[Application of self-made stretch pants in patients with burn in special sites].
The change and fixation of dressing are difficult in patients with burn in special sites of perineum, buttocks, and bilateral thighs. Therefore, we designed and made stretch pants by ourselves for dressing fixation after dressing change in patients with burns in abdomen, buttocks, and bilateral thighs. The stretch pants are made by cutting and splicing elastic fabric according to perimeters of abdomen and legs. The stretch pants are used after wound dressing change, which can fix the dressing stably, accelerate wound healing, and reduce the medical workers' labor intensity of dressing change and economic burden of patients. And patients can walk out of bed early. It's especially suitable for dressing fixation of infants and other patients who are unwilling to cooperate. Besides, it's easy to make with low cost and suitable for clinical promotion.


Enhanced Catalytic Conversion of Polysulfides Using Bimetallic Co7Fe3 for High-Performance Lithium-Sulfur Batteries.
Practical applications of lithium-sulfur (Li-S) batteries have been severely hindered by their low capacity, poor rate performance, and fast capacity degradation, which mainly originate from the notorious polysulfide shuttle effect. Herein, with density functional theory calculations, we show that the alloying of Fe into carbon-coated Co not only provides moderate binding interactions with the polysulfides to hinder their diffusion but also serves as an active catalyst in the spontaneous and successive lithiation of S8 to Li2S. Based on the fast migration of Li ions and the spontaneous lithiation of Li2S2 on the carbon-coated Fe-Co alloy, the entrapping-conversion processes of polysulfides are both thermodynamically and kinetically promoted in redox cycling. Experimentally, rationally designed Co7Fe3@porous graphite carbon-carbon nanotubes (Co7Fe3@PGC-CNT) electrocatalysts are introduced into Li-S batteries through separator functionalization. Consistent with theoretical predictions, Li-S batteries with Co7Fe3@PGC-CNT modified separators exhibit a dramatically enhanced rate capacity (788 and 631 mAh g-1 at 10 and 15 C rates, respectively) and cycling stability (a slow capacity decay of 0.05% per cycle over 1000 cycles at 2.0 C), which are superior to those of most reported Li-S batteries coupled with state-of-the-art separators. Furthermore, it is shown that the excellent hindering of the shuttle effects enables a high areal capacity of 4.7 mAh cm-2 after 90 cycles at a high sulfur loading of 6.7 mg cm-2. Our work provides a feasible method for developing high-energy and long-life Li-S batteries, which might drive the commercialization of Li-S batteries.


Hispanic children with asthma: morbidity.
Hispanic children represent a large and growing segment of the poor and disadvantaged children in our country. Asthma and other chronic respiratory diseases have a significant impact on poor children. Yet there are few descriptions of the specific morbidities and barriers to health that Hispanic children with asthma encounter, and data on predictors of morbidity among these children are unavailable. The purpose of this study is to describe the morbidity associated with asthma in Hispanic children and to identify factors that predict morbidity. A group of Hispanic children with moderate asthma followed in the clinics of the University of Texas Health Science Center at San Antonio were studied. Children aged 6 to 16 years with at least two acute-care visits or one hospitalization for asthma during the previous year were enrolled. Data sources included standardized questionnaires, spirometry, medical records, and school attendance records. Seventy-eight Hispanic children were enrolled in the study (mean age = 9.4 +/- 2.7 [SD]; 62% male). Fifty-two (67%) of children had been hospitalized previously. The other morbidity variables (mean +/- SD) were number of days/week impaired (1.1 +/- 1.2), number of days absent from school per year (13 +/- 9.6), number of acute-care visits per year (3.3 +/- 2.4), and number of hospital admissions per year (0.6 +/- 0.8). The mean forced expiratory volume in 1 second/forced vital capacity was 79.3% (+/- 9.1) and the mean forced expiratory flow, mid-expiratory phase, percent predicted was 69.9% (+/- 25.1). Thirty-four children (44%) were exposed to cigarette smoke in the home.(ABSTRACT TRUNCATED AT 250 WORDS)


A three-dimensional analysis of flow in the pivot regions of an ATS bileaflet valve.
Bileaflet heart valves are currently the most commonly implanted type of mechanical prosthetic valve, because of their low transvalvular pressure drop, centralised flow and durability. However, in common with all mechanical heart valves, implanted bileaflet valves show an inherent tendency for blood clot formation at the valve site. Fluid dynamical phenomena associated with blood clotting are elevated blood shear stresses and regions of persistent blood recirculation, particularly when both occur together. Using three-dimensional CFD modelling, combined with enlarged scale experimental modelling, we investigated the blood flow through the ATS bileaflet valve during forward flow, with particular attention to the leaflet pivot regions. Recirculating regions were found both within and downstream of the valve housing ring. Qualitative assessment of the entire cardiac cycle suggested that recirculating blood within the housing ring will be washed away whilst the valve is closed, but as with all bileaflet valve designs recirculating blood downstream of the valve may have a residence time much longer than one cardiac cycle.


Occurrence of thyroid papillary carcinoma in young patients. A Chernobyl connection?
The risk of thyroid papillary carcinoma is increased by external radiation particularly in children under 15 years of age as shown by a marked increase in those exposed to radiation after Chernobyl. We were recently confronted in Belgium over a short period with four patients (3 F, 1 M) with papillary thyroid carcinoma who were aged 10 years, 2 months, 2 years and 6 years when the Chernobyl accident occurred. We thus raise the question of a possible relationship. The patients were aged 17, 11, 10, 19 years at presentation. They all presented fortuitously over 3 years which was a very unusual increase in our extensive experience in thyroid surgery (62 cases of thyroid cancer among 1014 thyroidectomies in adults vs 4 cases in 18 children since the Chernobyl accident in 1986). Two out of the four patients had psammoma bodies (identifiable on CT scanning and ultrasound) and thyroglobulin autoantibodies (TgAb). The first patient had positive lymph nodes at the time of surgery. The incidence of thyroid cancers in Belarus and Ukraine rose just 4 years after the Chernobyl disaster; because radioactive clouds passed over Belgium, we wonder whether the occurrence of thyroid cancer in our patients could be related to this irradiation. The mechanism of increased incidence of radiation-induced thyroid cancer is thought to be due to rearrangement of the tyrosine kinase domains of the RET and TTK genes. The other important similarities in our patients are the presence of psammoma bodies that can be visualized on radiological examination and the presence of TgAb that are more frequent in differentiated thyroid cancers. Whether or not these cases reflect an increased incidence in the population as a whole, clinicians must remain vigilant for this rare but curable cancer in young patients, especially if suggestive radiological features or TgAb are present.


Late spinal deformity in quadriplegic children and adolescents.
Sixty-four quadriplegic children and adolescents were evaluated to determine the benefits of bracing and spinal fusion on the progression and extent of their spinal curves. All those injured before 14 years of age developed a spinal deformity. Bracing in a body jacket assists in maintaining sitting balance and posture and also helps to minimize complications of quadriplegia such as pressure sores. Bracing within 6 months of injury, when the spine is still straight, lessens the incidence, extent, and progression of deformity. Spinal fusion and instrumentation are often necessary for progressive curves to maintain sitting balance and preserve existing function.


Optical biopsy identification and grading of gliomas using label-free visible resonance Raman spectroscopy.
Glioma is one of the most refractory types of brain tumor. Accurate tumor boundary identification and complete resection of the tumor are essential for glioma removal during brain surgery. We present a method based on visible resonance Raman (VRR) spectroscopy to identify glioma margins and grades. A set of diagnostic spectral biomarkers features are presented based on tissue composition changes revealed by VRR. The Raman spectra include molecular vibrational fingerprints of carotenoids, tryptophan, amide I/II/III, proteins, and lipids. These basic in situ spectral biomarkers are used to identify the tissue from the interface between brain cancer and normal tissue and to evaluate glioma grades. The VRR spectra are also analyzed using principal component analysis for dimension reduction and feature detection and support vector machine for classification. The cross-validated sensitivity, specificity, and accuracy are found to be 100%, 96.3%, and 99.6% to distinguish glioma tissues from normal brain tissues, respectively. The area under the receiver operating characteristic curve for the classification is about 1.0. The accuracies to distinguish normal, low grade (grades I and II), and high grade (grades III and IV) gliomas are found to be 96.3%, 53.7%, and 84.1% for the three groups, respectively, along with a total accuracy of 75.1%. A set of criteria for differentiating normal human brain tissues from normal control tissues is proposed and used to identify brain cancer margins, yielding a diagnostic sensitivity of 100% and specificity of 71%. Our study demonstrates the potential of VRR as a label-free optical molecular histopathology method used for in situ boundary line judgment for brain surgery in the margins.


Results of arthroscopic treatment of posterosuperior glenoid impingement in tennis players.
Twenty-eight tennis players with symptomatic posterosuperior glenoid impingement limiting their participation underwent arthroscopic debridement of the supraspinatus tendon and glenoid lesions associated with this diagnosis after nonoperative treatment had failed. The dominant extremity was affected in all patients; the patients' average age was 26.9 years. Eighteen patients participated at the highest level of competition for their age, and the remaining patients participated at the intermediate level. Patients were evaluated at an average of 45.7 months after surgery by physical examination, an activities questionnaire, a subjective result questionnaire, and a questionnaire regarding their return to activity. Postoperatively, the patients averaged 26.9 of 30 possible points on the activities questionnaire. Twenty-three of the patients were subjectively satisfied with the surgical result. Twenty-two patients had returned to tennis. Despite their return, 20 of the 22 patients reported some persistent pain with participation. To our knowledge, this is the first report detailing the results of operative treatment for posterosuperior glenoid impingement in a population limited to tennis players. Even though the results are encouraging in terms of the high number of patients returning to tennis, the effects of this persistent pain with activity, although diminished in severity, on long-term participation is unknown.


Find novel dual-agonist drugs for treating type 2 diabetes by means of cheminformatics.
The high prevalence of type 2 diabetes mellitus in the world as well as the increasing reports about the adverse side effects of the existing diabetes treatment drugs have made developing new and effective drugs against the disease a very high priority. In this study, we report ten novel compounds found by targeting peroxisome proliferator-activated receptors (PPARs) using virtual screening and core hopping approaches. PPARs have drawn increasing attention for developing novel drugs to treat diabetes due to their unique functions in regulating glucose, lipid, and cholesterol metabolism. The reported compounds are featured with dual functions, and hence belong to the category of dual agonists. Compared with the single PPAR agonists, the dual PPAR agonists, formed by combining the lipid benefit of PPARα agonists (such as fibrates) and the glycemic advantages of the PPARγ agonists (such as thiazolidinediones), are much more powerful in treating diabetes because they can enhance metabolic effects while minimizing the side effects. This was observed in the studies on molecular dynamics simulations, as well as on absorption, distribution, metabolism, and excretion, that these novel dual agonists not only possessed the same function as ragaglitazar (an investigational drug developed by Novo Nordisk for treating type 2 diabetes) did in activating PPARα and PPARγ, but they also had more favorable conformation for binding to the two receptors. Moreover, the residues involved in forming the binding pockets of PPARα and PPARγ among the top ten compounds are explicitly presented, and this will be very useful for the in-depth conduction of mutagenesis experiments. It is anticipated that the ten compounds may become potential drug candidates, or at the very least, the findings reported here may stimulate new strategies or provide useful insights for designing new and more powerful dual-agonist drugs for treating type 2 diabetes.


