Hippocampal theta activity related to elicitation and inhibition of approach locomotion.
This study determined if the hippocampal theta rhythm showed phase relationships or changes in amplitude and frequency with the onset of stimuli and locomotion in a task in which auditory cues initiated and suppressed approach locomotion. Rats with electrodes in the dorsal hippocampus lapped at a milk dipper and were presented a tone which predicted the delivery of a food pellet. In some trials the pellet cue tone was negated by 60-Hz clicks beginning 0.3 s after onset, and no pellet was delivered. A video capture system (20-ms sampling) synchronized to the hippocampal recording system (10-ms sampling) was used to determine the onset of locomotor approach to the pellet area. The findings failed to support proposals that phase-related mechanisms play a role in encoding and retrieval of movement-related information. Neither the pellet cue nor the negating cue reset the theta rhythm, and they did not produce differential evoked potentials. During milk lapping, theta amplitude increased in the 1/2s prior to all pellet cues regardless of their locomotor effect. Frequency also rose but only when a non-negated pellet elicited short-latency locomotion. During locomotor execution, theta peak amplitude peaked earlier than theta frequency by approximately one period. In general during performance of this task, increasing theta amplitude reflected a general preparation to process the cue and increasing theta frequency reflected the readiness to respond to the cue with locomotion.


Involvement of reactive oxygen species in angiotensin II-induced endothelin-1 gene expression in rat cardiac fibroblasts.
The aim of this study was to investigate the effects of angiotensin II (Ang II) on fibroblast proliferation and endothelin-1 (ET-1) gene induction, focusing especially on reactive oxygen species (ROS)-mediated signaling in cardiac fibroblasts. Angiotensin II increases ET-1 expression, which plays an important role in Ang II-induced fibroblast proliferation. Angiotensin II also stimulates ROS generation in cardiac fibroblasts. However, whether ROS are involved in Ang II-induced proliferation and ET-1 expression remains unknown. Cultured neonatal rat cardiac fibroblasts were stimulated with Ang II, and then [(3)H]thymidine incorporation and the ET-1 gene expression were examined. We also examined the effects of antioxidants on Ang II-induced proliferation and mitogen-activated protein kinase (MAPK) phosphorylation to elucidate the redox-sensitive pathway in fibroblast proliferation and ET-1 gene expression. Both AT(1) receptor antagonist (losartan) and ET(A) receptor antagonist (BQ485) inhibited Ang II-increased DNA synthesis. Endothelin-1 gene was induced with Ang II as revealed by Northern blotting and promoter activity assay. Angiotensin II increased intracellular ROS levels, which were inhibited with losartan and antioxidants. Antioxidants further suppressed Ang II-induced ET-1 gene expression, DNA synthesis, and MAPK phosphorylation. PD98059, but not SB203580, fully inhibited Ang II-induced ET-1 expression. Truncation and mutational analysis of the ET-1 gene promoter showed that AP-1 binding site was an important cis-element in Ang II-induced ET-1 gene expression. Our data suggest that ROS are involved in Ang II-induced proliferation and ET-1 gene expression. Our findings imply that the combination of AT(I) and ET(A) receptor antagonists plus antioxidants may be beneficial in preventing the formation of excessive cardiac fibrosis.


Endoscopic sympathectomy treatment for craniofacial hyperhidrosis.
To present endoscopic T-2 sympathectomy as a minimally invasive therapy for craniofacial hyperhidrosis (CH). Follow-up study of 30 patients with CH treated by the new method in a 4-year period. The duration of follow-up was from 8 to 44 months (mean, 15 months). University hospital. Thirty consecutive patients with CH (18 men, 12 women) treated by the new method. All patients were essentially in good health except that they suffered from distressing CH to the extent that their daily activities were often disturbed. Their ages ranged from 7 to 63 years (mean age, 42.8 years). Endoscopic sympathectomy on both sides was carried out in a 1-stage operation for all patients. The patients were interviewed 1 week and then 3 months after surgery and then followed up by telephone interview about the alleviation or recurrence of CH and complications. All of the treated patients obtained a satisfactory alleviation of CH. One case was complicated by a mild and transient ptosis of the left eye. No recurrence of CH was noticed during the follow-up period. This therapeutic procedure is minimally invasive and effective. It causes minimal discomfort and was associated with no major complications in this series. The patients require only an overnight hospital stay and the operation scars are small. Endoscopic sympathectomy has proven to be an effective method in treating patients with distressing CH.


