from 11 dead bodies (control group--accident death) and those who had dilated and alcoholic cardiomyopathy (DCMP and ACMP, respectively). Catecholamine luminescence intensity (CLI) was higher in ACMP compared to control. On the contrary, CLI was low in chromaffin adrenal tissue in DCMP. The histofluorescent results corresponded to those obtained by a light microscopy by Wood method. The differences in results concerning catecholamines obtained in ACMP and DCMP were probably due to the differences in their activities in patients when they were alive (low in DCMP and high in ACMP).


Design and Validation of a Biosensor Implantation Capsule Robot.
We have proposed a long-term, noninvasive, nonrestrictive method of delivering and implanting a biosensor within the body via a swallowable implantation capsule robot (ICR). The design and preliminary validation of the ICR's primary subsystem-the sensor deployment system-is discussed and evidence is provided for major design choices. The purpose of the sensor deployment system is to adhere a small biosensor to the mucosa of the intestine long-term, and the modality was inspired by tapeworms and other organisms that employ a strategy of mechanical adhesion to soft tissue via the combined use of hooks or needles and suckers. Testing was performed to refine the design of the suction and needle attachment as well as the sensor ejection features of the ICR. An experiment was conducted in which needle sharpness, needle length, and vacuum volume were varied, and no statistically significant difference was observed. Finally, preliminary testing, coupled with prior work within a live porcine model, provided evidence that this is a promising approach for implanting a biosensor within the small intestine.


Fat necrosis of the newborn--report on two cases.
Subcutaneous fat necrosis of the newborn is an uncommon disorder occurring during the prenatal stage. Generally occurring in full-term neonates or during the first four weeks after a traumatic delivery, the disorder is characterized by the appearance of hard subcutaneous nodules or plaques on the trunk, buttocks or thighs. It is normally a benign and transient condition, although it may be complicated by hypocalcemia, which requires close monitoring until skin lesions are cured. The authors describe two cases of subcutaneous fat necrosis of the newborn, one occurring in a full-term neonate and the other in a premature newborn, both related to traumatic delivery and fetal distress.


Lyme carditis: a clinical presentation and long time follow-up.
The acute disease and a follow-up carried out up to 7 years after definite Lyme carditis in 6 patients is described. At the time of diagnosis all 6 patients had 2-3 degrees AV block, 4 patients presented with syncopes, and 1 revealed episodes of non-sustained ventricular tachycardia. The diagnosis of Lyme carditis was confirmed by Borrelia burgdorferi-specific IgM and IgG antibody determinations in consecutive serum samples. All patients were treated with antibiotics. At follow-up, a clinical examination, a 2D and M-mode echocardiogram, and an exercise test did not reveal sequelae to Lyme carditis.


beta 2-Glycoprotein I: a plasma inhibitor of the contact activation of the intrinsic blood coagulation pathway.
The general hypothesis for the biological function of beta 2-glycoprotein I is that it neutralizes all negatively charged macromolecules that might enter the bloodstream and diminishes unwanted activation of the blood coagulation. In the present study we report that beta 2-glycoprotein I inhibits the activation of the contact phase system of the intrinsic pathway of blood coagulation. Activation was accomplished by an ellagic acid-phospholipid suspension (Cephotest) and measured by the appearance of amidolytic activity using the chromogenic substrate H-D-Pro-Phe-Arg-p-nitroanilide (S-2302). This inhibitory effect of beta 2-glycoprotein I was observed both when Cephotest was preincubated with beta 2-glycoprotein I and when the amount of beta 2-glycoprotein I in plasma was increased by addition of beta 2-glycoprotein I to either normal or beta 2-glycoprotein I-deficient plasma. The inhibitory effect of beta 2-glycoprotein I on the contact phase activation could be one of the physiological functions of this protein.


[Analysis of oral health attention in the Family Health Strategy of the Sanitary District VI, Recife, Pernambuco State].
The aim of this study was to analyze the work process developed by the oral health teams of the VI Sanitary District of Recife, Pernambuco State, in 2006. It is a descriptive study of qualitative approach in that secondary data were obtained of a previous research accomplished in Recife, where the Sanitary District VI is located. Four semi-structured interviews were accomplished with the oral health coordinator, two surgeon-dentists and a nurse that acted in the Family Health Strategy. The results showed that some practices accomplished by the teams are still incipient such as the epidemic survey, patient reference and counter reference, and the control and evaluation of the actions. However, the progress in the preventive vision and in education practice in the professional health became evidenced through the interviews. In conclusion, in spite of the difficulties for the execution of the practices established by the National Policies of Oral Health, it is noticed a change in the attention model in oral health, being necessary some adjustments and corrections in the activity of the teams, besides a larger participation of other administration levels for the full exercise of oral health in the Family Health Strategy.


Identifying appropriate reference data models for comparative effectiveness research (CER) studies based on data from clinical information systems.
The need for a common format for electronic exchange of clinical data prompted federal endorsement of applicable standards. However, despite obvious similarities, a consensus standard has not yet been selected in the comparative effectiveness research (CER) community. Using qualitative metrics for data retrieval and information loss across a variety of CER topic areas, we compare several existing models from a representative sample of organizations associated with clinical research: the Observational Medical Outcomes Partnership (OMOP), Biomedical Research Integrated Domain Group, the Clinical Data Interchange Standards Consortium, and the US Food and Drug Administration. While the models examined captured a majority of the data elements that are useful for CER studies, data elements related to insurance benefit design and plans were most detailed in OMOP's CDM version 4.0. Standardized vocabularies that facilitate semantic interoperability were included in the OMOP and US Food and Drug Administration Mini-Sentinel data models, but are left to the discretion of the end-user in Biomedical Research Integrated Domain Group and Analysis Data Model, limiting reuse opportunities. Among the challenges we encountered was the need to model data specific to a local setting. This was handled by extending the standard data models. We found that the Common Data Model from the OMOP met the broadest complement of CER objectives. Minimal information loss occurred in mapping data from institution-specific data warehouses onto the data models from the standards we assessed. However, to support certain scenarios, we found a need to enhance existing data dictionaries with local, institution-specific information.


Inhibitory effect of beta-thujaplicin on ultraviolet B-induced apoptosis in mouse keratinocytes.
Sunburn cells are thought to represent ultraviolet B-induced apoptotic keratinocytes. It has been demonstrated that enzymatic and nonenzymatic antioxidants effectively suppress sunburn cell formation, indicating that reactive oxygen species may play a role in the progression of ultraviolet B-induced apoptosis. Metallothionein, a cytosol protein, has antioxidant activity, and overexpression of metallothionein has been reported to reduce the number of sunburn cells in mouse skin. We have also demonstrated that overexpression of metallothionein inhibits ultraviolet B-induced DNA ladder formation in mouse keratinocytes. These findings support the hypothesis that cellular metallothionein may play an important role in the inhibition of ultraviolet B-induced apoptosis in keratinocytes through its antioxidant activity. In the present study, we investigated the effects of beta-thujaplicin, an extract from the woods of Thuja plicata D. Don. and Chamaecyparis obtuse, Sieb. et Zucc., on ultraviolet B-induced apoptosis in keratinocytes and on metallothionein induction. Topical application of beta-thujaplicin decreased the number of ultraviolet B-mediated sunburn cells and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling-positive cells in mouse ear skin. Incubation with beta-thujaplicin suppressed ultraviolet B-induced DNA ladder formation in cultured mouse keratinocytes. Histochemical analysis showed that topical application of beta-thujaplicin induced metallothionein protein in mouse skin. Northern analysis and western blotting revealed significant induction of metallothionein mRNA and metallothionein protein, respectively, in beta-thujaplicin-treated cultured mouse keratinocytes. These findings indicate that beta-thujaplicin inhibits ultraviolet B-induced apoptosis in keratinocytes and strongly suggest that the inhibitory mechanism is due to the antioxidant activity of metallothionein induced by the agent.


Surgery for Chronic Traumatic Atlantoaxial Dislocation Associated With Myelopathy.
A retrospective study. To evaluate the outcomes of myelopathy caused by atlantoaxial dislocation (AAD). No reports to date have accurately evaluated the results of surgery for delayed myelopathy for patients with chronic AAD. Thus, the appropriate surgical time and methods of decompression and fusion remain a hot debate. In our study, 18 patients underwent decompression, fixation, and fusion. Demographic data, operation time, blood loss, and complications were evaluated. The Japanese Orthopedic Association Scale, severity of disability and visual analogue scale were evaluated. The fusion rate, space available for the cord, instability index, cord compression index, and cord decompression rate were also assessed. The average time of operation was 248±50 minutes, and blood loss was 350±200 mL. Five patients in grade I maintained their neurological status, and the others had improved neurological status. With average follow-up time of 15.3±9.6 months, the Japanese Orthopedic Association score improved, the visual analogue scale score decreased, the space available for the cord improved, and the instability index and cord compression index decreased. Cord decompression rate was 65.9%. Fusion rate reached 83%. There is a high risk of delayed myelopathy for patients with AAD who do not undergo timely surgical treatment. There is no need for complete reduction for treatment of chronic AAD. Whether it can be reduced or not, sufficient decompression and solid fusion for AAD are required. Both C1-C2 fusion for reducible dislocation and occipital-cervical fusion for irreducible dislocation have satisfactory outcomes.