Acute myeloid leukemia following treatment with cladribine for hairy cell leukemia: a case report and review of the literature.
The overall survival of patients with hairy cell leukemia (HCL) has significantly increased in recent years because of the development of effective treatments such as interferon alpha and purine analogs. Several reports have described an increased risk of secondary cancers, particularly solid tumors, in patients with HCL. We describe a case of a patient with HCL, who had prolonged pancytopenia after a single course of cladribine. Fifteen months after the diagnosis of HCL the patient developed acute myeloid leukemia (AML) and died shortly afterwards. Review of the literature shows few reports of acute leukemia in HCL patients. All of the 11 reported cases of leukemia in patients with HCL have been in patients who have been treated with either interferon alpha or purine analogs, and developed several years (mean 4.3 years; range 1.6-6.4 years) after the diagnosis of HCL. Our case is unusual in that the patient developed AML shortly (1.2 years) after the diagnosis and treatment of HCL. Further studies are needed to clarify whether leukemias seen in patients following the treatment of their HCL are incidental findings or related to HCL and its treatments.


The Utility of Breath Analysis in the Diagnosis and Staging of Parkinson's Disease.
The analysis of volatile organic compounds (VOCs) collected in breath samples has the potential to be a rapid, non-invasive test to aid in the clinical diagnosis and tracking of chronic conditions such as Parkinson's disease (PD). To assess the feasibility and utility of breath sample analysis done, both at point of collection in clinic and when sent away to be analyzed remotely, to diagnose, stratify and monitor disease course in a moderately large cohort of patients with PD. Breath samples were collected from 177 people with PD and 37 healthy matched control individuals followed over time. Standard clinical data (MDS-UPDRS & cognitive assessments) from the PD patients were collected at the same time as the breath sample was taken, these measures were then correlated with the breath test analysis of exhaled VOCs. The breath test was able to distinguish patients with PD from healthy control participants and correlated with disease stage. The off-line system (remote analysis) gave good results with overall classification accuracies across a range of clinical measures of between 73.6% to 95.6%. The on-line (in clinic) system showed comparable results but with lower levels of correlation, varying between 33.5% to 82.4%. Chemical analysis identified 29 potential molecules that were different and which may relate to pathogenic pathways in PD. Breath analysis shows potential for PD diagnostics and monitoring. Both off-line and on-line sensor systems were easy to do and provided comparable results which will enable this technique to be easily adopted in clinic if larger studies confirm our findings.


Stoichiometry of the redox neutral deamination and oxidative dehydrogenation reactions catalyzed by the radical SAM enzyme DesII.
DesII from Streptomyces venezuelae is a radical SAM (S-adenosyl-l-methionine) enzyme that catalyzes the deamination of TDP-4-amino-4,6-dideoxy-d-glucose to form TDP-3-keto-4,6-dideoxy-d-glucose in the biosynthesis of TDP-d-desosamine. DesII also catalyzes the dehydrogenation of the nonphysiological substrate TDP-D-quinovose to TDP-3-keto-6-deoxy-d-glucose. These properties prompted an investigation of how DesII handles SAM in the redox neutral deamination versus the oxidative dehydrogenation reactions. This work was facilitated by the development of an enzymatic synthesis of TDP-4-amino-4,6-dideoxy-d-glucose that couples a transamination equilibrium to the thermodynamically favorable oxidation of formate. In this study, DesII is found to consume SAM versus TDP-sugar with stoichiometries of 0.96 +/- 0.05 and 1.01 +/- 0.05 in the deamination and dehydrogenation reactions, respectively, using Na(2)S(2)O(4) as the reductant. Importantly, no significant change in stoichiometry is observed when the flavodoxin/flavodoxin NADP(+) oxidoreductase/NADPH reducing system is used in place of Na(2)S(2)O(4). Moreover, there is no evidence of an uncoupled or abortive process in the deamination reaction, as indicated by the observation that dehydrogenation can take place in the absence of an external source of reductant whereas deamination cannot. Mechanistic and biochemical implications of these results are discussed.


Molecular basis underlying the poly C binding protein 1 as a regulator of the proximal promoter of mouse mu-opioid receptor gene.
Previous studies showed poly C binding protein 1 (PCBP) participating in the mu-opioid receptor (MOR) gene regulation via binding to a single-stranded (ss) DNA element. In this report, we therefore investigate the molecular basis of PCBP regulating the MOR gene expression. Various truncated PCBPs, including one domain (KH1, KH2, variable or KH3), two- (K12, K2v or Kv3) or three-sequential domains (K12v or K2v3), were constructed. The MOR ssDNA binding abilities of these truncated PCBPs were examined using electrophoretic mobility shift assay (EMSA). KH1 domain possessed a strong MOR ssDNA binding activity. Variable domain displayed no binding, and KH2 or KH3 domain possessed a weak MOR ssDNA binding activity. Binding of two-domain PCBPs indicated an additive effect of two-domain combinations. Interestingly, K2v3, a three-domain PCBP, displayed as strong ssDNA binding as that of K12v, suggesting synergism of KH2, KH3 and variable domains for the binding activity. Functional analysis demonstrated one-domain PCBPs exhibiting no transactivation on the MOR proximal promoter. Two-domain PCBPs displayed approximately 20% activity, while three-domain PCBPs displayed 70%-85% of full-length PCBP activity. Taken together, these results suggested that no single domain possessed sufficient functional activity to serve as an independent transactivation domain, and the combination of three sequential domains was necessary for its optimal activity to activate the MOR proximal promoter. In summary, our data suggested that cooperativity of three sequential domains is essential for PCBP functioning as a MOR gene regulator. Various ways in which this cooperativity could occur are discussed.


Concordance rate in cattle and sheep between genotypes differing in Illumina GenCall quality score.
Proper quality control of data prior to downstream analyses is fundamental to ensure integrity of results; quality control of genomic data is no exception. While many metrics of quality control of genomic data exist, the objective of the present study was to quantify the genotype and allele concordance rate between called single nucleotide polymorphism (SNP) genotypes differing in GenCall (GC) score; the GC score is a confidence measure assigned to each Illumina genotype call. This objective was achieved using Illumina beadchip genotype data from 771 cattle (12 428 767 genotypes in total post-editing) and 80 sheep (1 557 360 SNPs genotypes in total post-editing) each genotyped in duplicate. The called genotype with the lowest associated GC score was compared to the genotype called for the same SNP in the same duplicated animal sample but with a GC score of >0.90 (assumed to represent the true genotype). The mean genotype concordance rate for a GC score of <0.300, 0.300-0.549, and ≥0.550 in the cattle (sheep in parenthesis) was 0.9467 (0.9864), 0.9707 (0.9953), and 0.9994 (0.99997) respectively; the respective allele concordance rate was 0.9730 (0.9930), 0.9849 (0.9976), and 0.9997 (0.99998). Hence, concordance eroded as the GC score of the called genotype reduced, albeit the impact was not dramatic and was not very noticeable until a GC score of <0.55. Moreover, the impact was greater and more consistent in the cattle population than in the sheep population. Furthermore, an impact of GC score on genotype concordance rate existed even for the same SNP GenTrain value; the GenTrain value is a statistical score that depicts the shape of the genotype clusters and the relative distance between the called genotype clusters.


LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling.
The liver X receptors (LXRs) are transcriptional regulators of lipid homeostasis that also have potent anti-inflammatory effects. The molecular basis for their anti-inflammatory effects is incompletely understood, but has been proposed to involve the indirect tethering of LXRs to inflammatory gene promoters. Here we demonstrate that the ability of LXRs to repress inflammatory gene expression in cells and mice derives primarily from their ability to regulate lipid metabolism through transcriptional activation and can occur in the absence of SUMOylation. Moreover, we identify the putative lipid transporter Abca1 as a critical mediator of LXR's anti-inflammatory effects. Activation of LXR inhibits signaling from TLRs 2, 4 and 9 to their downstream NF-κB and MAPK effectors through Abca1-dependent changes in membrane lipid organization that disrupt the recruitment of MyD88 and TRAF6. These data suggest that a common mechanism-direct transcriptional activation-underlies the dual biological functions of LXRs in metabolism and inflammation.


Clinical and epidemiological trends in childhood leprosy: A 20-year retrospective analysis from a tertiary care hospital in Jammu, North India.
Background Slightly more than half the total number of childhood leprosy cases worldwide are from India. Aim To analyze the clinical and epidemiological trends of childhood leprosy over 20 years in a tertiary care hospital. Methods We retrieved the medical records of all children less than 15 years of age registered in the leprosy clinic between April 1998 and March 2018. We tabulated and analyzed data pertaining to demographic details along with clinical findings such as cutaneous lesions, nerves involved, sensory loss, deformities, reactions, smear status, histopathology and treatment. Results Out of total 1548 leprosy cases registered during the study period, 55 (3.55%) cases of childhood leprosy were diagnosed. Thirty five (63.6%) children were in the age group of 11-15 years and 83.7% were migrants from other states. Thirteen (23.6%) children reported contact with a diagnosed case of leprosy, mainly in close contacts. Fifty three (96.4%) children presented with cutaneous lesions while 2 (3.6%) had pure neural involvement. Borderline tuberculoid leprosy was the most common clinical presentation in 27 (49.1%) followed by borderline lepromatous leprosy in 11 (18%). Thickened peripheral nerve trunks were detected in 42 (76.4%), most commonly the ulnar nerve. Reactional episodes occurred in 12 (21.8%) cases (Type 1 reaction, 10 (18.2%); Type 2 reaction, 2 (3.6%)). Grade 2 disability was detected in 4 (7.3%). Multidrug therapy was started in all patients, multibacillary (MB) regimen in 42 (76.3%) patients and paucibacillary (PB) regimen in 13 (23.7%). Twenty five (45.4%) children defaulted from the treatment. On comparing the data of 2008-18 with that of the previous decade (1998-2007), there was a higher proportion of migrant cases as compared to local cases (3:1-11:1) and MB cases as compared to PB cases (2:1-6:1). The proportion of treatment defaulters declined from 60% to 36%. Limitations Relapse rate could not be calculated due to inadequate follow-up period. As it is a hospital-based retrospective study with no active surveys, these findings may not reflect trends in the community. Conclusion Childhood leprosy continues to be a significant problem. There is a clear need to strengthen early detection, treatment and regular follow-up of these cases in both high and low endemic settings.