In situ synthesis and biocompatibility of nano hydroxyapatite on pristine and chitosan functionalized graphene oxide.
Motivated by the success of using graphene oxide (GO) as a nanofiller of composites, there is a drive to search for this new kind of carbon material as a reinforcing phase in biocomposites. In the present work, graphene oxide and chitosan (CS) functionalized graphene oxide were introduced as templates to fabricate hydroxyapatite (HA) using a facile solution-based in situ synthesis method, and GO-HA and CS-GO-HA nanocomposites were successfully prepared for the first time. It was found that the spindle like HA nanoparticles with a diameter of about 27 ± 7 nm and a length around 150 ± 25 nm were decorated randomly and strongly on the surface or aggregated at the edges of the pristine and chitosan functionalized GO matrix. Compared with HA, the prepared GO-based HA nanocomposites displayed an increased elastic modulus and hardness. The in vitro cytotoxicity of the prepared nanocomposites was investigated using CCK-8 assay on murine fibroblast L-929 cell line and human osteoblast-like MG-63 cell line, respectively. Both of the nanocomposites exhibited a high cell proliferation rate for L-929 and MG-63, and the CS-GO-HA could provide significantly higher cell viability and alkaline phosphatase activity compared to the GO-HA composite. These findings may provide new prospects for utilizing the GO-based hydroxyapatite biocomposites in bone repair, bone augmentation, as well as coating of biomedical implants and broaden the application of GO sheets in biological areas.


Subconjunctival hemorrhage: overview and management.
Subconjunctival hemorrhage is a commonly presenting clinical problem for the optometrist. Although it is usually benign, it can be caused by a variety of entities, each with their own important sequelae. It is necessary to perform a comprehensive work-up of a patient with this problem including a thorough case history to rule out trauma, infection, medications, or systemic disease as the causative agent. The anatomy of the conjunctiva is reviewed, examination procedures are described, management issues are discussed, and case reports are presented.


Analysis of lymphoedema as first symptom of a neoplasm in a series of 650 patients with limb involvement.
In a series of 650 patients with lymphoedema of the extremities, a clinically suspected primary lymphoedema in 60 patients was found upon roentgenological examination to be secondary lymphoedema. After lymphography, tomography and in some cases selective supplementary angiographic examination, the causitive factor for almost all patients could be established and was confirmed after biopsy/operation and pathological-anatomical-anatomical examination. This is a very important finding, because a developing lymphoedema may be the first symptom of a malignant process characterized by tumour infiltration into the lymph nodes. It is exactly in these patients that lymphography may often give rise to unexpected amazing findings, which in certain cases may contribute to the possibility of starting effective treatment.