Airway Epithelial Barrier Dysfunction in Chronic Obstructive Pulmonary Disease: Role of Cigarette Smoke Exposure.
The epithelial lining of the airway forms the first barrier against environmental insults, such as inhaled cigarette smoke, which is the primary risk factor for the development of chronic obstructive pulmonary disease (COPD). The barrier is formed by airway epithelial junctions, which are interconnected structures that restrict permeability to inhaled pathogens and environmental stressors. Destruction of the epithelial barrier not only exposes subepithelial layers to hazardous agents in the inspired air, but also alters the normal function of epithelial cells, which may eventually contribute to the development of COPD. Of note, disruption of epithelial junctions may lead to modulation of signaling pathways involved in differentiation, repair, and proinflammatory responses. Epithelial barrier dysfunction may be particularly relevant in COPD, where repeated injury by cigarette smoke exposure, pathogens, inflammatory mediators, and impaired epithelial regeneration may compromise the barrier function. In the current review, we discuss recent advances in understanding the mechanisms of barrier dysfunction in COPD, as well as the molecular mechanisms that underlie the impaired repair response of the injured epithelium in COPD and its inability to redifferentiate into a functionally intact epithelium.


Determinants of Low Birth Weight Among Newborns Delivered in Public Hospitals in Addis Ababa, Ethiopia: Case-Control Study.
Birth weight predicts the infant's future health, growth, and viability. It is a good summary measure of many public health problems that include long-term maternal malnutrition, and poor health care during pregnancy. In developing countries, a birth weight below 2500 g is the leading cause of infant and child mortality. In Ethiopia, LBW had more than 13% prevalence. Determinants of low birth weight were yet to be completely understood. Therefore, this study investigates the predictors of low birth weight. To identify determinants of low birth weight among newborns delivered at Addis Ababa public hospitals, 2019. Institution-based unmatched case-control study was conducted among 279 (93 cases and 186 controls) newborns delivered from March 15 to April 30, 2019, in Addis Ababa public hospitals. Consecutive and systematic random sampling were employed to select cases and controls, respectively. Data were collected by interview using structured and pretested questionnaire. Finally, data were entered using Epi-data 4.2 and analysed using SPSS version 25. Factors having P-value < 0.25 in the bivariable logistic regression model were entered into a multivariable logistic regression model. Statistical significance was declared at P-value ≤ 0.05. From 279 selected participants, 270 new-borns (90 cases and 180 controls) participated. In logistic regression model, significant association was found with gestational hypertension [AOR 3.7 (95% CI 1.6-8.7)], maternal height [AOR 5.7 (95% CI 1.7-19.7)], incomplete antenatal visit [AOR 6.7 (95% CI 3.2-15.3)], and low maternal educational status [AOR 3.8 (95% CI 1.3-10.9)]. Predictors of low birth weight were maternal height <155 cm, complications during pregnancy, gestational hypertension, and incomplete Antenatal visit, and low maternal education. Stakeholders would better work together to reduce low birth weight by preparing appropriate intervention and monitoring policy.


The synthetic progestin levonorgestrel is a potent androgen in the three-spined stickleback (Gasterosteus aculeatus).
The use of progestins has resulted in contamination of aquatic environments and some progestins have in experimental studies been shown to impair reproduction in fish and amphibians at low ng L(-1) concentrations. The mechanisms underlying their reproductive toxicity are largely unknown. Some progestins, such as levonorgestrel (LNG), exert androgenic effects in mammals by activating the androgen receptor (AR). Male three-spined stickleback (Gasterosteus aculeatus) kidneys produce spiggin, a gluelike glycoprotein used in nest building, and its production is directly governed by androgens. Spiggin is normally absent in females but its production in female kidneys can be induced by AR agonists. Spiggin serves as the best known biomarker for androgens in fish. We exposed adult female sticklebacks to LNG at 5.5, 40, and 358 ng L(-1) for 21 days. Androgenic effects were found at LNG concentrations ≥40 ng L(-1) including induction of spiggin transcription, kidney hypertrophy, and suppressed liver vitellogenin transcription. These are the first in vivo quantitative data showing that LNG is a potent androgen in fish supporting the contention that androgenic effects of certain progestins contribute to their reproductive toxicity.


The Use of Tilted Implant for Posterior Atrophic Maxilla.
To retrospectively analyze the influence of implant inclination on marginal bone loss at freestanding implant-supported fixed partial prostheses (FPPs) over a medium-term period of functional loading. Twenty-nine partially edentulous patients with freestanding FPDs supported by two implants placed in a two-stage procedure comprised the study group. The anterior implant was placed axially, and the posterior tilted distally. Mesial or distal inclination of each implant was measured in relation to the vertical axis perpendicular to the occlusal plane. Average bone loss was compared between straight and tilted implants, smokers, and nonsmokers. Mean angulation of the anterior axial-positioned implant was 3.45 degrees distally (range 0-8) and of the distal implants was 32.83 degrees distally (range 20-50 degrees). Average bone loss after 1, 3, and 5 years was 0.89 (SD = 0.73), 1.18 (SD = 0.74), and 1.50 (SD = 0.81), respectively, for axial implants, and 0.98 (SD = 0.69), 1.10 (SD = 0.60) and 1.50 (SD = 0.67) for tilted implants, with no significant correlation between implant angulation and bone loss. A significant correlation between implant angulation and annual bone loss was obtained for tilted implants only (r = 0.52, p = .004).Using Albrektsson criteria, the success rate was 89.6% (26 out of 29 implants) for straight and 93.1% (27 out of 29) for tilted implants. The study demonstrates no effect of implant angulation on peri-implant bone loss in the posterior maxilla.


Incidence and time trends of sarcoma (2000-2013): results from the French network of cancer registries (FRANCIM).
The exhaustive collection of new sarcoma cases and their second histologic review offer a unique opportunity to study their incidence and time trends in France according to the major subtypes. Data were collected from population-based cancer registries covering 22% of the French population. Crude and world age-standardized incidence rates (ASR) were estimated according to anatomic, histological and genetic groups, age and sex over the 2010-2013 period. Time trends in incidence were calculated by the annual percent change over the 2000-2013 period. During the most recent period (2010-2013), 3942 patients with sarcoma were included. The ASR of soft-tissue and bone sarcomas, and gastro-intestinal stromal tumors (GIST) were 2.1, 1.0 and 0.6, respectively. For the four most frequent histological subtypes (unclassified, leiomyosarcoma, GIST and liposarcoma), the ASR ranged from 0.4 to 0.7. ASRs were 1.9 for complex genomic and 1.3 for recurrent translocation sarcomas. The time-trend analysis showed a significant increase of sarcoma incidence rate between 2000 and 2005, which stabilized thereafter. Incidence rates increased for four histological subtypes (GIST, chondrosarcoma, myxofibrosarcoma, solitary fibrous tumors) and decreased for three (leiomyosarcomas, Kaposi sarcoma and fibrosarcoma). To our knowledge, this study is the first to investigate sarcoma incidence based on a systematic pathological review of these cancers and on the updated sarcoma classifications. Due to the paucity of literature on sarcomas, future studies using data from population-based cancer registries should consider a standardized inclusion criterion presented in our study to better describe and compare data between countries.


Unsuspected uterine leiomyosarcoma: magnetic resonance imaging findings before and after focused ultrasound surgery.
Uterine leiomyosarcoma, initially diagnosed as leiomyoma on magnetic resonance (MR) images, was disclosed after focused ultrasound surgery (FUS). The tumor did not display high signal intensity on either T1- or T2-weighted images on the patient's first visit. Four months thereafter, T2-weighted images revealed a high signal intensity area within the tumor, while T1-weighted images showed low signal intensity. Six months after FUS, the nonperfused volume calculated on meglumine gadoterate-enhanced T1-weighted images decreased markedly and an intermediate signal intensity in a circular area on T2-weighted images appeared to be atypically increasing in volume. After laparoscopic myomectomy, this tumor was diagnosed as uterine leiomyosarcoma coexistent with leiomyoma. The early stages of uterine leiomyosarcoma are clinically difficult to diagnose; therefore, both careful monitoring during FUS and close follow-up after the procedure are vital.