Complications of pediatric cataract surgery.
Cataract surgery in young children poses different challenges and potential complications compared to those encountered in adult populations. We performed a literature review of the complications of pediatric cataract surgery. Literature review of complications of pediatric cataract surgery. Complications in children vary based on the age of the patient at surgery and the cause of the cataract. Common events discussed include increased inflammatory response, opacification of the posterior capsule, lens reproliferation, pupillary membrane, and amblyopia; less common events include infections, significant bleeding, and retinal detachment. Complications after cataract surgery in children are often associated with a robust inflammatory reaction or secondary opacity and, in infants, glaucoma. Late complications can occur decades later, so that long-term follow-up is required. Though surgery carries significant risks, the consequences of no surgery and irreversible deprivation amblyopia in very young children should be considered.


Melanocyte-specific microphthalmia-associated transcription factor isoform activates its own gene promoter through physical interaction with lymphoid-enhancing factor 1.
Waardenburg syndrome type 2 (WS2) is associated with heterozygous mutations in the gene encoding microphthalmia-associated transcription factor (MITF) and characterized by deafness and hypopigmentation due to lack of melanocytes in the inner ear and skin. Melanocyte-specific MITF isoform (MITF-M) is essential for melanocyte differentiation and is transcriptionally induced by Wnt signaling that is mediated by beta-catenin and LEF-1. Here we show that MITF-M transactivates its own promoter (M promoter) by interacting with LEF-1, as judged by transient expression assays and in vitro protein-protein binding assays, whereas no transactivation of the M promoter was detected with MITF-M alone or with the combination of MITF-M and dominant-negative LEF1 that lacks the beta-catenin-binding domain. This synergy depends on the three LEF-1-binding sites that are clustered in the proximal M promoter. Importantly, MITF-M recruited on the M promoter could function as a non-DNA-binding cofactor for LEF-1. Thus, MITF-M may function as a self-regulator of its own expression to maintain a threshold level of MITF-M that is required for melanocyte development. We suggest that MITF-M haploinsufficiency may impair the dosage-sensitive role of MITF-M or the correct assembly of multiple transcription factors, involving MITF-M, on the M promoter, which could account for dominant inheritance of WS2.


The association of histological and radiological indicators of breast cancer risk.
Previous work has shown that extensive mammographic dysplasia in women aged less than 50 was strongly associated with breast cancer but that the radiological appearance of ductal prominence was not associated with risk. In the present paper we examine the association between these mammographic signs in the breast and histological patterns in the terminal ductal lobular unit (TDLU), the region of the breast where breast cancer is believed to originate. Surgical biopsies from a consecutive series of women aged less than 50 were reviewed and classified according to the histopathology of the epithelium in the TDLU. Mammograms from the same subjects were independently classified according to the extent of the radiological signs of dysplasia and ductal prominence. Degree of histopathology and the extent of mammographic dysplasia were associated and atypia of the ductal type was found more frequently in patients with extensive dysplasia. However, the strength and statistical significance of the association varied according to the radiologist who classified the mammograms. No association was found between degree of histopathology and ductal prominence. These results add to the evidence that extensive mammographic dysplasia in women aged less than 50 is a risk factor for breast cancer. They do not indicate that the radiological signs of dysplasia are caused by histological changes in the TDLU.


Building capacity for acute care in developing countries.
The article provides a 'short journey' to neighbours in the Australasian region to highlight some innovation in health policy, rural health education, and professional teams, in developing countries. The innovations are described and challenges discussed.


Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets.
The human serotonin transporter (5-HTT), encoded by a single gene on chromosome 17q11.2, is expressed in brain and blood cells. 5-HTT is implicated in mood and anxiety regulation, and is where antidepressant and antianxiety drugs initially act in the brain. A 5-HTT-linked promoter region (5-HTTLPR) insertion/deletion polymorphism with long (l) and short (s) forms affects transporter expression and function. The s variant reduced 5-HTT gene transcription in a reporter gene construct and human lymphoblasts, resulting in reduced transporter levels and 5-HT uptake, acting as a dominant allele. In this study, we investigated the expression and function of 5-HTT in platelets from healthy male volunteers. The l variant was associated with more rapid initial platelet 5-HT uptake (Vmax), the index of platelet 5-HTT function most clearly heritable, while the s allele was dominant. The 5-HTTLPR genotype had no effect on platelet [3H]paroxetine binding (Bmax), affinity for [3H]5-HT or [3H]paroxetine, or 5-HT content. The 5-HT uptake findings support a functional difference in the two 5-HTTLPR variants, reinforcing their attractiveness as candidate genes in neuropsychiatric research.


Maternal Vitamin D Levels During Pregnancy in Association With Autism Spectrum Disorders (ASD) or Intellectual Disability (ID) in Offspring; Exploring Non-linear Patterns and Demographic Sub-groups.
Increasing vitamin D deficiency and evidence for vitamin D's role in brain and immune function have recently led to studies of neurodevelopment; however, few are specific to autism spectrum disorder (ASD) and vitamin D in pregnancy, a likely susceptibility period. We examined this in a case-control study of 2000-2003 Southern Californian births; ASD and intellectual disability (ID) were identified through the Department of Developmental Services and controls from birth certificates (N = 534, 181, and 421, respectively, in this analysis). Total 25-Hydroxyvitamin D (25(OH)D) was measured in mid-pregnancy serum, categorized as deficient (<50 nmol/L), insufficient (50-74 nmol/L), or sufficient (≥75 nmol/L, referent category), and examined continuously (per 25 nmol/L). Crude and adjusted odds ratios (AORs) and 95% confidence intervals (95% CI) were calculated. Non-linearity was examined with cubic splines. AORs (95% CI) for ASD were 0.79 (0.49-1.3) for maternal deficiency (9.5%), 0.93 (0.68-1.3) for insufficiency (25.6%), and 0.95 (0.86, 1.05) for linear continuous 25(OH)D. Results were similarly null for ASD with or without ID, and ID only. Interactions were observed; non-Hispanic whites (NHW) (AOR = 0.82, 95% CI = 0.69-0.98) and males (AOR = 0.89, 95% CI = 0.80-0.99) had protective associations for ASD with continuous 25(OH)D. A positive association with ASD was observed in females (AOR = 1.40, 95% CI = 1.06-1.85). With splines, a non-linear inverted j-shaped pattern was seen overall (P = 0.009 for non-linearity), with the peak around 100 nmol/L; a non-linear pattern was not observed among NHW, females, nor for ID. Our findings from a large study of ASD and prenatal vitamin D levels indicate that further research is needed to investigate non-linear patterns and potentially vulnerable sub-groups. LAY SUMMARY: We studied whether mothers' vitamin D levels during pregnancy were related to their children having autism (or low IQ) later. Low vitamin D levels were not related to greater risk of autism or low IQ in children overall. With higher levels of mothers' vitamin D, risk of autism went down in boys, but went up in girls. Risk of autism also went down in children of non-Hispanic white mothers with higher vitamin D levels, but we did not find a relation in other race/ethnic groups.


Role of renal DJ-1 in the pathogenesis of hypertension associated with increased reactive oxygen species production.
The D(2) dopamine receptor (D(2)R) is important in the pathogenesis of essential hypertension. We have already reported that systemic deletion of the D(2)R gene in mice results in reactive oxygen species (ROS)-dependent hypertension, suggesting that the D(2)R has antioxidant effects. However, the mechanism of this effect is unknown. DJ-1 is a protein that has antioxidant properties. D(2)R and DJ-1 are expressed in the mouse kidney and colocalize and coimunoprecipitate in mouse renal proximal tubule cells. We hypothesized that D(2)Rs regulate renal ROS production in the kidney through regulation of DJ-1 expression or function. Heterozygous D(2)(+/-) mice have increased blood pressure, urinary 8-isoprostanes, and renal Nox 4 expression, but decreased renal DJ-1 expression. Silencing D(2)R expression in mouse renal proximal tubule cells increases ROS production and decreases the expression of DJ-1. Conversely, treatment of these cells with a D(2)R agonist increases DJ-1 expression and decreases Nox 4 expression and NADPH oxidase activity, effects that are partially blocked by a D(2)R antagonist. Silencing DJ-1 expression in mouse renal proximal tubule cells increases ROS production and Nox 4 expression. Selective renal DJ-1 silencing by the subcapsular infusion of DJ-1 siRNA in mice increases blood pressure, renal Nox4 expression, and NADPH oxidase activity. These results suggest that the inhibitory effects of D(2)R on renal ROS production are at least, in part, mediated by a positive regulation of DJ-1 expression/function and that DJ-1 may have a role in the prevention of hypertension associated with increased ROS production.


Children's knowledge of eating: An integrative review of the literature.
Behaviors associated with eating are often cited as one of many factors contributing to the development of childhood obesity. Behavior is thought to be guided, in part, by personal beliefs and tacit knowledge, which arise from the interpretation of sensory-motor experiences. Tacit knowledge, however, differs from declarative knowledge or the acquisition of factual information attained during formal education. Yet, there are no known publications that review children's and adolescent's tacit and declarative knowledge of eating. The purpose of this integrative review was to examine the evidence regarding children's and adolescents' knowledge of eating. Literature searches were conducted in CINAHL, PsycINFO, Web of Science, and Google Scholar. Selected publications included in the integrative review were empirical studies written in English that described children's and adolescent's knowledge of eating. A total of 548 publications resulted from the searches. Thirty met the inclusion criteria. Preschool-age children understood concepts related to edibleness, nutrition, and digestion as a result of their experiences with food and eating. School-age children and adolescents correctly identified not only facts about food, nutrition, and health, but also factors that influenced their decisions about eating. School-age children and adolescents also expressed concern about their diet, barriers to being healthy, and their appearance. Evidence presented in this integrative review revealed that children, including those of preschool-age, know a great deal about eating. Moreover, the evidence suggests that beliefs and tacit knowledge are more influential in directing eating behaviors than declarative knowledge or knowing facts about food, nutrition, the body, or health. Understanding what children believe and tacitly know about eating will be useful in tailoring interventions to prevent the development of childhood obesity.