Evaluation of multienzyme supplementation and fiber levels on nutrient and energy digestibility of diets fed to gestating sows and growing pigs.
The objective was to investigate the effect of a multienzyme blend (MEblend) and inclusion level on apparent total tract digestibility (ATTD) of energy and nutrients, as well as ileal digestibility of crude protein (CP) and amino acids (AA) in gestation diets with low (LF) or high dietary fiber (HF) fed to gestation sows. For comparison, growing pigs were fed the same HF diets to directly compare ATTD values with the gestating sows. In Exp.1, 45 gestating sows (parity 0 to 5; 187 ± 28 kg bodyweight; BW) were blocked by parity in a 2 x 3 factorial arrangement and fed 2.2 kg/d of the HF (17.5% neutral detergent fiber; NDF) or LF (13% NDF) diet and one of 3 levels of MEblend (0.0, 0.08, and 0.1%) to determine impacts of MEblend on ATTD. Twenty-seven growing pigs (initial 35.7 ± 3.32 kg BW) were fed the same HF diet (5% of BW) and one of 3 MEblend inclusions. The MEblend at both 0.08% and 0.1% increased ATTD of energy, NDF, and acid detergent fiber (ADF) (P < 0.05) in gestating sows but ATTD of total non-starch polysaccharides (NSP) and its residues were not affected. Sows fed HF, regardless of MEblend, had greater ATTD of NDF, xylose, and total NSP (P < 0.05) in comparison to grower pigs. In Exp. 2, ileal cannulas were placed in 12 gestating sows (parity 0 to 2; BW 159 ± 12 kg) to determine apparent and standardized ileal digestibility (AID and SID) of AA and NSP. In a cross-over design, sows were fed the same six diets, as in Exp. 1, and a nitrogen-free diet during 5 periods of 7 days each to achieve 8 replicates per diet. There was no interaction between diet fiber level and MEblend inclusion. Supplementation of MEblend to gestating sow diets did not impact SID of CP and AA regardless of dietary fiber level. The SID of His, Ile, Lys, Phe, Thr, Trp, and Val were 3 to 6% lower (P < 0.09) in HF than LF independent of MEblend. Supplementation of MEblend did not impact AID of NSP components, but sows fed HF had higher AID of arabinose (LF: 26.5% vs. HF: 40.6%), xylose (LF: 3.5% vs. HF: 40.9%), and total NSP (LF: 25.9% vs. HF: 40.0%) compared to sows fed LF (P < 0.05). Dietary supplementation of MEblend increased ATTD of nutrients, NSP, and energy in diets fed to gestating sows regardless of inclusion level, with MEblend having a greater incremental increase in diets with lower NDF levels. Inclusion of MEblend impacted neither SID of AA nor AID of NSP in low- or high-fiber gestation diets, but high-fiber diet, negatively affected SID of AA.


A single-array preprocessing method for estimating full-resolution raw copy numbers from all Affymetrix genotyping arrays including GenomeWideSNP 5 & 6.
High-resolution copy-number (CN) analysis has in recent years gained much attention, not only for the purpose of identifying CN aberrations associated with a certain phenotype, but also for identifying CN polymorphisms. In order for such studies to be successful and cost effective, the statistical methods have to be optimized. We propose a single-array preprocessing method for estimating full-resolution total CNs. It is applicable to all Affymetrix genotyping arrays, including the recent ones that also contain non-polymorphic probes. A reference signal is only needed at the last step when calculating relative CNs. As with our method for earlier generations of arrays, this one controls for allelic crosstalk, probe affinities and PCR fragment-length effects. Additionally, it also corrects for probe sequence effects and co-hybridization of fragments digested by multiple enzymes that takes place on the latest chips. We compare our method with Affymetrix's CN5 method and the dChip method by assessing how well they differentiate between various CN states at the full resolution and various amounts of smoothing. Although CRMA v2 is a single-array method, we observe that it performs as well as or better than alternative methods that use data from all arrays for their preprocessing. This shows that it is possible to do online analysis in large-scale projects where additional arrays are introduced over time.


Single droplet detection of immune checkpoints on a multiplexed electrohydrodynamic biosensor.
Monitoring soluble immune checkpoints in circulating fluids has the potential for minimally-invasive diagnostics and personalised therapy in precision medicine. Yet, the sensitive detection of multiple immune checkpoints from small volumes of liquid biopsy samples is challenging. In this study, we develop a multiplexed immune checkpoint biosensor (MICB) for parallel detection of soluble immune checkpoints PD-1, PD-L1, and LAG-3. MICB integrates a microfluidic sandwich immunoassay using engineered single chain variable fragments and alternating current electrohydrodynamic in situ nanofluidic mixing for promoting biosensor-target interaction and reducing non-specific non-target binding. MICB provides advantages of simultaneous analysis of up to 28 samples in <2 h, requires as little as a single sample drop (i.e., 20 μL) per target immune checkpoint, and applies high-affinity yeast cell-derived single chain variable fragments as a cost-effective alternative to monoclonal antibodies. We investigate the assay performance of MICB and demonstrate its capability for accurate immune checkpoint detection in simulated patient serum samples at clinically-relevant levels. MICB provides a dynamic range of 5 to 200 pg mL-1 for PD-1 and PD-L1, and 50 to 1000 pg mL-1 for LAG-3 with a coefficient of variation <13.8%. Sensitive immune checkpoint detection was achieved with limits of detection values of 5 pg mL-1 for PD-1, 5 pg mL-1 for PD-L1, and 50 pg mL-1 for LAG-3. The multiplexing capability, sensitivity, and relative assay simplicity of MICB make it capable of serving as a bioanalytical tool for immune checkpoint therapy monitoring.