Reduced basal ganglia blood flow and volume in pre-symptomatic, gene-tested persons at-risk for Huntington's disease.
The aim of this study was to examine basal ganglia volumes and regional cerebral blood flow in asymptomatic subjects at-risk for Huntington's disease who had undergone genetic testing. We determined which measures were the best 'markers' for the presence of the mutation and for the onset of symptoms. Twenty subjects who were Huntington's disease gene mutation-positive and 24 Huntington's disease gene mutation-negative participants, all of whom had a parent with genetically confirmed Huntington's disease, and were therefore 50% at-risk for inheriting the Huntington's disease gene mutation, were included in the study. To evaluate basal ganglia structure and function, MRI and single photon emission computed tomography (SPECT) were used. Quantitative measures of regional volumes and relative measures of regional perfusion were calculated. SPECT and MRI scans were co-registered so that MRI anatomy could be used accurately to place SPECT regions. Estimated years-to-onset in the mutation-positive subjects was calculated based on a regression formula that included gene (CAG)(n) repeat length and parental age of onset. Changes in imaging measures in relation to estimated years-to-onset were assessed. The imaging measure that was most affected in mutation-positive subjects was putamen volume. This was also the measure that correlated most strongly with approaching onset. In subjects >/=7 years from estimated onset age, the putamen volume measures were similar to those of the mutation-negative subjects. However, in subjects </=6 years from estimated onset age, there were dramatic reductions in putamen volume, resulting in >90% discrimination from both the far-from-onset and the mutation-negative subjects. Caudate volume and bicaudate ratio also showed a significant decline in the close-to-onset subjects, although to a lesser degree than putamen volume reductions. Furthermore, SPECT basal ganglia perfusion deficits were observed in mutation-positive subjects. Imaging markers of neuropathological decline preceding clinical onset are important for assessing the effects of treatments aimed at slowing the course of Huntington's disease. The current study suggests that quantitative assessment of basal ganglia may provide a means to track early signs of decline in individuals with the Huntington's disease gene mutation prior to clinical onset.


Isolation and purification of schisandrol A from the stems of Schisandra chinensis and cytotoxicity against human hepatocarcinoma cell lines.
Schisandrol A, a lignan with anticancer effects, is one of the representative components that identifies Schisandra chinensis. A method for purifying schisandrol A from the stems of S. chinensis was established using an octadecylsilyl (ODS) column combined with preparative high-performance liquid chromatography (HPLC). Crude extracts obtained from the stems of S. chinensis using 70% ethanol were separated on an AB-8 macroporous resin column and then eluted with a graded ethanol series. After 70% methanol was used in an ODS column separation, preparative HPLC was used for subsequent purification. The structure was identified by electrospray ionization-mass spectrometry, (1)H-nuclear magnetic resonance, and (13)C-nuclear magnetic resonance. HepG2 and Bel-7402 hepatocellular carcinoma cell lines were used for toxicological evaluation. 21.4 mg of schisandrol A with a purity of 95.2% were collected. The cytotoxicity of the ODS-purified sample and schisandrol A were significantly stronger than that of a resin-purified sample. Schisandrol A was successfully extracted from the stems of S. chinensis and separated with an ODS column combined with preparative HPLC. The samples obtained during the purification process showed different levels of cytotoxicity on the HepG2 and Bel-7402 hepatocellular carcinoma cell lines.


Impact of aging on the development of hepatocellular carcinoma in patients with hepatitis C virus infection in Japan.
It is difficult to study the long-term outcome of hepatitis C virus (HCV) infection because chronic infection is often asymptomatic and duration of the disease is prolonged. The clinical outcome of HCV infection remains unclear in patients of advanced age. Among 575 patients consecutively diagnosed with hepatocellular carcinoma (HCC) from 1988 to 1999 at Hiroshima University, we examined 430 with HCV. We studied the differences between males and females in the following characteristics: age at first diagnosis of HCC, Child grade, various tumour factors, history of blood transfusion, duration to development of HCC, and history of alcohol intake. The incidence of HCC patients with HCV increased in elderly persons, including female patients. Background liver function was significantly better for female patients (P < 0.001). In both genders, the duration between blood transfusion and diagnosis of HCC was significantly shorter when the patients received blood transfusion at an older age (P < 0.001). In habitual drinkers, the average age at first diagnosis of HCC was significantly younger (P < 0.001), and duration to development of HCC significantly shorter (P < 0.05). The percentage of atomic bomb survivors among HCV-positive HCC patients was significantly higher than that among HCV-negative HCC patients (P < 0.05). Patients with HCV might exhibit slow disease progression and develop HCC finally with aging regardless of gender. Patients of advanced age with HCV, even female patients, should therefore be closely followed.


Shade and wind barrier effects on summertime feedlot cattle performance.
In each of three summertime trials conducted over consecutive years, approximately 110 predominantly black and black-white-face steers were blocked by weight and randomly allotted to one of 16 pens in a 2x2 factorial arrangement of treatments. Factors consisted of cattle being fed in facilities with or without wind barriers and with or without shade. Steers were fed dry-rolled corn-based diets (1.43 Mcal/ kg, NEg). Mean starting date and days on feed were June 26 and 79, respectively. In unshaded areas, temperature and humidity averaged 21.6 degrees C and 77.9%, and the blackglobe-humidity index (BGHI) at 1500 averaged between 84.0 and 89.1. Each of four 6.1-x6.1-m structures (mean height = 3.4 m) with white steel roofs provided shade (2.65 m2/steer) for two pens. In facilities with wind barriers provided, airflow was reduced from the north and northwest by a 25-m-wide shelterbelt containing six rows of trees. For cattle fed in pens with wind barriers, shade increased (P<.05) gain from 0 to 56 d and decreased (P<.05) DMI/ADG from 0 to 28 d. Differences (P<.05) in performance were not found between shaded and unshaded cattle in any portion of the feeding period for cattle fed in the pens without wind barriers and over the entire feeding period in either type of facility. The shade response in pens with wind barriers seemed to be greater the 1st yr than in subsequent years. Differences in weather patterns among years, especially air temperature, humidity, and solar radiation, may partially explain this interaction. Also, in yr 1, cattle tended to have greater fat thickness at finish than in yr 2 and 3. Correlations between BGHI and DMI tended to be greater during the early portion of the trial (0 to 28 d) than over the entire trial. Correlations between the difference in BGHI under shade vs no shade and percentage of shade use had the greatest magnitude and were significant only in the first 28 d vs over the entire feeding period. Although no heat-related cattle deaths occurred in this study, results suggest that shade improves cattle performance in the summer when they are fed in facilities with winter wind protection available and have not become acclimated to hot conditions. Once cattle are acclimated or hot conditions subside, compensation by unshaded cattle offsets much of the initial benefits of providing shade.


[Contraindications of multifocal lenses and progressive lenses].
Reasons of contra-indications, absolute or relative, of multifocals an progressive glasses may be objective and/or subjective. This work considers some principal of them. Their knowledge and the comprehension of their mechanisms must help the ophthalmologist to understand the reasons of some defeats and to avoid some others.


Estimation of the effective and functional human cortical connectivity with structural equation modeling and directed transfer function applied to high-resolution EEG.
Different brain imaging devices are presently available to provide images of the human functional cortical activity, based on hemodynamic, metabolic or electromagnetic measurements. However, static images of brain regions activated during particular tasks do not convey the information of how these regions are interconnected. The concept of brain connectivity plays a central role in the neuroscience, and different definitions of connectivity, functional and effective, have been adopted in literature. While the functional connectivity is defined as the temporal coherence among the activities of different brain areas, the effective connectivity is defined as the simplest brain circuit that would produce the same temporal relationship as observed experimentally among cortical sites. The structural equation modeling (SEM) is the most used method to estimate effective connectivity in neuroscience, and its typical application is on data related to brain hemodynamic behavior tested by functional magnetic resonance imaging (fMRI), whereas the directed transfer function (DTF) method is a frequency-domain approach based on both a multivariate autoregressive (MVAR) modeling of time series and on the concept of Granger causality. This study presents advanced methods for the estimation of cortical connectivity by applying SEM and DTF on the cortical signals estimated from high-resolution electroencephalography (EEG) recordings, since these signals exhibit a higher spatial resolution than conventional cerebral electromagnetic measures. To estimate correctly the cortical signals, we used a subject's multicompartment head model (scalp, skull, dura mater, cortex) constructed from individual MRI, a distributed source model and a regularized linear inverse source estimates of cortical current density. Before the application of SEM and DTF methodology to the cortical waveforms estimated from high-resolution EEG data, we performed a simulation study, in which different main factors (signal-to-noise ratio, SNR, and simulated cortical activity duration, LENGTH) were systematically manipulated in the generation of test signals, and the errors in the estimated connectivity were evaluated by the analysis of variance (ANOVA). The statistical analysis returned that during simulations, both SEM and DTF estimators were able to correctly estimate the imposed connectivity patterns under reasonable operative conditions, that is, when data exhibit an SNR of at least 3 and a LENGTH of at least 75 s of nonconsecutive EEG recordings at 64 Hz of sampling rate. Hence, effective and functional connectivity patterns of cortical activity can be effectively estimated under general conditions met in any practical EEG recordings, by combining high-resolution EEG techniques and linear inverse estimation with SEM or DTF methods. We conclude that the estimation of cortical connectivity can be performed not only with hemodynamic measurements, but also with EEG signals treated with advanced computational techniques.