An unusually stable G-quadruplex within the 5'-UTR of the MT3 matrix metalloproteinase mRNA represses translation in eukaryotic cells.
MT3-MMP is a matrix metalloproteinase involved in the regulation of cancer cell invasion and metastasis. The MT3-MMP mRNA contains a 20-nucleotide G-rich region (M3Q) upstream of the initiation codon. Herein, we report that the M3Q purine-only sequence forms an extremely stable intramolecular G-quadruplex structure and has an inhibitory role on translation of a reporter gene in eukaryotic cells. The formation of the G-quadruplex structure was indicated by circular dichroism (CD) spectroscopy and enzymatic footprinting with RNase T1. The unusual stability of the G-quadruplex was evidenced when addition of only 1 mM KCl resulted in about a 30 degrees C increase in the melting temperature (T(m)), as compared to that obtained in the absence of added salt. The T(m) was independent of the RNA concentration, suggesting an intramolecular G-quadruplex structure. Additionally, in a dual luciferase reporter assay performed in eukaryotic cells, the M3Q motif present in the context of the entire 5'-UTR of MT3-MMP repressed activity of its downstream gene by more than half. To the best of our knowledge, the naturally occurring M3Q sequence forms one of the most stable, intramolecular RNA G-quadruplexes reported. This report is the first to establish a functional role of a G-quadruplex forming sequence within the MT3-MMP 5'-UTR in the regulation of translation in eukaryotic cells.


Potentiation of human immunoglobulin E synthesis by plasma immunoglobulin E binding factors from patients with the hyperimmunoglobulin E syndrome.
Affinity-purified IgE-binding factors from the plasma of patients with the hyper IgE syndrome (HIE) were assessed for their capacity to enhance IgE synthesis by B cells derived from patients with allergic rhinitis or normal nonatopic donors. IgE-binding factors from three of four HIE patients enhanced IgE synthesis by B cells from patients with perennial allergic rhinitis, or with seasonal allergic rhinitis (SAR) and recent pollen exposure, but did not enhance IgE synthesis by B cells from nonatopic donors or from SAR patients with no recent pollen exposure. IgG synthesis was not affected by HIE IgE binding factors. In contrast, IgE binding factors from three of three nonatopic donors failed to enhance IgE or IgG synthesis. Plasma IgE-binding factors from the fourth patient with HIE contained a mixture of IgE-potentiating activity and IgE-suppressive activity. These two activities could be separated on concanavalin A Sepharose or peanut agglutinin agarose columns. Human IgE potentiating factor, but not IgE suppressive factor, had affinity for concanavalin A but not peanut agglutinin and fractionated into two peaks on gel filtration over Sephadex G-75: one peak with a molecular size of approximately 15,000 D and the other with a molecular size of approximately 60,000 D. The isolation of functional IgE binding factors which potentiate IgE synthesis from the plasma of patients with HIE suggests that IgE-binding factors play an important role in the in vivo regulation of IgE synthesis in man.


Extracellular αB-crystallin modulates the inflammatory responses.
Neuroinflammation is considered a challenging clinical problem. Chronic inflammatory responses play important roles in the onset and progression of various neurodegenerative diseases, including multiple sclerosis (MS). Previous studies have shown that astrocytes express small heat shock protein αB-crystallin (CRYAB) which is capable of inhibiting inflammatory responses in astrocytes per se. However, the underlying mechanisms of CRYAB-induced modulation of neuroinflammation are still not fully understood. In the present study, we investigated the role of extracellular CRYAB in the interaction between microglia and astrocytes in the context of MS-associated neuroinflammation. We found that the expression of CRYAB was profoundly increased in EAE mice. CRYAB was preferentially expressed in astrocytes and could be secreted via exosomes. Levels of exosomal CRYAB secreted from astrocytes were markedly increased under stress conditions. Furthermore, incubation of immortalized astrocytes or microglia cell lines with CRYAB remarkably suppressed astrocytes and microglia-mediated inflammatory responses in both autocrine and paracrine manners. Our results reveal a novel function for extracellular CRYAB in the regulation of neuroinflammation. Targeting extracellular CRYAB-modulated neuroinflammation is a potential therapeutic intervention for MS.


c-Jun N-terminal kinase activation responses induced by hippocampal kindling are mediated by reactive astrocytes.
Hippocampal kindling, a model of mesial temporal lobe epilepsy, is developed through repetitive stimulation of the hippocampus and leads to increased after-discharges as measured by EEG and an enduring seizure-prone state. Synthesis of new proteins is thought to form the basis for sustained seizure-induced physiological and/or pathological changes in synaptic reorganization and apoptotic/necrotic neuronal death. Here we examined the effect of kindling on stimulus-induced c-Jun N-terminal kinase (JNK) and p38 phosphorylation, events postulated to lie upstream of seizure-induced changes in gene transcription. We found that stimulus-induced phosphorylation of JNK, but not of p38, is significantly enhanced in kindled animals compared with their naive counterparts in the CA1 subregion of the hippocampus. Immunofluorescent staining confirmed this region-specific pattern of JNK activation and revealed that reactive astrocytes mediate this effect. Astrocyte proliferation and hypertrophy, as well as upregulation of vimentin protein levels, common markers of astrogliosis, were present after 4 d of kindling. Moreover, this reactive astrogliosis was associated with neuronal death as visualized with Fluoro-jade B and anti-active caspase-3 staining. Stimulus-induced phosphorylation of the JNK substrate paxillin was enhanced in kindled animals, but not that of c-Jun. Moreover, a pan-antibody against MAPK/CDK (mitogen-activated protein kinases/cyclin-dependent kinase) substrates indicated the presence of phosphorylated proteins in cytosolic, membrane, and nuclear fractions. The consequence of these phosphorylation events is not completely understood, but these findings suggest a selective astrocytic signaling response to aberrant synaptic activity, signaling that may modulate kindling progression and/or neuronal death.


Efficacy of topical griseofulvin in treatment of tinea corporis.
Tinea infections are among the most common dermatological conditions throughout the world. Griseofulvin is a classical oral fungistatic antibiotic, active against Epidermophyton floccosum, Trichophyton and Microsporum species, the causative fungi of tinea corporis. To evaluate the efficacy of topical griseofulvin in the treatment of tinea circinata using three different vehicles for drug delivery. Sixteen patients with tinea circinata were instructed to apply either griseofulvin gel form in group A or a similar placebo gel for control group; a niosomal gel formulation of griseofulvin for group B or; a liposomal gel formulation of griseofulvin for group C. Patients were evaluated both clinically and mycologically after 3 weeks. Marked improvement was seen for groups A, B and C both clinically and mycologically while no improvement was observed in the placebo group. Mild and transient irritation was reported in four patients. Our results show that topical griseofulvin preparations may be effective and safe in treating tinea circinata and that further large-scale studies may establish the high efficacy of the niosomal gel formulation.


The managed care contract: the blueprint for monitoring agreements.
Healthcare providers generally undertake monitoring programs of managed care arrangements as a way of analyzing financial performance, uncovering lapses in contractually mandated performance that might expose the organization to financial loss, and gathering information that can be helpful in renegotiating the contract or negotiating new arrangements. To secure access to the information needed to achieve these goals, the provider should ensure that the contract spells out the information required, the health plan's obligations to supply this information, and the consequences of the plan's failure to meet those obligations. Such consequences may include financial penalties for the plan and special termination rights for the provider. Without a contractually explicit assurance that the needed information will be available, a provider may find itself with no way to achieve its contract-monitoring goals.


Transcriptome and Metabolome Analyses Provide Insights into the Stomium Degeneration Mechanism in Lily.
Lily (Lilium spp.) is a widely cultivated horticultural crop that has high ornamental and commercial value but also the serious problem of pollen pollution. However, mechanisms of anther dehiscence in lily remain largely unknown. In this study, the morphological characteristics of the stomium zone (SZ) from different developmental stages of 'Siberia' lily anthers were investigated. In addition, transcriptomic and metabolomic data were analyzed to identify the differentially expressed genes (DEGs) and secondary metabolites involved in stomium degeneration. According to morphological observations, SZ lysis occurred when flower buds were 6-8 cm in length and was completed in 9 cm. Transcriptomic analysis identified the genes involved in SZ degeneration, including those associated with hormone signal transduction, cell structure, reactive oxygen species (ROS), and transcription factors. A weighted co-expression network showed strong correlations between transcription factors. In addition, TUNEL (TdT-mediated dUTP nick-end labeling) assays showed that programmed cell death was important during anther SZ degeneration. Jasmonates might also have key roles in anther dehiscence by affecting the expression of the genes involved in pectin lysis, water transport, and cysteine protease. Collectively, the results of this study improve our understanding of anther dehiscence in lily and provide a data platform from which the molecular mechanisms of SZ degeneration can be revealed.


The hazards of hypercaloric nutritional support in respiratory disease.
This case illustrates the dangers of hypercaloric feeding in a patient with limited respiratory reserve, in this instance secondary to heart-lung transplantation. The patient's postoperative course was complicated by repeated bouts of infection and/or rejection that resulted in intubation and ventilatory support. The excessive caloric and protein load given to the patient resulted in increased CO2 generation with subsequent inability to wean the patient off the ventilator. Recognition of the problem and appropriate decreases in substrate intake permitted extubation.


A metalloporphyrin superoxide dismutase mimetic protects against paraquat-induced lung injury in vivo.
We employed a low-molecular-weight metalloporphyrin superoxide dismutase mimetic, MnTBAP, to protect mice against a known pulmonary toxicant, paraquat. Paraquat creates toxicity by elevating intracellular levels of superoxide through redox cycling with cellular diaphorases and oxygen. In vitro, paraquat-induced cell injury can be attenuated by MnTBAP. We assessed whether inhaled MnTBAP would protect whole animals from a single i.p. dose of paraquat. Mice were given either saline (10 ml/ kg, i.p.) or paraquat (45 mg/kg, i.p.) and 30 min later exposed to aerosolized saline or MnTBAP (5 mM) for 30 min twice daily. Mice were killed 48 hr after paraquat treatment. Lung injury was assessed by measuring lactate dehydrogenase (LDH), protein, and percentage polymorphonuclear leukocytes (PMN) in bronchoalveolar lavage (BAL) fluid and by histopathology. Paraquat treatment increased levels of BAL fluid LDH, protein, and number of PMNs and produced extensive blebbing of the type I epithelium. MnTBAP reduced lung injury as indicated by lower LDH levels, protein levels, and PMN influx in BAL fluid. This correlated with the reduction of type I epithelial damage in the group of mice that received paraquat. These data suggest that metalloporphyrins may be effective therapeutic agents against pathologies that involve overproduction of reactive oxygen species.