Synthesis of 2'-deoxy-9-deaza nucleosides using Heck methodology.
During the synthesis of a series of 2'-deoxy-9-deaza nucleosides using Heck methodology, the necessity for a pyrrole protecting group was discovered. The results of this brief study revealed that the benzyloxymethyl (BOM) group proved optimal, and Heck coupling using Jeffery conditions increased the coupling yield significantly. The results are reported herein.


CD5 negatively regulates the T-cell antigen receptor signal transduction pathway: involvement of SH2-containing phosphotyrosine phosphatase SHP-1.
The negative regulation of T- or B-cell antigen receptor signaling by CD5 was proposed based on studies of thymocytes and peritoneal B-1a cells from CD5-deficient mice. Here, we show that CD5 is constitutively associated with phosphotyrosine phosphatase activity in Jurkat T cells. CD5 was found associated with the Src homology 2 (SH2) domain containing hematopoietic phosphotyrosine phosphatase SHP-1 in both Jurkat cells and normal phytohemagglutinin-expanded T lymphoblasts. This interaction was increased upon T-cell receptor (TCR)-CD3 cell stimulation. CD5 co-cross-linking with the TCR-CD3 complex down-regulated the TCR-CD3-increased Ca2+ mobilization in Jurkat cells. In addition, stimulation of Jurkat cells or normal phytohemagglutinin-expanded T lymphoblasts through TCR-CD3 induced rapid tyrosine phosphorylation of several protein substrates, which was substantially diminished after CD5 cross-linking. The CD5-regulated substrates included CD3zeta, ZAP-70, Syk, and phospholipase Cgammal but not the Src family tyrosine kinase p56(lck). By mutation of all four CD5 intracellular tyrosine residues to phenylalanine, we found the membrane-proximal tyrosine at position 378, which is located in an immunoreceptor tyrosine-based inhibitory (ITIM)-like motif, crucial for SHP-1 association. The F378 point mutation ablated both SHP-1 binding and the down-regulating activity of CD5 during TCR-CD3 stimulation. These results suggest a critical role of the CD5 ITIM-like motif, which by binding to SHP-1 mediates the down-regulatory activity of this receptor.


Decoding structural complexity in conical carbon nanofibers.
Conical carbon nanofibers (CNFs) exist primarily as graphitic ribbons that fold into a cylindrical structure with the formation of a hollow core. Structural analysis aided by molecular modeling proves useful for obtaining a full picture of how the size of the central channel varies from fiber to fiber. From a geometrical perspective, conical CNFs possibly have cone tips that are nearly closed. On the other hand, their fiber wall thickness can be reduced to a minimum possible value that is determined solely by the apex angle, regardless of the outer diameter. A formula has been developed to express the number of carbon atoms present in conical CNFs in terms of measurable structural parameters. It appears that the energetically preferred fiber wall thickness increases not only with the apex angle, but also with the number of atoms in the constituent graphitic cones. The origin of the empirical observation that conical CNFs with small apex angles tend to have a large hollow core lies in the fact that in graphene sheets that are more highly curved the curvature-induced strain energy rises more rapidly as the fiber wall thickens.


Transposable elements re-wire and fine-tune the transcriptome.
What good are transposable elements (TEs)? Although their activity can be harmful to host genomes and can cause disease, they nevertheless represent an important source of genetic variation that has helped shape genomes. In this review, we examine the impact of TEs, collectively referred to as the mobilome, on the transcriptome. We explore how TEs-particularly retrotransposons-contribute to transcript diversity and consider their potential significance as a source of small RNAs that regulate host gene transcription. We also discuss a critical role for the mobilome in engineering transcriptional networks, permitting coordinated gene expression, and facilitating the evolution of novel physiological processes.