Distal oblique bundle influence on distal radioulnar joint stability: a biomechanical study.
Chronic instability of the distal radioulnar joint (DRUJ) presents a highly disabling condition. Several surgical techniques have been reported for its treatment. These involve reconstruction of the distal oblique bundle (DOB) of the interosseous membrane (IOM) of the forearm. The aim of this study was to examine whether surgical reconstruction of the DOB is necessary to restore DRUJ stability following trauma with DOB disruption and to compare two restoration techniques utilizing a tendon or suture-button graft. Stability in supination and pronation was assessed by means of maximum torque and force in twenty forearms. Test cycles were performed with the DOB/IOM in an intact condition, with the DOB or distal IOM transected, and following surgical reconstruction of the DOB with either tendon graft or suture-button system. In pronation, the relative change in maximum axial force was significantly lower in samples with a transected DOB in comparison to samples without a preexisting DOB. No statistically significant differences were observed between forearms including DOB reconstruction and specimens in the intact and transected state. Neither were there statistically significant differences concerning the two surgical techniques. From a biomechanical perspective, surgical DOB reconstruction is hence not indicated in cases of isolated DOB rupture.


Trigeminal nerve injury associated with injection of local anesthetics: needle lesion or neurotoxicity?
The authors used comprehensive national registry and clinical data to conduct a study of adverse drug reactions (ADRs), in particular neurosensory disturbance (NSD), associated with local anesthetics used in dentistry The study included data sets of annual sales of local anesthetics (from 1995 through 2007), 292 reports to the Danish Medicines Agency, Copenhagen, Denmark, of adverse reactions to local anesthetic drugs, and a clinical sample of 115 patients with NSD associated with local anesthetics. The authors assessed lidocaine 2 percent, mepivacaine 2 percent and 3 percent, prilocaine 3 percent, and articaine 4 percent sold in cartridges. The study results showed a highly significant overrepresentation of NSDs associated with articaine 4 percent, in particular with mandibular blocks. The distribution of NSDs was disproportionate to the market share of three of the four drugs in both national registry data and clinical data. These findings indicate that the main cause of injury was neurotoxicity resulting from administration of the local anesthetic rather than the needle penetration. Clinicians may consider avoiding use of high-concentration (4 percent) anesthetic formulations for block anesthesia in the trigeminal area in cases in which there are viable alternatives.


Cep68 can be regulated by Nek2 and SCF complex.
Centrosome cohesion maintains centrosomes in close proximity until mitosis, when cell cycle-dependent regulatory signaling events dissolve cohesion and promote centrosome separation in preparation for bipolar spindle assembly at mitosis. Cohesion is regulated by the antagonistic activities of the mitotic NIMA-related kinase 2 (Nek2), protein phosphatase 1, the cohesion fiber components rootletin, centrosomal Nek2-associated protein 1 (C-Nap1) and Cep68. The centrosomal protein Cep68 is essential for centrosome cohesion and dissociates from centrosomes at the onset of mitosis. Here, our cell line studies show the C-terminal 300-400 amino acids of Cep68 are necessary to localize Cep68 to interphase centrosomes while C-terminal 400-500 amino acids might regulate Cep68 dissociation from centrosomes at mitotic onset. In addition, Nek2 was demonstrated to phosphorylate Cep68 in vivo and this phosphorylation appears to promote Cep68 degradation in mitosis. We further show that the SCF complex destroys Cep68 at mitosis through recognition by the beta-Trcp F box component of SCF. Together, the findings provide a new insight into the control of centrosome separation by Cep68 during mitosis.


Mitochondrial DNA control region data from indigenous Angolan Khoe-San lineages.
Here we provide 129 complete mitochondrial control region sequences of indigenous Khoe-San individuals from Angola to contribute to the still underrepresented pool of data from Africa. The dataset consists of exclusively African lineages with a majority of Sub-Saharan haplogroups. The probability of a random match was calculated as 0.09. The data set comprises 21 haplotypes occurring more than once and 17 unique haplotypes. Upon publication, haplotypes were incorporated in the EMPOP database (www.empop.org; EMP00069) [1].


AutophagosOMES: identification of autophagosomal cargo in CD4+ T cells by proteomics.
Macroautophagy/autophagy, a cellular process that sequesters and breaks down cellular components in the lysosome/vacuole, is important in various events where cell composition undergoes changes. Broadly, autophagy is involved in T cell regulation including maintaining cell homeostasis. One process where a cell alters its composition is in the activation of helper T cells in the immune system. When helper (CD4+) T cells are activated by antigens, they both grow and alter their cellular components to become effector T cells. Autophagy is the process that facilitates the breakdown of these cellular components and is therefore hypothesized to have a role in CD4+ T cell activation. Previous research has concluded that CD4+ T cell activation induces autophagy, providing an avenue for further research aimed at examining the ways in which this induced autophagy affects CD4+ T cell proliferation and function. Toward this end, Zhou et al. researched the autophagosomal cargo present within CD4+ T cells and the impact this cargo has on CD4+ T cell proliferation.


BIR: Biomedical Information Retrieval System for Cancer Treatment in Electronic Health Record Using Transformers.
The rapid growth of electronic health records (EHRs) has led to unprecedented biomedical data. Clinician access to the latest patient information can improve the quality of healthcare. However, clinicians have difficulty finding information quickly and easily due to the sheer data mining volume. Biomedical information retrieval (BIR) systems can help clinicians find the information required by automatically searching EHRs and returning relevant results. However, traditional BIR systems cannot understand the complex relationships between EHR entities. Transformers are a new type of neural network that is very effective for natural language processing (NLP) tasks. As a result, transformers are well suited for tasks such as machine translation and text summarization. In this paper, we propose a new BIR system for EHRs that uses transformers for predicting cancer treatment from EHR. Our system can understand the complex relationships between the different entities in an EHR, which allows it to return more relevant results to clinicians. We evaluated our system on a dataset of EHRs and found that it outperformed state-of-the-art BIR systems on various tasks, including medical question answering and information extraction. Our results show that Transformers are a promising approach for BIR in EHRs, reaching an accuracy and an F1-score of 86.46%, and 0.8157, respectively. We believe that our system can help clinicians find the information they need more quickly and easily, leading to improved patient care.


A Novel HLA-DRB1*10:01-Restricted T Cell Epitope From Citrullinated Type II Collagen Relevant to Rheumatoid Arthritis.
Antibodies against citrullinated type II collagen (Cit-CII) are common in the sera and synovial fluid of patients with rheumatoid arthritis (RA); however, the known T cell epitope of CII is not dependent on citrullination. The aim of this study was to identify and functionally characterize the Cit-CII-restricted T cell epitopes that are relevant to RA. Peripheral blood mononuclear cells (PBMCs) from HLA-DRB1*10:01-positive patients with RA and healthy donors were stimulated in vitro with candidate CII peptides. CD154 up-regulation was measured as a marker of antigen-specific activation, and anti-HLA-DR-blocking experiments confirmed HLA restriction. Cytokine production was measured using a Luminex technique. Direct peptide-binding assays using HLA-DRB1*10:01 and HLA-DRB1*04:01 monomeric proteins were performed. The T cell receptor (TCR) β-chain of CD154-enriched antigen-specific T cells was analyzed using high-throughput sequencing. A novel Cit-CII peptide was identified based on its ability to activate CD4+ T cells from HLA-DRB1*10:01-positive individuals. When stimulated in vitro, Cit-CII autoreactive T cells produced proinflammatory cytokines. Cit-CII(311-325) bound (with low affinity) to HLA-DRB1*10:01 but not to HLA-DRB1*04:01, while the native form was unable to bind either protein. In addition, highly expanded clones were identified in the TCRβ repertoire of Cit-CII(311-325) -stimulated PBMCs. These results illustrate the ability of the citrullination process to create T cell epitopes from CII, a cartilage-restricted protein that is relevant to RA pathogenesis. The exclusive binding of Cit-CII(311-325) to HLA-DRB1*10:01 suggests that recognition of citrullinated epitopes might vary between individuals carrying different RA-associated HLA-DR molecules.


Spacer size heterogeneity in ribosomal DNA of Chironomus thummi is due to a 120 bp repeat homologous to a predominantly centromeric repeated sequence.
The rDNA of Ch. tepperi is homogeneous in structure with a repeat size of 8.4 kb. This size seems to be typical for the basic repeat unit in Chironomus species. Ch. th. piger rDNA cistrons are slightly increased in length (9.0 kb). In the non-transcribed spacer (NTS) an appr. 0.18 kb segment is additionally present in about 50% of the repeats. Ch. th. thumni DNA contains largely heterogeneous rDNA repeats, mainly between 10 and 16 kb. The heterogeneity is due to varying numbers of 120 bp elements present in the NTS. The different spacer size classes are not randomly distributed. The short repetitive 120 bp elements (Cla I elements) hybridize in situ with the nucleolus and with centromere regions. The Cla I elements are regularly present in the thummi NTS, but are absent in the piger NTS. Only very few piger rDNA cistrons may contain Cla I elements.