Isolation and Characterization of Protein Bodies in Lupinus angustifolius.
Using Nycodenz, a novel density gradient medium, we isolated intact protein bodies from developing seeds of Lupinus angustifolius L. (cultivar Unicrop) and achieved excellent separation from the endoplasmic reticulum, mitochondria, and other organelles. The distribution of the storage protein conglutin-beta was taken as evidence that up to 96% of the protein bodies remained intact on the gradients and banded at 1.25 grams per milliliter. The protein bodies also contained the three other abundant proteins present in L. angustifolius seeds: conglutins-alpha, -gamma, and -delta. Pulse labeling experiments were carried out to determine the site of proteolytic processing of conglutin-alpha, a legumin-like 11Svedberg unit storage protein. Cotyledons aged either 33 or 40 days after flowering were pulsed with [(3)H]leucine. Protein bodies obtained from the cotyledons aged 33 days after flowering contained only the labeled precursors of conglutin-alpha with molecular weights 85,000, 72,000, and 64,000, even after a 4 hour chase of the radioactivity. Protein bodies obtained from the cotyledons aged 40 days after flowering contained the same radioactive precursors if the tissue had been pulsed for 2 hours, and the processing products of these precursors when the tissue had been chased for 4 hours. These studies confirm that the subcellular location of proteolytic cleavage of this legumin-like protein is the protein body, that this activity is detected only in protein bodies from lupin seeds aged between 33 and 40 days of seed development after flowering and that protein bodies from seeds younger than this contain only unprocessed conglutin-alpha.


Area measurement at long-distance using a circular Dammann grating.
We describe a novel method of noncontact mode area measurement at long distance of 11.25 m by borrowing the concept of a circular Dammann grating (CDG). The area of objects can be determined accurately by measuring the circular spectrum diameter of the CDG. This noncontact mode measurement requires neither a large amount of image data nor any pattern recognition approach. The spectrum diameter is derived from simple lens formulas. From the fractional Fourier transform, we find that there exists a linear relationship between the spectrum diameter and the distance traveled by the CDG. Compared with the conventional methods, this technique has the advantages of a simple design with good accuracy of better than 3%, low cost, noncontact mode, and a more compact design. Finally, we present several experimental results demonstrating the effectiveness of this system.


Sgp3 and Sgp4 control expression of distinct and restricted sets of xenotropic retroviruses encoding serum gp70 implicated in murine lupus nephritis.
The envelope glycoprotein gp70 of endogenous retroviruses implicated in murine lupus nephritis is secreted by hepatocytes and its expression is controlled by Sgp3 (serum gp70 production 3) and Sgp4 loci derived from lupus-prone mice. Among three different endogenous retroviruses (ecotropic, xenotropic and polytropic), xenotropic viruses are considered to be the major source of serum gp70. Although the abundance of xenotropic viral gp70 RNA in livers was up-regulated by the presence of these two Sgp loci, it has not yet been clear whether Sgp3 and Sgp4 regulate the expression of a fraction or multiple xenotropic viruses present in mouse genome. To address this question, we determined the genetic origin of xenotropic viral sequences expressed in wild-type and two different Sgp congenic C57BL/6 mice. Among 14 xenotropic proviruses present in the C57BL/6 genome, only two proviruses (Xmv10 and Xmv14) were actively transcribed in wild-type C57BL/6 mice. In contrast, Sgp3 enhanced the transcription of Xmv10 and induced the transcription of three additional xenotropic viruses (Xmv15, Xmv17 and Xmv18), while Sgp4 induced the expression of a different xenotropic virus (Xmv13). Notably, stimulation of TLR7 in Sgp3 congenic C57BL/6 mice led to a highly enhanced expression of potentially replication-competent Xmv18. These results indicated that Sgp3 and Sgp4 independently regulated the transcription of distinct and restricted sets of xenotropic viruses in trans, thereby promoting the production of nephritogenic gp70 autoantigens. Furthermore, the induced expression of potentially replication-competent xenotropic viruses by Sgp3 may contribute to the development of autoimmune responses against gp70 through the activation of TLR7.


[The indices of pro- and antioxidant state of the gastro-esophageal junction tissues in experimental gastroesophageal reflux disease].
Experimental investigation on studying of pro- and antioxidant state in esophageal tissues was performed. It was established, that accumulation of products of the proteins and lipids oxidation during inflammatory process course coincides with significant lowering of the antioxidant enzymes activity. The data obtained trusts the various diagnostic significance of diienic conjugates and malonic dialdehyde (MDA) levels. The increase of MDA concentration as well as of products of the oxidational modifications proteins, owing basic character, was revealed as a typical biochemical marker of acid-peptic injury of esophageal tissues.


Pearls & Oy-sters: Familial Verbal Auditory Agnosia Due to C9orf72 Repeat Expansion.
Chromosome 9 open reading frame 72 (C9orf72) gene pathogenic variants have been typically associated with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), but recent studies suggest their involvement in other disorders. This report describes a family with an autosomal dominant pattern of inheritance of progressive verbal auditory agnosia due to GGGGCC repeat expansion in C9orf72. A 60-year-old right-handed male truck driver presented with slowly progressive poor speech perception for 8 years, which became most troublesome when receiving verbal orders over the phone. He had difficulty recognizing single-syllable spoken words beyond his hearing loss but had no problem understanding complex written language. He had a heterozygous pathogenic variant carrying 160 hexanucleotide repeats in the C9orf72 gene. His family history included his deceased mother with similar symptoms that had progressed over 30 years, as well as his older brother and youngest sister who experienced speech perception difficulty beginning in their early fifties. His asymptomatic younger brother had a heterozygous 2 repeat in the C9orf72 gene, while his symptomatic youngest sister had a heterozygous 159 repeat. The patient and his sister exhibited more pronounced cortical thinning in the frontotemporoparietal areas. The discrepancy observed between the distribution of atrophy and the presentation of symptoms in patients with C9orf72 pathogenic repeat expansion may be attributable to the slow progression of their clinical course over time. The variable symptom presentation of C9orf72 pathogenic repeat expansion highlights the importance of considering this pathogenic variant as a potential cause of autosomal dominant degenerative brain diseases beyond FTD and ALS.


Dose-response relationship between urinary cadmium concentration and beta2-microglobulinuria using logistic regression analysis.
Logistic regression analysis was used to investigate the dose-response relationship for environmental cadmium exposure and to consider the effect age had on this association. The target population comprised 3178 inhabitants of Japan who were more than 50 y of age and who lived in a cadmium-polluted area and 1134 inhabitants who lived in nonpolluted areas of Japan. Logistic regression analysis was completed on the dose-response relationship between urinary cadmium concentration (i.e., an indicator of cadmium body burden) and beta2-microglobulinuria (i.e., an index of renal tubular dysfunction caused by exposure to cadmium). Both age and urinary cadmium concentration were associated significantly with beta2-microglobulinuria. Based on the relationship that was determined, we calculated, by age and sex, the values of urinary cadmium concentration that corresponded to the prevalence rates of beta2-microglobulinuria in the nonpolluted population. The resulting values were 1.6-3.0 micrograms/g creatinine for men and 2.3-4.6 micrograms/g creatinine for women.


Production of recombinant bovine lactoferrin N-lobe in insect cells and its antimicrobial activity.
Lactoferrin is a multifunctional, iron-binding glycoprotein found in physiological fluids of mammals. In the present study, a gene encoding the N-terminal half (N-lobe) of bovine lactoferrin was cloned and expressed in cultured insect cells using a baculovirus expression system. One mutation was found in the lactoferrin N-lobe gene, but it resulted in no amino acid substitution. The recombinant lactoferrin N-lobe was secreted into the culture medium and partially purified by means of an immobilized heparin column. The recombinant lactoferrin N-lobe secreted was not glycosylated, but it possessed antimicrobial activity toward Escherichia coli O111. The recombinant product synthesized and accumulated in the host cells exhibited greater electrophoretic mobility on SDS-PAGE than the secreted product and showed no potency to inhibit the growth of bacteria. It is thought that the product accumulated intracellularly lacks antimicrobial ability due to its degradation in the host cells or due to disruption of the active conformation.


Recent Insights into the pathogenesis of pre-eclampsia.
Pre-eclampsia is more than pregnancy induced hypertension. The emerging view described in this presentation is that pre-eclampsia is secondary to the interactions of reduced placental perfusion with diverse maternal factors that alter endothelial function. The maternal contribution is from factors that antedate pregnancy and are influenced by the usual metabolic adaptations of pregnancy. The endothelium and other targets for the effects of these interactions are more sensitive to insults during pregnancy because of activation of the inflammatory cascade as a normal part of pregnancy. At least part of the response to reduced placental perfusion may be a fetal adaptive response to attempt to overcome the reduced delivery of nutrients. A reasonable convergence point for the interaction is at the level of oxidative stress. This hypothesis has both encouraging and discouraging corollaries. The diversity of maternal factors argues that there will be no single gene to explain the disorder and no single 'magic bullet' to treat the disorder. However, it is encouraging that the recognition of maternal predisposition to the disorder directs therapy to prevent pre-eclampsia at a specific target in subsets of women. Finally, the suggestion that some of the maternal alterations are due to fetal adaptive responses encourages careful choices of agents and meticulous infant follow up in well planned clinical trials.


Cloning, expression, and sequence analysis of the three genes encoding quinoline 2-oxidoreductase, a molybdenum-containing hydroxylase from Pseudomonas putida 86.
The three genes coding for quinoline 2-oxidoreductase (Qor) of Pseudomonas putida 86 were cloned and sequenced. The qor genes are clustered in the transcriptional order medium (M) small (S), large (L) and code for three subunits of 288 (QorM), 168 (QorS), and 788 (QorL) amino acids, respectively. Formation of active quinoline 2-oxidoreductase and degradation of quinoline occurred in a recombinant P. putida KT2440 clone. The amino acid sequences of Qor show significant homology to various prokaryotic molybdenum containing hydroxylases and to eukaryotic xanthine dehydrogenases. QorS contains two conserved motifs for [2Fe-2S] clusters. The binding motif for the N-terminal [2Fe-2S] cluster corresponds to the binding site of bacterial and chloroplast-type [2Fe-2S] ferredoxins, whereas the amino acid pattern of the internal [2Fe-2S] center apparently is a distinct feature of molybdenum-containing hydroxylases, showing no homology to any other described [2Fe-2S] binding motif. The medium subunit QorM presumably contains the FAD, but no conserved sequence areas or described motifs of FAD, NAD, NADP, or ATP binding were detected. Putative binding sites of the molybdopterin cytosine dinucleotide cofactor were detected in QorL by comparison with "contacting segments" recently described in aldehyde oxidoreductase from Desulfovibrio gigas (Romão, M. J., Archer, M., Moura, I., Moura, J. J. G., LeGall, J., Engh, R., Schneider, M., Hof, P., and Huber, R. (1995) Science 270, 1170-1176).