Inverse design of the absorbing layer for detection enhancement in near-infrared range.
In spite of rapidly increasing demand and various applications of infrared (IR) detectors, their design process for the performance improvement has been mostly dependent on researchers' intuition and knowledge. We present two-dimensional unit structure design of the absorbing layer in IR detectors. A systematic approach is introduced to enhance the absorbing efficiency of incident beam in the near-infrared wavelength range. We derived a layered structure composed of a silicon nitride (Si₃N₄) layer and an amorphous silicon (a-Si) one in turn by the so called topology optimization in association with the time variant finite element analysis (FEA). It is confirmed that thickness at each layer is in associated with the IR wavelength so that detail dimensions of each layer are inferred. A prototype of the layered structure was fabricated and its performance has been verified through experimental measurement.


Unprecedented selective homogeneous cobalt-catalysed reductive alkoxylation of cyclic imides under mild conditions.
The first general and efficient non-noble metal-catalysed reductive C2-alkoxylation of cyclic imides (phthalimides and succinimides) is presented. Crucial for the success is the use of [Co(BF4)2·6H2O/triphos (L1)] combination and no external additives are required. Using the optimal cobalt-system, the hydrogenation of the aromatic ring of the parent phthalimide is avoided and only one of the carbonyl groups is selectively functionalized. The resulting products, N- and aryl-ring substituted 3-alkoxy-2,3-dihydro-1H-isoindolin-1-one and N-substituted 3-alkoxy-pyrrolidin-2-one derivatives, are prepared under mild conditions in good to excellent isolated yields. Intramolecular reductive couplings can also be performed affording tricyclic compounds in a one-step process. The present protocol opens the way to the development of new base-metal processes for the straightforward synthesis of functionalized N-heterocyclic compounds of pharmaceutical and biological interest.


A high confidence, manually validated human blood plasma protein reference set.
The immense diagnostic potential of human plasma has prompted great interest and effort in cataloging its contents, exemplified by the Human Proteome Organization (HUPO) Plasma Proteome Project (PPP) pilot project. Due to challenges in obtaining a reliable blood plasma protein list, HUPO later re-analysed their own original dataset with a more stringent statistical treatment that resulted in a much reduced list of high confidence (at least 95%) proteins compared with their original findings. In order to facilitate the discovery of novel biomarkers in the future and to realize the full diagnostic potential of blood plasma, we feel that there is still a need for an ultra-high confidence reference list (at least 99% confidence) of blood plasma proteins. To address the complexity and dynamic protein concentration range of the plasma proteome, we employed a linear ion-trap-Fourier transform (LTQ-FT) and a linear ion trap-Orbitrap (LTQ-Orbitrap) for mass spectrometry (MS) analysis. Both instruments allow the measurement of peptide masses in the low ppm range. Furthermore, we employed a statistical score that allows database peptide identification searching using the products of two consecutive stages of tandem mass spectrometry (MS3). The combination of MS3 with very high mass accuracy in the parent peptide allows peptide identification with orders of magnitude more confidence than that typically achieved. Herein we established a high confidence set of 697 blood plasma proteins and achieved a high 'average sequence coverage' of more than 14 peptides per protein and a median of 6 peptides per protein. All proteins annotated as belonging to the immunoglobulin family as well as all hypothetical proteins whose peptides completely matched immunoglobulin sequences were excluded from this protein list. We also compared the results of using two high-end MS instruments as well as the use of various peptide and protein separation approaches. Furthermore, we characterized the plasma proteins using cellular localization information, as well as comparing our list of proteins to data from other sources, including the HUPO PPP dataset. Superior instrumentation combined with rigorous validation criteria gave rise to a set of 697 plasma proteins in which we have very high confidence, demonstrated by an exceptionally low false peptide identification rate of 0.29%.


Prescription OxyContin abuse among patients entering addiction treatment.
OxyContin and other pharmaceutical opioids have been given special attention in the media, who frequently describe problematic users of the drug as previously drug-naive individuals who become addicted following legitimate prescriptions for medical reasons. The purpose of this study was to characterize the nature and origins of pharmaceutical opioid addiction among patients presenting at substance abuse treatment programs. The authors evaluated the prevalence and correlates of OxyContin use and abuse among a population of 27,816 subjects admitted to 157 addiction treatment programs in the United States from 2001-2004. The data collected included the lifetime and past 30-day use of OxyContin and other drugs prior to admission to addiction treatment, source of drug supply, and prior treatment history. Approximately 5% of all subjects who were admitted to the 157 addiction treatment programs reported prior use of OxyContin. Of those subjects, 4.5% reported using the drug on a regular basis for at least 1 year, and 2% reported use of the drug during the 30 days prior to admission. Seventy-eight percent of subjects who reported OxyContin use also reported that the drug had not been prescribed to them for any medical reason, 86% reported use of the drug to "get high or get a buzz," and 78% reported receiving prior treatment for a substance use disorder. The patients in this sample did not include individuals from private therapists or pain clinics. However, among treatment-seeking individuals who use OxyContin, the drug is most frequently obtained from nonmedical sources as part of a broader and longer-term pattern of multiple substance abuse.