Effectiveness of continuous or intermittent vital signs monitoring in preventing adverse events on general wards: a systematic review and meta-analysis.
Vital signs monitoring is an old hospital practice for patient safety but evaluation of its effectiveness is not widespread. We aimed to identify strategies to improve intermittent or continuous vital signs monitoring in general wards; and their effectiveness in preventing adverse events on general hospital wards. Publications searched between 1980 and June 2014 in five databases. Main outcome measures were in-hospital death, cardiac arrest, intensive care unit (ICU) transfers, length of stay, identification of physiological deterioration and activation of rapid response systems. Twenty-two studies assessing the effect of continuous (9) or intermittent monitoring (13) and reporting outcomes on 203,407 patients in-hospital wards across 13 countries were included in this review. Both monitoring practices led to early identification of patient deterioration, increased rapid response activations and improvements in timeliness or completeness of vital signs documentation. Innovative intermittent monitoring approaches are associated with modest reduction in in-hospital mortality over intermittent vital signs monitoring in 'usual care'. However, there was no evidence of significant reduction in ICU transfers or other adverse events with either intermittent or continuous monitoring. This review of heterogeneous monitoring approaches found no conclusive confirmation of improvements in prevention of cardiac arrest, reduction in length of hospital stay, or prevention of other neurological or cardiovascular adverse events. The evidence found to date is insufficient to recommend continuous vital signs monitoring in general wards as routine practice. Future evaluations of effectiveness need to be undertaken with more rigorous methods and homogeneous outcome measurements.


Overview of fetal arrhythmias.
Though fetal arrhythmias account for a small proportion of referrals to a fetal cardiologist, they may be associated with significant morbidity and mortality. The present review outlines the current literature with regard to the diagnosis and, in brief, some management strategies in fetal arrhythmias. Advances in echocardiography have resulted in significant improvements in our ability to elucidate the mechanism of arrhythmia at the bedside. At the same time, magnetocardiography is broadening our understanding of mechanisms of arrhythmia especially as it pertains to ventricular arrhythmias and congenital heart block. It provides a unique window to study electrical properties of the fetal heart, unlike what has been available to date. Recent reports of bedside use of fetal ECG make it a promising new technology. Fetal magnetocardiography is also developing. The underlying mechanisms resulting in immune-mediated complete heart block in a small subset of 'at-risk' fetuses is under investigation. There have been great strides in noninvasive diagnosis of fetal arrhythmias. However, we still need to improve our knowledge of the electromechanical properties of the fetal heart as well as the mechanisms of arrhythmia to further improve outcomes. Multiinstitutional collaborative studies are needed to help answer some of the questions regarding patient, drug selection and management algorithms.


Spatial organization and activity patterns of the masked palm civet (Paguma larvata) in central-south China.
Movement and activity patterns are important components of life history, being central to resource acquisition and defense, mating behavior, and individual survival and fitness. Here, we present results from the 1st systematic radiotracking study of the masked palm civet (Paguma larvata), a widespread viverrid found in subtropical and tropical forests of Asia. From June 2004 to November 2007, we radiotracked 12 masked palm civets (5 males and 7 females) in central-south China. Mean individual home-range size based on 95% minimum convex polygons was 192.6 ha ± 42.6 SE (range = 64-451 ha). Although males had larger mean home-range sizes than females (276.8 and 136.5 ha, respectively), these differences were not statistically significant. Males also exhibited greater daily movement distances and extents than females, but we found no evidence of sexual dimorphism in body size. Masked palm civets were predominantly nocturnal, but were active intermittently during the day. No significant seasonal (monthly) differences in daily activity patterns were apparent. We did, however, observe reduced hours of activity-but not continuous inactivity-during winter; consequently, we concluded that our study animals did not hibernate or semihibernate. We speculate that our observations of home-range overlap among individuals may indicate group living in the masked palm civet.


Evidence from Toxicology: The Most Essential Science for Prevention.
The most essential goal of medicine and public health is to prevent harm (primum non nocere). This goal is only fully achieved with primary prevention, which requires us to identify and prevent harms prior to human exposure through research and testing that does not involve human subjects. For that reason, public health policies place considerable reliance on nonhuman toxicological studies. However, toxicology as a field has often not produced efficient and timely evidence for decision making in public health. In response to this, the U.S. National Research Council called for the adoption of evidence-based methods and systematic reviews in regulatory decision making. The U.S. Environmental Protection Agency (EPA), the Food and Drug Administration (FDA), and the European Food Safety Agency (EFSA) have recently endorsed these methods in their assessments of safety and risk. In this commentary we summarize challenges and problems in current practices in toxicology as applied to decision making. We compare these practices with the principles and methods utilized in evidence-based medicine and health care, with emphasis on the record of the Cochrane Collaboration. We propose a stepwise strategy to support the development, validation, and application of evidence-based toxicology (EBT). We discuss current progresses in this field produced by the Office of Health Assessment and Translation (OHAT) of the National Toxicology Program and the Navigation Guide works. We propose that adherence to the Cochrane principles is a fundamental prerequisite for the development and implementation of EBT. The adoption of evidence-based principles and methods will enhance the validity, transparency, efficiency, and acceptance of toxicological evidence, with benefits in terms of reducing delays and costs for all stakeholders (researchers, consumers, regulators, and industry). Mandrioli D, Silbergeld EK. 2016. Evidence from toxicology: the most essential science for prevention. Environ Health Perspect 124:6-11; http://dx.doi.org/10.1289/ehp.1509880.


Association of Child Neurology-Indian Epilepsy Society Consensus Document on Parental Counseling of Children with Epilepsy.
When a child is diagnosed with epilepsy, counseling regarding the same is done by the treating doctor. Most parents are frightened and have poor knowledge about epilepsy. Therapeutic advice including drug dosage, administration and side effects takes up the major part of physician's time, thereby neglecting important issues like home seizure management, follow up and others. These lacunae in knowledge require systematic patient and family education. To address these issues, an expert group meeting of pediatric neurologists and epileptologists in India along with social workers/epilepsy educators, legal experts, parents, and teachers was held. The various aspects regarding parental counseling in children with epilepsy were discussed and a consensus document was formulated. Here authors present the group consensus statement on counseling parents and caregivers of children with epilepsy. This document is intended to help physicians and pediatricians counsel the families when a child is diagnosed with epilepsy.


Determination of intracellular glutathione and glutathione disulfide using high performance liquid chromatography with acidic potassium permanganate chemiluminescence detection.
Measurement of glutathione (GSH) and glutathione disulfide (GSSG) is a crucial tool to assess cellular redox state. Herein we report a direct approach to determine intracellular GSH based on a rapid chromatographic separation coupled with acidic potassium permanganate chemiluminescence detection, which was extended to GSSG by incorporating thiol blocking and disulfide bond reduction. Importantly, this simple procedure avoids derivatisation of GSH (thus minimising auto-oxidation) and overcomes problems encountered when deriving the concentration of GSSG from 'total GSH'. The linear range and limit of detection for both analytes were 7.5 × 10(-7) to 1 × 10(-5) M, and 5 × 10(-7) M, respectively. GSH and GSSG were determined in cultured muscle cells treated for 24 h with glucose oxidase (0, 15, 30, 100, 250 and 500 mU mL(-1)), which exposed them to a continuous source of reactive oxygen species (ROS). Both analyte concentrations were greater in myotubes treated with 100 or 250 mU mL(-1) glucose oxidase (compared to untreated controls), but were significantly lower in myotubes treated with 500 mU mL(-1) (p < 0.05), which was rationalised by considering measurements of H(2)O(2) and cell viability. However, the GSH/GSSG ratio in myotubes treated with 100, 250 and 500 mU mL(-1) glucose oxidase exhibited a dose-dependent decrease that reflected the increase in intracellular ROS.


Quantitative imaging of microvascular permeability in a rat model of lipopolysaccharide-induced sepsis: evaluation using cryostatic micro-computed tomography.
The aim of the present study was to evaluate the magnitude of endothelial defects by micro-computed tomography (CT) quantitation of contrast agent diffusion across the vascular endothelium in a rat model of vascular permeability caused by lipopolysaccharide (LPS)-induced sepsis. LPS was administered intraperitoneally (i.p.) at a dose of 10 mg/kg body weight in male Wistar rats (n = 18). Vascular leakage and vascular volume were quantified, by micro-CT and cryostatic micro-CT. The contrast agents used were Fenestra ( approximately 70-nm particle diameter), Microfil (large polymer), and iopamidol (Isovue, MW 777 Dalton). Micro-CT revealed an increase in endothelial permeability as indicated by entry of contrast agent (Fenestra) into the extravascular space after LPS administration (P < 0.01). Endotoxin exposure also induced a decrease of vascular luminal volume in the myocardium, liver, kidney, and colonic wall determined by micro-CT (P < 0.01). Vascular leakage, expressed as the ratio of extravascular to intravascular gray scale intensity (IE/II) after injection of contrast agent, increased significantly in the myocardium, liver, kidney, and colonic wall (P < 0.001). The elimination of iopamidol from the intravascular compartment in LPS-challenged rats was decreased compared with control rats. The endothelial defect size was estimated to be >70 nm and <1 microm. Contrast agents are useful to characterize vascular leakage and vascular volume fraction in an animal model of endotoxin priming.