Periorbital skin tightening with a broadband infrared device: preliminary study results.
Periorbital rhytids are often the first signs of aging skin for which young patients seek a non-invasive, no downtime treatment. Recently, several skin-tightening modalities based on deep dermal heating with various energy sources, such as monopolar and bipolar radiofrequency, as well as laser and broadband infrared light sources, have been introduced to treat mild wrinkles and skin laxity. This report presents preliminary study results using a new infrared device for the treatment of periorbital rhytids on 11 volunteer patients.


Tumor metabolism to blood flow ratio in pancreatic cancer: helpful in patient stratification?
Evaluation of: Komar G, Kauhanen S, Liukko K et al.: Decreased blood flow with increased metabolic activity: a novel sign of pancreatic tumor aggressiveness. Clin. Cancer Res. 15(17), 5511-5517 (2009). Novel methods in assessing pancreas cancer vascularization and metabolism are urgently needed for pretherapeutic patient stratification. Recently, noninvasive quantification of blood flow and metabolic activity of pancreatic tumors using [(15)O]H(2)O and [(18)F] fluorodeoxyglucose positron emission tomography/computed tomography imaging has been demonstrated to be a promising approach to assess these parameters. This also implied that high tumor metabolism and low blood flow (and thus probably also low tissue oxygenation) are linked with an aggressive cancer phenotype, and potentially reflect treatment resistance. Furthermore, such functional imaging might prove clinically that pancreatic cancer differs from other gastrointestinal cancer in its desmoplastic reaction and hypovascularity, which might well explain the enormous heterogeneity in treatment sensitivity. Therefore, determination of the metabolism to blood flow ratio could help in the decision on which (additional) chemotherapies or targeted agents to administer to a particular patient. Chemoresistance in pancreatic cancer might thus be regarded, at least in part, as a result of low drug delivery to the tumor cells, which is a consequence of a hypoxic environment contributing to the stromal reaction, rather than epithelial tumor cell resistance itself.


Genome-wide analysis of structural variants reveals genetic differences in Chinese pigs.
Pigs have experienced long-term selections, resulting in dramatic phenotypic changes. Structural variants (SVs) are reported to exert extensive impacts on phenotypic changes. We built a high resolution and informative SV map based on high-depth sequencing data from 66 Chinese domestic and wild pigs. We inferred the SV formation mechanisms in the pig genome and used SVs as materials to perform a population-level analysis. We detected the selection signals on chromosome X for northern Chinese domestic pigs, as well as the differentiated loci across the whole genome. Analysis showed that these loci differ between southern and northern Chinese domestic pigs. Our results based on SVs provide new insights into genetic differences in Chinese pigs.


In vivo monitoring of quantum dots in the extracellular space using push-pull perfusion sampling, online in-tube solid phase extraction, and inductively coupled plasma mass spectrometry.
To monitor the dynamic changes of extracellular quantum dots (QDs) in vivo in the livers of anesthetized rats, we developed an automatic online analytical system comprising push-pull perfusion (PPP) sampling, the established in-tube solid phase extraction (SPE) procedure, and inductively coupled plasma mass spectrometry (ICPMS). The method takes advantage of the retention of QDs onto the interior surface of a polytetrafluoroethylene (PTFE) tube as a means of extracting the QDs from complicated push-pull perfusates. For the injected QDs present in the liver extracellular fluid (ECF) at low picomolar levels, a temporal resolution of 10 min was required to collect sufficient amounts of QDs to meet the sensitivity requirements of the ICPMS system. To the best of our knowledge, this study is the first to exploit the PPP technique for the collection of QDs from living animals and PTFE tubing as a SPE adsorbent for the online extraction of QDs and the removal of biological matrix prior to ICPMS analysis of cadmium-containing inorganic nanocrystal. We confirmed the analytical reliability of this method from measurements of the spike recoveries of saline samples; in addition, we demonstrated the systems' applicability through in vivo monitoring of the time-dependent concentration profile of liver extracellular QDs in living rats after intravenous administration.


Modified gamma-cyclodextrins and their rocuronium complexes.
A series of per-6-substituted cyclodextrin derivatives was synthesized as synthetic host molecules for rocuronium, a steroidal muscle relaxant. By forming host-guest complexes with rocuronium, these cyclodextrin derivatives reverse the muscle relaxation induced by rocuronium in vitro and in vivo. The isothermal microcalorimetry data are consistent with the biological data supporting the encapsulation mechanism of action. Binary and biphasic complexes are reported with NMR experiments clearly showing free and bound rocuronium. [structure: see text]


Intraoperative 360-deg three-dimensional transvaginal ultrasound during needle insertions for high-dose-rate transperineal interstitial gynecologic brachytherapy of vaginal tumors.
Brachytherapy, a type of radiotherapy, may be used to place radioactive sources into or in close proximity to tumors, providing a method for conformally escalating dose in the tumor and the local area surrounding the malignancy. High-dose-rate interstitial brachytherapy of vaginal tumors requires precise placement of multiple needles through holes in a plastic perineal template to deliver treatment while optimizing dose and avoiding overexposure of nearby organs at risk (OARs). Despite the importance of needle placement, image guidance for adaptive, intraoperative needle visualization, allowing misdirected needles to be identified and corrected during insertion, is not standard practice. We have developed a 360-deg three-dimensional (3-D) transvaginal ultrasound (TVUS) system using a conventional probe with a template-compatible custom sonolucent vaginal cylinder and propose its use for intraoperative needle guidance during interstitial gynecologic brachytherapy. We describe the 3-D TVUS mechanism and geometric validation, present mock phantom procedure results, and report on needle localization accuracy in patients. For the six patients imaged, landmark anatomical features and all needles were clearly visible. The implementation of 360-deg 3-D TVUS through a sonolucent vaginal cylinder provides a technique for visualizing needles and OARs intraoperatively during interstitial gynecologic brachytherapy, enabling implants to be assessed and providing the potential for image guidance.


Essential role of caveolae in interleukin-6- and insulin-like growth factor I-triggered Akt-1-mediated survival of multiple myeloma cells.
Caveolae, specialized flask-shaped lipid rafts on the cell surface, are composed of cholesterol, sphingolipids, and structural proteins termed caveolins; functionally, these plasma membrane microdomains have been implicated in signal transduction and transmembrane transport. In the present study, we examined the role of caveolin-1 in multiple myeloma cells. We show for the first time that caveolin-1, which is usually absent in blood cells, is expressed in multiple myeloma cells. Analysis of myeloma cell-derived plasma membrane fractions shows that caveolin-1 is co-localized with interleukin-6 receptor signal transducing chain gp130 and with insulin-like growth factor-I receptor. Cholesterol depletion by beta-cyclodextrin results in the loss of caveola structure in myeloma cells, as shown by transmission electron microscopy, and loss of caveolin-1 function. Interleukin-6 and insulin-like growth factor-I, growth and survival factors in multiple myeloma, induce caveolin-1 phosphorylation, which is abrogated by pre-treatment with beta-cyclodextrin. Importantly, inhibition of caveolin-1 phosphorylation blocks both interleukin-6-induced protein complex formation with caveolin-1 and downstream activation of the phosphatidylinositol 3-kinase/Akt-1 pathway. beta-Cyclodextrin also blocks insulin-like growth factor-I-induced tyrosine phosphorylation of insulin-responsive substrate-1 and downstream activation of the phosphatidylinositol 3-kinase/Akt-1 pathway. Therefore, cholesterol depletion by beta-cyclodextrin abrogates both interleukin-6- and insulin-like growth factor-I-triggered multiple myeloma cell survival via negative regulation of caveolin-1. Taken together, this study identifies caveolin-1 and other structural membrane components as potential new therapeutic targets in multiple myeloma.


Comparison of the profiles of agonists as stimulants of the beta 3-adrenoceptor in vitro with their gastroprotective effects in the conscious rat.
1. This paper compares the activity of a range of agonists as stimulants of the beta 3-adrenoceptor in rat isolated oesophagus with their ability to afford protection against indomethacin-induced gastric damage in the conscious rat. 2. The beta 3-adrenoceptor agonists, CL 316243 and BRL 37344, the non-selective beta-adrenoceptor agonist, isoprenaline and the selective beta 2-adrenoceptor agonist, salmeterol, all evoked concentration-dependent relaxation of precontracted muscularis mucosa from rat oesophagus. The rank order of agonist potency was BRL 37344 > CL 316243 > isoprenaline >> salmeterol. The selective beta 1-adrenoceptor agonist, denopamine, did not relax the preparation. 3. The relaxant responses to all agonists were resistant to blockade by atenolol (10 microM), and ICI 118551 (1 microM) thus suggesting that they were not mediated by either beta 1- or beta 2-adrenoceptor stimulation. In contrast, cyanopindolol and propranolol did inhibit responses to BRL 37344, CL 316243 and isoprenaline, giving pA2 values or pKB estimates which were consistent with an interaction at beta 3-adrenoceptors (i.e. approximately 8.0 and 6.5 respectively). However, responses to salmeterol were resistant to blockade by all the antagonists tested, which suggests that the high (> 1 microM) concentrations of salmeterol used exerted non-specific relaxant effects. 4. The agonist effects of CL 316243 and BRL 37344 on beta 1- and beta 2-adrenoceptors were assessed on guinea-pig right atrium and precontracted trachea respectively. Both agonists had minimal activity as stimulants of heart rate, but did relax trachea, being 380 (CL 316243) and 21 (BRL 37344) fold less potent than isoprenaline. 5. CL 316243 and BRL 37344 were potent inhibitors of indomethacin-induced gastric antral ulceration in the conscious rat (ED50 values = 0.24 and 0.09 mumol kg-1, p.o.) Salmeterol was approximately 100 times less potent than BRL 37344 as a gastroprotective agent and denopamine was without effect. 6. The gastroprotective effects of CL 316243 and BRL 37344 were resistant to blockade by ICI 118551 (10 mg kg-1, p.o.) and propranolol (10 mg kg-1, p.o.). In contrast, both antagonists caused dose-related inhibition of the protective action of salmeterol (10 mg kg-1, p.o.). Cyanopindolol was not assessed as an antagonist in vivo because preliminary experiments revealed that it exacerbated indomethacin-induced gastric damage in its own right. 7. In conclusion, the beta 3-adrenoceptor agonists CL 316243 and BRL 37344 were potent inhibitors of indomethacin-induced gastric antral ulceration in the rat. These data suggest that an agonist which is potent and selective for the human beta 3-adrenoceptor may confer mucosal protection in man.