Eating disorders in children and adolescents: state of the art review.
Despite their high prevalence, associated morbidity and mortality, and available treatment options, eating disorders (EDs) continue to be underdiagnosed by pediatric professionals. Many adolescents go untreated, do not recover, or reach only partial recovery. Higher rates of EDs are seen now in younger children, boys, and minority groups; EDs are increasingly recognized in patients with previous histories of obesity. Medical complications are common in both full and subthreshold EDs and affect every organ system. No single cause of EDs has emerged, although neurobiological and genetic predispositions are emerging as important. Recent treatment paradigms acknowledge that they are not caused by families or chosen by patients. EDs present differently in pediatric populations, and providers should have a high index of suspicion using new Diagnostic and Statistical Manual, 5th edition diagnostic criteria because early intervention can affect prognosis. Outpatient family-based treatment focused on weight restoration, reducing blame, and empowering caregivers has emerged as particularly effective; cognitive behavioral therapy, individual therapy, and higher levels of care may also be appropriate. Pharmacotherapy is useful in specific contexts. Full weight restoration is critical, often involves high-calorie diets, and must allow for continued growth and development; weight maintenance is typically inappropriate in pediatric populations. Physical, nutritional, behavioral, and psychological health are all metrics of a full recovery, and pediatric EDs have a good prognosis with appropriate care. ED prevention efforts should work toward aligning with families and understanding the impact of antiobesity efforts. Primary care providers can be key players in treatment success.


Immune recognition of fungal beta-glucans.
The recognition of conserved microbial structures is a key aspect of metazoan immunity, and beta-glucans are emerging as a major target for the recognition of fungal pathogens. A number of receptors for these carbohydrates have been identified, which upon recognition, trigger a variety of immune responses. In contrast to many other systems, there is little apparent conservation in these mechanisms between vertebrates and invertebrates. In this review, we will highlight all the known receptors for beta-glucans and will discuss the various immune responses they can initiate, with reference to fungal infection, in both vertebrates and invertebrates.


Molecular evidence for the occurrence of a new sibling species within the Anopheles (Kerteszia) cruzii complex in south-east Brazil.
Anopheles cruzii (Diptera: Culicidae) has long been known as a vector of human and simian malaria parasites in southern and south-eastern Brazil. Previous studies have provided evidence that An. cruzii is a species complex, but the status of the different populations and the number of sibling species remains unclear. A recent analysis of the genetic differentiation of the timeless gene among An. cruzii populations from south and south-east Brazil has suggested that the population from Itatiaia, Rio de Janeiro State (south-east Brazil), is in a process of incipient speciation. A ~180 bp fragment of cpr, a gene encoding the NADPH-cytochrome P450 reductase, an enzyme involved in metabolic insecticide resistance and odorant clearance in insects, was used in this study as a molecular marker to analyse the divergence between five An. cruzii populations from south and south-east Brazil. Analysis of the genetic differentiation in the cpr gene revealed very high FST values and fixed differences between Itatiaia and the other four populations studied (Florianópolis, Cananéia, Juquitiba and Santa Teresa). In addition, the data also provided preliminary evidence that seems to indicate the occurrence of two sympatric sibling species in Itatiaia. Population genetics analysis of An. cruzii samples from different localities using a fragment of the cpr gene suggests that the Itatiaia sample represents at least one new sibling species in this complex.