Age- and sex-related variations in the brain white matter fractal dimension throughout adulthood: an MRI study.
To observe age- and sex-related differences in the complexity of the global and hemispheric white matter (WM) throughout adulthood by means of fractal dimension (FD). A box-counting algorithm was used to extract FD from the WM magnetic resonance images of 209 healthy adults from three structural layers, including general (gFD), skeleton (sFD), and boundaries (bFD). Model selection algorithms and statistical analyses, respectively, were used to examine the patterns and significance of the changes. gFD and sFD showed inverse U-shape patterns with aging, with a slighter slope of increase from young to mid-age and a steeper decrease to the old. bFD was less affected by age. Sex differences were evident, specifically in gFD and sFD, with men showing higher FDs. Age × sex interaction was significant mainly in the hemispheric analysis, with men undergoing sharper age-related changes. After adjusting for the volume effect, age-related results remained approximately the same, but sex differences changed in most of the features, with women indicating higher values, specifically in the left hemisphere and boundaries. Right hemisphere was still more complex in men. This study is the first that investigates the WM FD spanning adulthood, treating age both as a continuous and categorical variable. We found positive correlations between FD and volume, and our results show similarities with those investigating small-world properties of the brain networks, as well as those of functional complexity and WM integrity. These suggest that FD could yield a highly compact description of the structural changes and also might inform us about functional and cognitive variations.


Role of the CCA bulge of prohead RNA of bacteriophage ø29 in DNA packaging.
The oligomeric ring of prohead RNA (pRNA) is an essential component of the ATP-driven DNA packaging motor of bacteriophage ø29. The A-helix of pRNA binds the DNA translocating ATPase gp16 (gene product 16) and the CCA bulge in this helix is essential for DNA packaging in vitro. Mutation of the bulge by base substitution or deletion showed that the size of the bulge, rather than its sequence, is primary in DNA packaging activity. Proheads reconstituted with CCA bulge mutant pRNAs bound the packaging ATPase gp16 and the packaging substrate DNA-gp3, although DNA translocation was not detected with several mutants. Prohead/bulge-mutant pRNA complexes with low packaging activity had a higher rate of ATP hydrolysis per base pair of DNA packaged than proheads with wild-type pRNA. Cryoelectron microscopy three-dimensional reconstruction of proheads reconstituted with a CCA deletion pRNA showed that the protruding pRNA spokes of the motor occupy a different position relative to the head when compared to particles with wild-type pRNA. Therefore, the CCA bulge seems to dictate the orientation of the pRNA spokes. The conformational changes observed for this mutant pRNA may affect gp16 conformation and/or subsequent ATPase-DNA interaction and, consequently, explain the decreased packaging activity observed for CCA mutants.


Post-translational Modifications of Cyclophilin D Fine-Tune Its Conformational Dynamics and Activity: Implications for Its Mitochondrial Function.
Mitochondria are the powerhouse of a cell, whose disruption due to mitochondrial pore opening can cause cell death, leading to necrosis and many other diseases. The peptidyl-prolyl cis-trans isomerase cyclophilin D (CypD) is a key player in the regulation of the mitochondrial pore. The activity of CypD can be modulated by the post-translational modification (PTM). However, the detailed mechanism of this functional modulation is not well understood. Here, we investigate the catalytic mechanism of unmodified and modified CypD by calculating the reaction free energy profiles and characterizing the function-related conformational dynamics using molecular dynamics simulations and associated analyses. Our results show that unmodified and modified CypD considerably lower the isomerization free energy barrier compared to a free peptide substrate, supporting the catalytic activity of CypD in the simulation systems. The unmodified CypD reduces the free energy difference between the cis and trans states of the peptide substrate, suggesting a stronger binding affinity of CypD toward cis, consistent with experiments. In contrast, phosphorylated CypD further stabilizes trans, leading to a lower catalytic rate in the trans-to-cis direction. The differential catalytic activities of the unmodified and phosphorylated CypD are due to a significant shift of the conformational ensemble upon phosphorylation under different functional states. Interestingly, the local flexibility is both reduced and enhanced at distinct regions by phosphorylation, which is explained by a "seesaw" model of flexibility modulation. The allosteric pathway between the phosphorylation site and a distal site displaying substantial conformational changes upon phosphorylation is also identified, which is influenced by the presence of the substrate or the substrate conformation. Similar conclusions are obtained for the acetylation of CypD using the same peptide substrate and the influence of substrate sequence is also examined. Our work may serve as the basis for the understanding of other PTMs and PTM-initiated allosteric regulations in CypD.


Transcriptional up-regulation of the delayed early gene HRS/SRp40 during liver regeneration. Interactions among YY1, GA-binding proteins, and mitogenic signals.
Arg-Ser-rich domain-containing proteins (SR proteins), a family of splicing factors, can regulate pre-mRNA alternative splicing in a concentration dependent manner. Thus, the relative expression of various SR proteins may play an important role in alternative splicing regulation. HRS/SRp40, an SR protein and delayed early gene in liver regeneration, can mediate alternative splicing of fibronectin mRNA. Here we determined that transcription of the HRS/SRp40 gene is induced about 5-fold during liver regeneration, similar to the level of steady-state mRNA. We found that both mouse and human HRS promoters lack TATA and CAAT boxes. The mouse promoter region from -130 to -18, which contains highly conserved GA-binding protein (GABP) and YY1 binding sites, conferred high transcriptional activity. While GABPalpha/GABPbeta heterodimer transactivated the HRS promoter, YY1 functioned as a repressor. During liver regeneration, the relative amount of GABPalpha/GABPbeta heterodimer increased 3-fold, and YY1 changed little, which could partially account for the increase in HRS gene transcription. Interleukin-6, a critical mitogenic component of liver regeneration, was able to relieve the repressive activity of the YY1 site within the HRS promoter. The combined effect of small changes in the level of existing transcription factors and mitogenic signals may explain the transcriptional activation of the HRS gene during cell growth.


Distal intestinal obstructive syndrome in adults with cystic fibrosis: a surgical perspective.
Cystic fibrosis (CF) is the most common life-shortening hereditary disease affecting the white population. Respiratory complications are the greatest determinant of adult survival, but gastrointestinal manifestations result in significant morbidity. Distal intestinal obstructive syndrome (DIOS) describes partial or complete intestinal obstruction in patients with CF beyond the neonatal period and is characterized by abnormally viscid mucofeculent material in the terminal ileum and ascending colon. The medical management of DIOS has been described; however, the optimal surgical strategy for this condition is unknown. Herein, we present a surgical case series and review the therapeutic surgical options. Distal intestinal obstructive syndrome will become an increasingly common complication in the adult with CF who may require operative therapy. Surgeons should have a high index of suspicion for DIOS in patients with CF and the symptoms of small-bowel obstruction.


Do C-reactive protein level, white blood cell count, and pain location guide the selection of patients for computed tomography imaging in non-traumatic acute abdomen?
The value of abdominal computed tomography in non-traumatic abdominal pain has been well established. On the other hand, to manage computed tomography, appropriateness has become more of an issue as a result of the concomitant increase in patient radiation exposure with increased computed tomography use. The purpose of this study was to investigate whether C-reactive protein, white blood cell count, and pain location may guide the selection of patients for computed tomography in non-traumatic acute abdomen. Patients presenting with acute abdomen to the emergency department over a 12-month period and who subsequently underwent computed tomography were retrospectively reviewed. Those with serum C-reactive protein and white blood cell count measured on admission or within 24 h of the computed tomography were selected. Computed tomography examinations were retrospectively reviewed, and final diagnoses were designated either positive or negative for pathology relating to presentation with acute abdomen. White blood cell counts, C-reactive protein levels, and pain locations were analyzed to determine whether they increased or decreased the likelihood of producing a diagnostic computed tomography. The likelihood ratio for computed tomography positivity with a C-reactive protein level above 5 mg/L was 1.71, while this increased to 7.71 in patients with combined elevated C-reactive protein level and white blood cell count and right lower quadrant pain. Combined elevated C-reactive protein level and white blood cell count in patients with right lower quadrant pain may represent a potential factor that could guide the decision to perform computed tomography in non-traumatic acute abdomen.