Model selection based on combined penalties for biomarker identification.
The growing role of targeted medicine has led to an increased focus on the development of actionable biomarkers. Current penalized selection methods that are used to identify biomarker panels for classification in high-dimensional data, however, often result in highly complex panels that need careful pruning for practical use. In the framework of regularization methods, a penalty that is a weighted sum of the L1 and L0 norm has been proposed to account for the complexity of the resulting model. In practice, the limitation of this penalty is that the objective function is non-convex, non-smooth, the optimization is computationally intensive and the application to high-dimensional settings is challenging. In this paper, we propose a stepwise forward variable selection method which combines the L0 with L1 or L2 norms. The penalized likelihood criterion that is used in the stepwise selection procedure results in more parsimonious models, keeping only the most relevant features. Simulation results and a real application show that our approach exhibits a comparable performance with common selection methods with respect to the prediction performance while minimizing the number of variables in the selected model resulting in a more parsimonious model as desired.


Low-density granulocytes: functionally distinct, immature neutrophils in rheumatoid arthritis with altered properties and defective TNF signalling.
Our aim was to determine whether rheumatoid arthritis (RA) low-density granulocytes (LDGs) are functionally different from RA neutrophils. LDGs from 32 RA patients were characterized using flow cytometry and quantitative PCR (qPCR). RNA sequencing (RNA-Seq) was carried out on paired RA LDGs and neutrophils (n = 4) and validated using qPCR. Functional assays included chemotaxis, phagocytosis, reactive oxygen species (ROS) production, cell-cycle analysis, apoptosis, neutrophil extracellular trap (NET)osis, and measurement of cytokine production (n ≥ 5 paired RA LDGs/neutrophils). RA LDGs had a substantially altered transcriptome, expressing >5000 genes at significantly different levels compared with RA neutrophils, including elevated levels of transcripts for granule proteins [including elastase and myeloperoxidase (MPO)] and cell-cycle genes [including cyclin-dependent kinase (CDK)2, CDK4, and CDK6]. Approximately 1% of RA LDGs stained positive for the G2/S phase of the cell cycle. RA LDGs had a significantly lower constitutive rate of apoptosis compared with RA neutrophils and did not respond to TNF-α in culture. Expression of transcripts for cytokines and cytokine receptors was lower in RA LDGs. NET formation was lower in LDGs in response to PMA compared with RA neutrophils. Chemotaxis and phagocytosis was lower in RA LDGs compared with neutrophils. RA LDGs produced significantly lower amounts of ROS in response to fMLP following priming with TNF-α. Expression of TNFR1 and -2 mRNA and protein was significantly lower in LDGs. We conclude that RA LDGS are functionally different from RA neutrophils, representing an immature neutrophil population within peripheral blood. Their enhanced survival properties and decreased TNF signaling are likely to have important consequences for disease pathology and response to therapy.


Heterogeneous expression of glycoconjugates in the primary olfactory centre of the Japanese sword-tailed newt (Cynops ensicauda).
Histochemical organization of the Caudata olfactory system remains largely unknown, despite this amphibian order showing phylogenetic diversity in the development of the vomeronasal organ and its primary centre, the accessory olfactory bulb. Here, we investigated the glycoconjugate distribution in the olfactory bulb of a semi-aquatic salamander, the Japanese sword-tailed newt (Cynops ensicauda), by histochemical analysis of the lectins that were present. Eleven lectins showed a specific binding to the olfactory and vomeronasal nerves as well as to the olfactory glomeruli. Among them, succinylated wheat germ agglutinin (s-WGA), soya bean agglutinin (SBA), Bandeiraea simplicifolia lectin-I (BSL-I) and peanut agglutinin showed significantly different bindings to glomeruli between the main and accessory olfactory bulbs. We also found that s-WGA, SBA, BSL-I and Pisum sativum agglutinin preferentially bound to a rostral cluster of glomeruli in the main olfactory bulb. This finding suggests the presence of a functional subset of primary projections to the main olfactory system. Our results therefore demonstrated a region-specific glycoconjugate expression in the olfactory bulb of C. ensicauda, which would be related to a functional segregation of the olfactory system.


The Role of Extracellular Binding Proteins in the Cellular Uptake of Drugs: Impact on Quantitative In Vitro-to-In Vivo Extrapolations of Toxicity and Efficacy in Physiologically Based Pharmacokinetic-Pharmacodynamic Research.
A critical component in the development of physiologically based pharmacokinetic-pharmacodynamic (PBPK/PD) models for estimating target organ dosimetry in pharmacology and toxicology studies is the understanding of the uptake kinetics and accumulation of drugs and chemicals at the cellular level. Therefore, predicting free drug concentrations in intracellular fluid will contribute to our understanding of concentrations at the site of action in cells in PBPK/PD research. Some investigators believe that uptake of drugs in cells is solely driven by the unbound fraction; conversely, others argue that the protein-bound fraction contributes a significant portion of the total amount delivered to cells. Accordingly, the current literature suggests the existence of a so-called albumin-mediated uptake mechanism(s) for the protein-bound fraction (i.e., extracellular protein-facilitated uptake mechanisms) at least in hepatocytes and cardiac myocytes; however, such mechanism(s) and cells from other organs deserve further exploration. Therefore, the main objective of this present study was to discuss further the implication of potential protein-facilitated uptake mechanism(s) on drug distribution in cells under in vivo conditions. The interplay between the protein-facilitated uptake mechanism(s) and the effects of a pH gradient, metabolism, transport, and permeation limitation potentially occurring in cells was also discussed, as this should violate the basic assumption on similar free drug concentration in cells and plasma. This was made because the published equations used to calculate drug concentrations in cells in a PBPK/PD model did not consider potential protein-facilitated uptake mechanism(s). Consequently, we corrected some published equations for calculating the free drug concentrations in cells compared with plasma in PBPK/PD modeling studies, and we proposed a refined strategy for potentially performing more accurate quantitative in vitro-to-in vivo extrapolations (IVIVEs) of toxicity (efficacy) at the cellular level from data generated in cell assays. Overall, this present study may help to optimize the human dose prediction in preclinical and clinical studies, while prescribing drugs with narrow therapeutic windows that are highly bound to extracellular proteins and/or highly ionized at the physiological pH. This may facilitate building a more accurate safety (efficacy) profile for such drugs.


The effect of illusionary perception on mismatch negativity (MMN): An electroencephalography study.
Mismatch negativity (MMN) is a unique brain response elicited by any discernible change of features in a tone sequence. Although the occurrence of MMN is dependent upon the difference of a stimulus parameter, such as frequency or intensity, recent studies have suggested that MMN occurs as a result of a comparison between an internal representation created by perception and an incoming tone. The present study aimed to investigate MMN occurs based upon the physical properties of stimuli or as a result of the perception of the scale illusion. A scale illusion occurs during presentation of ascending and descending musical scales between C4 and C5. The tones of these scales are presented to the right and left ear alternately using a dichotic listening paradigm. Although the ascending/descending sequences are alternated between ears after each tone, we perceive the illusion of progressively ascending/descending tones as being separated by ear. The experiment was designed as an oddball task using the illusionary sequence and three different types of tone sequences as control conditions. Brain response to these sequences and infrequently presented deviants was measured using electroencephalography (EEG). All of the control sequences showed MMN in response to the deviant. However, the illusionary sequence did not result in a significant MMN. These results suggest that in the case of scale illusion, the occurrence of MMN is based upon the representation of tones created by perception, but not upon the physical properties of a tone sequence.


Improved Retention With 6-Month Clinic Return Intervals for Stable Human Immunodeficiency Virus-Infected Patients in Zambia.
Extending appointment intervals for stable HIV-infected patients in sub-Saharan Africa can reduce patient opportunity costs and decongest overcrowded facilities. We analyzed a cohort of stable HIV-infected adults (on treatment with CD4 >200 cells/μL for more than 6 months) who presented for clinic visits in Lusaka, Zambia. We used multilevel, mixed-effects logistic regression adjusting for patient characteristics, including prior retention, to assess the association between scheduled appointment intervals and subsequent missed visits (>14 days late to next visit), gaps in medication (>14 days late to next pharmacy refill), and loss to follow-up (LTFU; >90 days late to next visit). A total of 62084 patients (66.6% female, median age 38, median CD4 438 cells/μL) made 501281 visits while stable on antiretroviral therapy. Most visits were scheduled around 1-month (25.0% clinical, 44.4% pharmacy) or 3-month intervals (49.8% clinical, 35.2% pharmacy), with fewer patients scheduled at 6-month intervals (10.3% clinical, 0.4% pharmacy). After adjustment and compared to patients scheduled to return in 1 month, patients with six-month clinic return intervals were the least likely to miss visits (adjusted odds ratio [aOR], 0.20; 95% confidence interval [CI], 0.17-0.24); miss medication pickups (aOR, 0.47; 95% CI 0.39-0.57), and become LTFU prior to the next visit (aOR, 0.41; 95% CI, 0.31-0.54). Six-month clinic return intervals were associated with decreased lateness, gaps in medication, and LTFU in stable HIV-infected patients and may represent a promising strategy to reduce patient burdens and decongest clinics.


Considering the care of the suicidal client and the case for 'engagement and inspiring hope' or 'observations'.
Psychiatric/mental health (P/MH) nursing has rightly been described as a 'broad church', and one that contains many contested matters and areas of differing opinion. One such contested matter is that of the appropriate care for the person who is at risk of suicide. Recent, albeit limited, debate of this issue has taken place, and the literature, such as it is, indicates two principal (though linked) positions. These can be summarized as the 'engagement and hope inspiration' position and the 'observations' position. Given the P/MH nurse's unique position in providing 24-hour, day-to-day care to suicidal clients and the growing problem of suicide within people who suffer from mental health problems, it is both necessary and perhaps timely to consider this debate in more detail. Accordingly, this paper considers the debate regarding care for suicidal mental health care clients. First, the paper briefly describes the historical policy context of care for the suicidal client. Next, it focuses on 'observations' and concludes that there is a range of well-established, empirically based problems or drawbacks to this approach. Following this, it focuses on 'engagement, inspiring hope' and points out the key processes of engagement: forming a relationship, a human-human connection, conveying acceptance and tolerance, and hearing and understanding. The value and importance of these most fundamental of interpersonal processes is described and alluded to throughout the limited research into care of the suicidal client. The paper then describes the range of criticisms that have been levelled at the engagement-inspiring hope approach and considers these criticisms in more detail. As a result of this detailed examination, the paper then reiterates the need to replace 'observations' with 'engagement-hope inspiration' as the principal approach to caring for suicidal mental health clients.