The structure of everyday self-care decision making in chronic illness.
As health care reform strategists increasingly recognize the critically important potential of effective everyday self-care decision making for reducing the burden of illness and the strain on health service systems, we must find ways to understand and support it. In this study, the authors investigate persons with expertise in self-care management of type 2 diabetes, HIV/AIDS, and multiple sclerosis to understand how everyday self-care decision making is learned and experienced. They used interview, think-aloud, and focus groups to construct an account of how persons affected by these chronic diseases make decisions in relation to the choices in their everyday lives and learn to manage the untoward effects of these conditions according to their unique contexts and values. The findings form a conceptual foundation for ongoing inquiry into this complex phenomenon and provide insights that might assist clinicians to understand more fully the responses and attitudes of those they serve.


Remineralization of human natural caries and artificial caries-like lesions with an experimental whisker-reinforced ART composite.
This paper compares the remineralization of human natural caries and artificial caries-like dentin lesions treated with a novel whisker-reinforced experimental composite resin (ART composite) with a resin-modified glass ionomer cement (RM-GIC) as control. Ten molars with moderate natural dentin caries were prepared (N). Artificial caries-like dentin lesions were prepared in occlusal dentin of 10 caries-free molars and demineralized at pH 4.3 for 48 h (A). The cavities were restored with ART composite or RM-GIC. All restored teeth were sliced into 120 μm sections. Transverse microradiography combined with digital image analysis was performed to analyze the change in mineral density at the same position in the specimens before and after 4 and 8 weeks remineralization/demineralization treatment. The mean percent remineralization ± standard deviation after 4 and 8 weeks are: N with ART composite, 27 ± 9 and 46 ± 14, respectively; N with RM-GIC, 18 ± 6 and 36 ± 11, respectively; A with ART composite, 48 ± 9 and 66 ± 11, respectively; A with RM-GIC, 50 ± 13 and 62 ± 11, respectively. There was a significant difference between the ART composite and RM-GIC for the remineralization of natural caries (P<0.05). For both restoratives there were significant differences between the remineralization of natural and artificial caries (P<0.001). The ART composite and RM-GIC remineralized natural and artificial caries differently, most likely due to differences in the microstructure and composition of the caries dentin.


Cross-sectional study of the prevalence of feather pecking in laying hens in alternative systems and its associations with management and disease.
A cross-sectional study of risk factors for feather pecking in layings hens in alternative systems was carried out in July 1998. A total of 637 questionnaires were sent out to farmers and producer groups and, after two reminders, the final response rate was 51.5 per cent. The outcome variable was feather pecking after point of lay. Over 55 per cent of the farmers reported that feather pecking had occurred in the last depopulated flock. This outcome was compared with the management procedures reported by flock managers by using univariate statistics. Factors associated with feather pecking with a significance < or = 0.05 were then tested in two logistic regression models. In the first model the following factors were associated with an increased risk of feather pecking: less than 50 per cent of the flock using the outdoor area on a fine and sunny day, the occurrence of egg peritonitis and the occurrence of infectious bronchitis. The direction of the association between feather pecking and these infectious diseases was unclear, so in the second model only factors which were consistent throughout the laying period were tested. The following factors were associated with an increased risk of feather pecking: less than 50 per cent of the flock using the outdoor area on a fine and sunny day; three or more changes of diet during lay; the inspection of the flock by one person; an absence of loose litter at the end of lay; a temperature in the hen house of less than 20 degrees C; turning the lights up when the flock was inspected; and the use of bell-drinkers. It is concluded that some of these factors could inhibit foraging and dust-bathing behaviour and others may increase competition or frustration, both of these changes having been shown experimentally to initiate feather pecking behaviour.


Leucine-rich repeat kinase 2 promotes the development of experimental severe acute pancreatitis.
Translocation of gut bacteria into the pancreas promotes the development of severe acute pancreatitis (SAP). Recent clinical studies have also highlighted the association between fungal infections and SAP. The sensing of gut bacteria by pattern recognition receptors promotes the development of SAP via the production of proinflammatory cytokines; however, the mechanism by which gut fungi mediate SAP remains largely unknown. Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein that regulates innate immunity against fungi via Dectin-1 activation. Here, we investigated the role of LRRK2 in SAP development and observed that administration of LRRK2 inhibitors attenuated SAP development. The degree of SAP was greater in Lrrk2 transgenic (Tg) mice than in control mice and was accompanied by an increased production of nuclear factor-kappaB-dependent proinflammatory cytokines. Ablation of the fungal mycobiome by anti-fungal drugs inhibited SAP development in Lrrk2 Tg mice, whereas the degree of SAP was comparable in Lrrk2 Tg mice with or without gut sterilization by a broad range of antibiotics. Pancreatic mononuclear cells from Lrrk2 Tg mice produced large amounts of IL-6 and TNF-α upon stimulation with Dectin-1 ligands, and inhibition of the Dectin-1 pathway by a spleen tyrosine kinase inhibitor protected Lrrk2 Tg mice from SAP. These data indicate that LRRK2 activation is involved in the development of SAP through proinflammatory cytokine responses upon fungal exposure.