Functional Reorganization of Local Circuit Connectivity in Superficial Spinal Dorsal Horn with Neuropathic Pain States.
The spinal dorsal horn is the first relay structure coding for pain transmission and modulation. Previous anatomical and electrophysiological studies have examined spinal dorsal horn circuit connections and network activity. Further work is required to understand spinal cord sensory information processing that underlies pathological neuropathic pain states. Our previous studies suggest that peripheral nerve injury enhances presynaptic excitatory input onto spinal superficial dorsal horn neurons, which in turn contributes to pathologic nociception. The potential changes in local postsynaptic circuits in the dorsal horn that lead to pathologically heightened behavioral responses to pain remain largely unexplored. We combined whole-cell electrophysiological recordings with laser-scanning photostimulation to test whether peripheral nerve injury in the spinal nerve ligation (SNL) mouse model of neuropathic pain leads to alterations in the functional connectivity of spinal cord circuits including lamina II excitatory interneurons. Here we show that SNL enhances excitation and decreases inhibition to lamina II excitatory interneurons along with their increased glutamate-evoked excitability. The enhanced excitatory postsynaptic input and connectivity evoked by SNL eventually return to normal levels concurrently with the resolution of the neuropathic pain states. The physiological pattern highly correlates with mouse pain behaviors following SNL, supporting a neurophysiological mechanism of central sensitization and neuropathic pain that is functionally localized to the spinal dorsal horn. Together, these data support that SNL induces functional changes in synaptic input and connectivity to lamina II excitatory interneurons that code for pain perception, and thus provide new insights into the mechanism and locus of pain hypersensitivity.


The mortal cause of sudden ECG changes in patients with chronic aortic insufficiency: Aortic dissection.
The symptoms of aortic dissection (AD) may be highly variable and may mimic other much common conditions. Thus, a high index of suspicion should be maintaned, especially when the risk factors for AD are present or signs and symptoms suggest this possibility. However, sometimes AD may be asymptomatic or progression may be subclinical. Various electrocardiographical (ECG) changes may be seen in AD patients such as ST segment elevation in aVR as well as ST segment depression and T-wave inversion. In this case report, we reported a patient with acute AD whose ECG revealed ST segment elevation in aVR lead in addition to diffuse ST segment depression in other leads.


Direct electrochemical analyses of a thermophilic thioredoxin reductase: interplay between conformational change and redox chemistry.
Thioredoxin reductases (TrxRs) are flavin-containing dithioloxidoreductases that couple reduction equivalents from the soluble NAD(P)H pool to the soluble protein thioredoxin (Trx). Previous crystallographic studies of the Escherichia coli enzyme ( ecTrxR) have shown that low molecular weight TrxRs can adopt two distinct conformations: the first (FO) is required for the oxidation of the flavin cofactor and the generation of reduced Trx; the second (FR) is adopted for the reduction of the flavin by NAD(P)H. Here, protein electrochemistry has been used to interrogate the equilibrium between the oxidized and reduced conformations of the ecTrxR and a novel, low molecular weight TrxR from the thermophilic archaeon Thermoplasma acidophilum ( taTrxR) that is characterized structurally and biochemically in the accompanying paper [Hernandez et al. (2008) Biochemistry 47, 9728-9737]. A reversible electrochemical response is observed that reveals a dynamic behavior dependent upon the temperature of the experiment. At low temperatures (283 K) a broad, quasi-reversible electrochemical envelope is observed centered at a value of approximately -300 mV and displaying a peak width of over 150 mV. The voltammetric response sharpens dramatically as the temperature increases, becoming much more reversible (as determined by peak separation and peak width). The overall potential and shape of the voltammetric data indicate that the flavin (FAD/FADH 2) and disulfide/dithiol couples are very close in thermodynamic potentials, and the data are interpreted in terms of the model of two-state conformational change between flavin reducing (FR) and flavin oxidizing (FO) states, where the difference in potential for the flavin and disulfide cofactors must be within 40 mV of one another. In this model, the low temperature peak broadening is interpreted as an indication of a heterogeneous population of TrxR conformations that exist at low temperature; at higher temperatures, FO and FR conformers can rapidly interconvert, and voltammetry reports upon an average potential of the conformations.


Sudden death during exercise.
Although death during exercise is rare, vigorous physical activity is associated with increased risk for fatality, particularly in individuals with overt cardiac disease or a high coronary risk profile. The mechanism of death is usually a lethal ventricular arrhythmia, but this may vary depending on the underlying cardiac condition. Cardiac disease is present in the great majority of individuals who die during exercise. In young persons, hypertrophic cardiomyopathy and congenital coronary anomalies are most frequent, whereas older victims usually have coronary artery atherosclerosis. Cardiac disease is typically unrecognized before the fatal event in young individuals; in the older group, most have overt coronary disease or identifiable risk factors. Screening asymptomatic subjects to identify increased cardiac risk during exercise is problematical in terms of logistics, expense and accuracy. However, careful evaluation, including exercise testing, is mandatory before a program of increased physical activity is initiated in cardiac patients. For other individuals, firm guidelines are lacking, and the extent of the evaluation must be determined on an individual basis.


SARS-related perceptions in Hong Kong.
To understand different aspects of community responses related to severe acute respiratory syndrome (SARS), 2 population-based, random telephone surveys were conducted in June 2003 and January 2004 in Hong Kong. More than 70% of respondents would avoid visiting hospitals or mainland China to avoid contracting SARS. Most respondents believed that SARS could be transmitted through droplets, fomites, sewage, and animals. More than 90% believed that public health measures were efficacious means of prevention; 40.4% believed that SARS would resurge in Hong Kong; and approximately equals 70% would then wear masks in public places. High percentages of respondents felt helpless, horrified, and apprehensive because of SARS. Approximately 16% showed signs of posttraumatic symptoms, and approximately equals 40% perceived increased stress in family or work settings. The general public in Hong Kong has been very vigilant about SARS but needs to be more psychologically prepared to face a resurgence of the epidemic.


Surgical resection of the inferior vena cava for leiomyosarcoma.
Our case of primary leiomyosarcomas involved retrohepatic, suprarenal, and infrarenal inferior vena cava (IVC). Preoperative phlebography proved that there was adequate collateral circulation formed, which allowed us to achieve en bloc resection including segment I and II IVC without either extracorporeal circulation or prosthetic revascularization of the IVC and renal vessels. Our choice of en bloc resection including segment I and II IVC without extracorporeal circulation or prosthetic replacement of the vessels was justified as the patient had normal liver and kidney function after the operation.


Effect of a Flexor Digitorum Superficialis Hemitenodesis on Reducing Volar Plate Strains for Swan Neck Deformities.
Flexor digitorum superficialis (FDS) hemitenodesis is a common procedure to treat swan neck deformity (SND). We hypothesize that this surgical technique is a biomechanically effective way to reduce strain in the volar plate at the proximal interphalangeal joint (PIPJ). Fifteen digits from 5 cadaveric specimens were tested using a novel in vitro active finger motion simulator under 4 finger conditions: intact, SND, FDS hemitenodesis, and FDS hemitenodesis with distal interphalangeal (DIP) joint fusion. Tensile loads in FDS and flexor digitorum profundus (FDP) and joint ranges of motion were measured by electromagnetic tracking. In addition, strain gauges were inserted under the volar plate to measure strain during PIPJ hyperextension. Results were analyzed using 1-way repeated-measures analysis of variance tests. The SND condition increased volar plate strain by 176% ± 25% (P < .001) compared with the intact condition. The FDS hemitenodesis repair relieved more than 50% of the SND strain, restoring it to within no statistical difference from intact. The DIP fusion further reduced strain with no further statistical significance. At full flexion, FDS and FDP tendon loads diverged as a function of the test condition (P < .001). With the FDS hemitenodesis, the FDP load increased by 2.1 ± 1.5 N from the SND condition (P < .001), whereas the FDS load decreased by 1.3 ± 1.3 N (P = .012). The FDS hemitenodesis repair restored strains to within 3.0 milli-strain of the intact condition with no significant difference. Application of DIP fusion did not further protect the PIPJ from increased hyperextension and further exacerbated the imbalance of flexor tendon loads.