Reliability, minimum detectable change, and minimum clinically important difference of the balance subtest of the Bruininks-Oseretsky test of motor proficiency-second edition in children with cerebral palsy.
This study aimed to investigate the internal consistency, inter-rater, and test-retest reliability of the balance subtest of the Bruininks-Oseretsky test of motor proficiency-second edition (BOT-2) and to estimate the minimum detectable change (MDC) and minimum clinically important difference (MCID) of the balance subtest of the BOT-2 in children with cerebral palsy (CP). In total, 20 children with CP participated in the present study. Internal consistency, test-retest, and inter-rater reliability were computed to establish reliability of the balance subtest of the BOT-2. The MDC95 was estimated from the standard error of measurement (SEM) to determine a real change for an individual child with CP. The anchor- and distribution-based MCID were calculated to determine the smallest change that might be important to clinicians. For concurrent validity, the correlation between the balance subtest of the BOT-2 and the pediatric balance scale (PBS) were calculated using Spearman's correlation. Internal consistency was good (Cronbach's alpha coefficient = 0.89). The BOT-2 had excellent test-retest (ICC = 0.99, p < 0.001) and inter-rater reliability (ICC = 0.99, p < 0.001). The balance subtest of the BOT-2 had an SEM of 0.70, MDC95 of 9.61, and MCIDs of 2.54 (anchor-based) and 1.38 (distribution-based). Additionally, there was a moderate positive correlation between the balance subtest of the BOT-2 and the PBS (Spearman's rho = 0.629, p = 0.003). Our experimental results indicate that the balance subtest of the BOT-2 had good internal consistency, along with excellent test-retest and inter-rater reliability. The change in scores of an individual child with CP should attain 9.61 points on the balance subtest of the BOT-2 to indicate a clinically important change. The MDC95 and MCID values could be helpful in understanding therapeutic effects and evaluating balancing ability using the balance subtest of the BOT-2 in children with CP.


The impact of diabetes counseling and education: clinical and cost outcomes from a large population of US managed care patients with type 2 diabetes.
The purpose of this study is to examine outcomes in adult patients with type 2 diabetes mellitus who received diabetes counseling and education (C/E) services compared with those who did not. A matched, retrospective cohort study of 17 483 C/E recipients and 17 470 non-C/E controls was followed for up to 12 months. Outcomes included glycemic control (glycosylated hemoglobin A1C levels <7.0%), hypoglycemic events, and health care utilization and costs. Compared with the non-C/E group, patients in the C/E group had significantly lower A1C (7.7% vs 7.2%) and were more likely to achieve glycemic control at 6 months' follow-up; they were also more likely to have a hypoglycemic event. During the 1-year period following the index date, C/E recipients had more inpatient visits (0.21 vs 0.20 visits per patient) and ambulatory visits (21.5 vs 18.6 visits per patient) compared with non-C/E controls. The increased use of health care services in the C/E groups was associated with $2388 higher annual overall costs and $827 higher diabetes-related costs. Diabetes C/E is associated with improved glycemic control, albeit with a slight increase in the risk of hypoglycemia. C/E was associated with higher health care costs across 12 months. Further analyses are needed to evaluate long-term cost-effectiveness of diabetes counseling and education.


Lithium-Metal Batteries Using Sustainable Electrolyte Media and Various Cathode Chemistries.
Lithium-metal batteries employing concentrated glyme-based electrolytes and two different cathode chemistries are herein evaluated in view of a safe use of the highly energetic alkali-metal anode. Indeed, diethylene-glycol dimethyl-ether (DEGDME) and triethylene-glycol dimethyl-ether (TREGDME) dissolving lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) and lithium nitrate (LiNO3) in concentration approaching the solvents saturation limit are used in lithium batteries employing either a conversion sulfur-tin composite (S:Sn 80:20 w/w) or a Li+ (de)insertion LiFePO4 cathode. Cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) clearly show the suitability of the concentrated electrolytes in terms of process reversibility and low interphase resistance, particularly upon a favorable activation. Galvanostatic measurements performed on lithium-sulfur (Li/S) batteries reveal promising capacities at room temperature (25 °C) and a value as high as 1300 mAh gS -1 for the cell exploiting the DEGDME-based electrolyte at 35 °C. On the other hand, the lithium-LiFePO4 (Li/LFP) cells exhibit satisfactory cycling behavior, in particular when employing an additional reduction step at low voltage cutoff (i.e., 1.2 V) during the first discharge to consolidate the solid electrolyte interphase (SEI). This procedure allows a Coulombic efficiency near 100%, a capacity approaching 160 mAh g-1, and relevant retention particularly for the cell using the TREGDME-based electrolyte. Therefore, this work suggests the use of concentrated glyme-based electrolytes, the fine-tuning of the operative conditions, and the careful selection of active materials chemistry as significant steps to achieve practical and safe lithium-metal batteries.


The effect of preincubation with cimetidine on the N-hydroxylation of dapsone by human liver microsomes.
We have examined the ability of cimetidine to inhibit the oxidative metabolism and hence haemotoxicity of dapsone in vitro, using a two compartment system in which two Teflon chambers are separated by a semi-permeable membrane. Compartment A contained a drug metabolizing system (microsomes prepared from human or rat liver +/- NADPH), whilst compartment B contained human red cells. Preincubation (30 min) of human liver microsomes with cimetidine (0-1000 microM) and NADPH prior to the addition of dapsone (100 microM) and NADPH (1 mM) resulted in a concentration-dependent decrease in the concentrations of dapsone hydroxylamine (from 179 +/- 47 to 40 +/- 6 ng) in compartment B. This reduction of hydroxylamine metabolite was reflected in the concentration-dependent reduction in methaemoglobin measured (from 7.1 +/- 0.7 to 3.5 +/- 1.5%) in parallel experiments. Preincubation of microsomes with cimetidine in the absence of NADPH had no effect. The effect of cimetidine pretreatment on dapsone-dependent methaemoglobin was confirmed using microsomes prepared from a further three sources of human liver, as well as from rat liver.


Optic neuritis and multiple sclerosis.
Review of the association between optic neuritis (ON) and multiple sclerosis (MS). MS often presents as acute unilateral ON. While it is clear that many patients with ON suffer from a generalized disease of the central nervous system that will go on to clinically definite MS (CDMS), it is also clear that others do not. With more and more well-informed patients and the emerging pharmacotheraphy for MS, the distinction between those patients with ON who have MS and those who do not, has become more important than ever before. Recently, a large randomized clinical trial on patients with ON or other clinically isolated syndromes suggestive of MS and evidence of prior subclinical demyelination on magnetic resonance imaging of the brain, found that treatment with recombinant interferon-beta-1a is beneficial by reducing the development of CDMS. Ophthalmologists should refer their patients with acute ON to a neurologist for MS-directed investigations and decisions regarding early institution of disease modifying therapy.


Diagnosis and treatment of nutritional deficiencies in alcoholic liver disease: Overview of available evidence and open issues.
Malnutrition is common in alcoholic liver disease and is associated with high rates of complications and mortality. In this article, the current literature was reviewed to highlight the relevance of proper nutritional management providing levels of evidence, when available. A PubMed search was performed for English-language publications from 1980 through 2014 with the keywords: alcoholic liver disease, nutritional deficiencies, nutritional support, enteral nutrition, parenteral nutrition, and protein-energy malnutrition. Manuscripts focused on nutritional approach in patients with alcoholic liver disease were selected. Although nutritional support for malnourished patients improves the outcome of hospitalization, surgery, transplantation and reduces the complications of liver disease and the length of hospital stay, specific guidelines are scanty. Both enteral and parenteral nutrition appear to improve nutritional parameters and liver function; however data on survival is often conflicting. As micronutrient depletion is common in alcoholic liver disease and each deficiency produces specific sequelae, all cirrhotic patients should be screened at baseline for deficiencies of micronutrient and supplemented as needed. In summary, protein-energy malnutrition and micronutrient depletion are clinical concerns in alcoholic liver disease. Nutritional therapy, including enteral nutrition, parenteral nutrition and micronutrient supplementation should be part of the multidisciplinary management of these patients.


Liquid Chromatography Mass Spectrometry Detection of Antibiotic Agents in Sputum from Persons with Cystic Fibrosis.
Antibiotic therapy is expected to impact host microbial communities considerably, yet many studies focused on microbiome and health are often confounded by limited information about antibiotic exposure. Given that antibiotics have diverse pharmacokinetic and antimicrobial properties, investigating the type and concentration of these agents in specific host specimens would provide much needed insight into their impact on the microbes therein. Here, we developed liquid chromatography mass spectrometry (LC-MS) methods to detect 18 antibiotic agents in sputum from persons with cystic fibrosis. Antibiotic spike-in control samples were used to compare three liquid extraction methods on the Waters Acquity Quattro Premier XE. Extraction with dithiothreitol captured the most antibiotics and was used to detect antibiotics in sputum samples from 11 people with cystic fibrosis, with results being compared to the individuals' self-reported antibiotic use. For the sputum samples, two LC-MS assays were used; the Quattro Premier detected nanomolar or micromolar concentrations of 16 antibiotics, whereas the Xevo TQ-XS detected all 18 antibiotics, most at subnanomolar levels. In 45% of tested sputum samples (71/158), at least one antibiotic that was not reported by the subject was detected by both LC-MS methods, a discordance largely explained by the thrice weekly administration and long half-life of azithromycin. For ∼37% of samples, antibiotics reported as taken by the individual were not detected by either instrument. Our results provide an approach for detecting a variety of antibiotics at the site of infection, thereby providing a means to include antibiotic usage data into microbiome studies.


Competitive diffusion into two reactive spheres of different reactivity and size.
Exact series solutions for the reaction rates of two reactive spheres of different reactivity and size are presented. The reaction rates are explicitly expressed in terms of the interparticle distance from reaction- to diffusion-limited conditions. The competitive diffusion favors the larger particle and the reaction rate of the smaller one is significantly reduced as the size ratio increases. For interactions between a diffusion-limited sink and a reaction-limited one, the diffusive interaction favors the reaction rate of the former and hinders that of the latter. Several approximate expressions have been proposed and compared with the exact results. The monopole approximation always underestimates the rate of the smaller sink for diffusion-limited reaction. The asymptotic limit of large size ratio is also analyzed. The asymptotic expression gives a quite accurate result if the smaller particle is regarded as a point sink plus a point dipole.