Magnetically Controlled Devices Parallel to the Spine in Children with Spinal Muscular Atrophy.
Children with severe spinal deformity frequently are managed with growth-friendly implants. After initial surgery, externally controlled magnetic rods allow spinal deformity correction during growth without further surgical intervention. The ability to lengthen the spine without additional surgical procedures is especially beneficial in high-risk children, such as those with spinal muscular atrophy (SMA). The purpose of the present study was to assess the level of control of spinal deformity in a homogeneous group of patients with SMA who were managed with magnetically controlled implants for 2 years. This prospective, nonrandomized study included 21 non-ambulatory children with type-II SMA and progressive scoliosis who were managed bilaterally with a magnetically controlled implant that was inserted parallel to the spine with use of rib-to-pelvis hook fixation. Radiographic measurements of scoliotic curves, kyphosis, lordosis, pelvic obliquity, and spinal length were performed before and after implantation of the magnetically controlled device and during external lengthening. The mean duration of follow-up was 2 years. The mean main curve of patients without prior vertical expandable prosthetic titanium rib (VEPTR) treatment decreased from 70° before implantation of the magnetically controlled device to 30° after implantation of the device. Correction was maintained during the follow-up period, with a mean curve of 31° at the time of the latest follow-up at 2.2 years. Pelvic obliquity was surgically corrected by 76% (from 17° to 4°) and remained stable during follow-up. Thoracic kyphosis could not be corrected within the follow-up period. Spinal length of children without prior spinal surgery increased by >50 mm immediately after device implantation and steadily increased at a rate of 13.5 mm/yr over the course of treatment. During treatment, 4 general complications occurred and 6 lengthening procedures failed, with 3 patients requiring surgical revision. Bilateral implantation of an externally controlled magnetic rod with rib-to-pelvis fixation represents a safe and efficient method to control spinal deformity in children with SMA, achieving sufficient and stable curve correction as well as increased spinal length. The complication rate was lower than those that have been described for VEPTR and other growing rod instrumentation strategies. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Folding graft copolymer with pendant drug segments for co-delivery of anticancer drugs.
A graft copolymer with pendant drug segments can fold into nanostructures in a protein folding-like manner. The graft copolymer is constructed by directly polymerizing γ-camptothecin-glutamate N-carboxyanhydride (Glu(CPT)-NCA) on multiple sites of poly(ethylene glycol) (PEG)-based main chain via the ring open polymerization (ROP). The "purely" conjugated anticancer agent camptothecin (CPT) is hydrophobic and serves as the principal driving force during the folding process. When exposed to water, the obtained copolymer, together with doxorubicin (Dox), another anticancer agent, can fold into monodispersed nanocarriers (with a diameter of around 50 nm) for dual-drug delivery. Equipped with a PEG shell, the nanocarriers displayed good stability and can be internalized by a variety of cancer cell lines via the lipid raft and clathrin-mediated endocytotic pathway without premature leakage, which showed a high synergetic activity of CPT and Dox toward various cancer cells. In vivo study validated that the nanocarriers exhibited strong accumulation in tumor sites and showed a prominent anticancer activity against the lung cancer xenograft mice model compared with free drugs.


Management of pediatric laryngotracheal stenosis.
In the past 6 years, 40 children underwent surgery for laryngotracheal stenosis; 32 by the external approach and 8 by endoscopic CO2 laser. Twenty-seven children (67%) were less than 5 years old at the time of treatment and 80% of the stenoses (n = 32) corresponded to an etiology that is secondary to endotracheal intubation and/or tracheotomy. By grading the stenoses according to the amount of narrowing of the lumen, the authors emphasize the interest of conservative treatment (endoscopic for grade I [less than 70%, n = 8], and treatment by external surgical methods for grade II [70% to 90%, n = 13], grade III [90% to 99%, n = 14], and grade IV [total obstruction, n = 5]). At this time, the most commonly used technique is laryngotracheoplasty with costal cartilage interposition. In this series, 88% of the patients were successfully decannulated. As for the treatment of stenosis in infants, the authors describe their recent experience of laryngotracheofissure in 7 patients as an alternative to either tracheotomy in cases of difficult extubation or laryngotracheoplasty when the child is underweight.


Assessment of Instruments for Measurement of Delirium Severity: A Systematic Review.
Measurement of delirium severity has been recognized as highly important for tracking prognosis, monitoring response to treatment, and estimating burden of care for patients both during and after hospitalization. Rather than simply rating delirium as present or absent, the ability to quantify its severity would enable development and monitoring of more effective treatment approaches for the condition. To present a comprehensive review of delirium severity instruments, conduct a methodologic quality rating of the original validation study of the most commonly used instruments, and select a group of top-rated instruments. This systematic review was conducted using literature from Embase, PsycINFO, PubMed, Web of Science, and Cumulative Index to Nursing and Allied Health Literature, from January 1, 1974, through March 31, 2017, with the key words delirium, severity, tests, measures, and intensity. Inclusion criteria were original articles assessing delirium severity and using a delirium-specific severity instrument. Final listings of articles were supplemented with hand searches of reference listings to ensure completeness. At least 2 reviewers independently completed each step of the review process: article selection, data extraction, and methodologic quality assessment of relevant articles using a validated rating scale. All discrepancies between raters were resolved by consensus. Of 9409 articles identified, 228 underwent full text review, and we identified 42 different instruments of delirium severity. Eleven of the 42 tools were multidomain, delirium-specific instruments providing a quantitative rating of delirium severity; these instruments underwent a methodologic quality review. Applying prespecified criteria related to frequency of use, methodologic quality, construct or predictive validity, and broad domain coverage, an expert panel used an iterative modified Delphi process to select 6 final high-quality instruments meeting these criteria: the Confusion Assessment Method-Severity Score, Confusional State Examination, Delirium-O-Meter, Delirium Observation Scale, Delirium Rating Scale, and Memorial Delirium Assessment Scale. The 6 instruments identified may enable accurate measurement of delirium severity to improve clinical care for patients with this condition. This work may stimulate increased usage and head-to-head comparison of these instruments.


The Mediator complex subunit MED25 interacts with HDA9 and PIF4 to regulate thermomorphogenesis.
Thermomorphogenesis is, among other traits, characterized by enhanced hypocotyl elongation due to the induction of auxin biosynthesis genes like YUCCA8 by transcription factors, most notably PHYTOCHROME INTERACTING FACTOR 4 (PIF4). Efficient binding of PIF4 to the YUCCA8 locus under warmth depends on HISTONE DEACETYLASE 9 (HDA9) activity, which mediates histone H2A.Z depletion at the YUCCA8 locus. However, HDA9 lacks intrinsic DNA-binding capacity, and how HDA9 is recruited to YUCCA8, and possibly other PIF4-target sites, is currently not well understood. The Mediator complex functions as a bridge between transcription factors bound to specific promoter sequences and the basal transcription machinery containing RNA polymerase II. Mutants of Mediator component Mediator25 (MED25) exhibit reduced hypocotyl elongation and reduced expression of YUCCA8 at 27°C. In line with a proposed role for MED25 in thermomorphogenesis in Arabidopsis (Arabidopsis thaliana), we demonstrated an enhanced association of MED25 to the YUCCA8 locus under warmth and interaction of MED25 with both PIF4 and HDA9. Genetic analysis confirmed that MED25 and HDA9 operate in the same pathway. Intriguingly, we also showed that MED25 destabilizes HDA9 protein. Based on our findings, we propose that MED25 recruits HDA9 to the YUCCA8 locus by binding to both PIF4 and HDA9.


Chitosan-Poly(caprolactone) Nanofibers for Skin Repair.
Dermal wounds, both acute and chronic, represent a significant clinical challenge and therefore the development of novel biomaterial-based skin substitutes to promote skin repair is essential. Nanofibers have garnered attention as materials to promote skin regeneration due to the similarities in morphology and dimensionality between nanofibers and native extracellular matrix proteins, which are critical in guiding cutaneous wound healing. Electrospun chitosan-poly(caprolactone) (CPCL) nanofiber scaffolds, which combine the important intrinsic biological properties of chitosan and the mechanical integrity and stability of PCL, were evaluated as skin tissue engineering scaffolds using a mouse cutaneous excisional skin defect model. Gross assessment of wound size and measurement of defect recovery over time as well as histological evaluation of wound healing showed that CPCL nanofiber scaffolds increased wound healing rate and promoted more complete wound closure as compared with Tegaderm, a commercially available occlusive dressing. CPCL nanofiber scaffolds represent a biomimetic approach to skin repair by serving as an immediately available provisional matrix to promote wound closure. These nanofiber scaffolds may have significant potential as a skin substitute or as the basis for more complex skin tissue engineering constructs involving integration with biologics.


Invasive cutaneous squamous cell carcinoma incidence in US health care workers.
Little data on cutaneous squamous cell carcinoma (SCC) epidemiology within the United States are currently available. Prior studies have focused on populations outside of the United States or been limited to regions within the US. In this study, prospective data were collected via biennial questionnaires from a total of 261,609 participants, which included women in the Nurses' Health Study (NHS, 1976-2008) and Nurses' Health Study II (NHS II, 1989-2009), and men in the Health Professionals Follow-Up Study (HPFS, 1986-2008). History of physician-diagnosed invasive SCC was confirmed by pathology record review. Over the entire follow-up period for each cohort, there were 1,265 invasive SCC cases per 100,000 persons in the NHS cohort, 389 cases per 100,000 persons in NHS II, and 2,154 cases per 100,000 persons in HPFS. An 18-year follow-up of participants in these cohorts revealed increasing invasive SCC incidence rates over time, with rates for men being consistently higher than those for women. In women, a larger proportion of invasive SCC lesions occurred on the lower extremities as compared to men (21 % in NHS vs. 6 % in HPFS, p < 0.0001; 14 % in NHS II vs. 6 % in HPFS, p < 0.0001), while in men, a larger proportion occurred on the head/neck (43 % in NHS vs. 60 % in HPFS, p < 0.0001; 48 % in NHS II vs. 60 % in HPFS, p < 0.0001). In summary, invasive SCC incidence rates among US men have been greater than those for women with distinct sites of common occurrence between men and women.