Real-Time-Capable Muscle Force Estimation for Monitoring Robotic Rehabilitation Therapy in the Intensive Care Unit.
In this paper, a method is proposed to enable real-time monitoring of muscle forces during robotic rehabilitation therapy in the ICU. This method is solely based on sensor information provided by the rehabilitation robot. In current clinical practice, monitoring primarily takes place in the later stages of rehabilitation, but it would also be highly beneficial during early stages. Musculoskeletal models have large, mostly unrealized potential to support and improve patient monitoring. The method presented in this paper is based on a state-of-the-art muscle-tendon path model, which is applied to the use case of the robotic rehabilitation device VEMOTION. The muscle force estimation is validated against surface electromyography measurements of lower limb muscles from 12 healthy volunteers The results show an overall correlation of R = 0.70 0.25 for the single-joint muscle m. iliopsoas, which has a ±major contribution to hip flexion. Given this correlation, the proposed model could be used for real-time monitoring of active patient participation.


[Othello syndrome--jealousy and jealous delusions as symptoms of psychiatric disorders].
Jealousy as a psychopathological symptom has long been neglected by psychiatric research. Despite the obvious difficulty to prove or exclude the infidelity of a spouse, delusional jealousy can clearly be considered as pathological, but the evaluation and classification of non-psychotic jealousy remains a challenge. Typical psychopathological symptoms which usually accompany pathological jealousy and the prevalence of delusional jealousy in different psychiatric disorders are described. In delusional jealousy neuroleptic treatment is necessary. Positive results have been reported especially with pimozide. For non-psychotic jealousy various forms of psychotherapy have been advocated to improve self-esteem or to treat other psychological disorders. Other possible interventions are alcohol therapy or family counselling. Many studies show that jealousy is a frequent motive in homicide with the spouse being nearly exclusively the victim. Finally some forensic aspects of jealousy are discussed.


Scoliosis and growth. An analysis of the literature.
A review of the literature discloses the buckling phenomenon as responsible for the initiation of lateral deformation and the progression of small curves in idiopathic scoliosis. From the point of view of parsimony, buckling explains how ligamentous laxity, increased interdiscal flexibility, muscular asymmetries, neurologic lesions, morphologic, anthropometric, and sexual differences would contribute to development of the deformity. Thus, a buckling theory seems to embody the fragmented character of present information about the etiology of idiopathic scoliosis.


Clinical-epidemiological analysis of HDL2 and HDL3 subfractions in adults from Maracaibo city, Venezuela.
To carry out a clinical-epidemiological analysis of high-density lipoprotein cholesterol subfractions (HDL-C) in adults from Maracaibo, Venezuela. A descriptive and cross-sectional study of the database from the Metbolic Syndrome Prevalence in Maracaibo Study was carried out. HDL3 and HDL2 serum concentration, as well as the HDL2/HDL3 ratio, were determined in 359 individuals of both sexes, over 18 years of age. Values obtained were evaluated according to sociodemographic, clinical and biochemical characteristics. Mean population age was 39.4 ± 15.2 years, and 51.5% were female. Differences in HDL-C subfraction levels were only observed in those subjects with low HDL-C levels. Women with hypertriglyceridemia showed significantly lower serum HDL3 and HDL2 concentrations than those with normal triglycerides (p=0.033), as well as a lower HDL3 level and HDL2 / HDL3 ratio in those with higher levels of ultra-sensitive C-reactive protein (us-CRP) (p<0.001). A significantly lower concentration of HDL2 was observed in men with some degree of hypertension (p=0.031), insulin resistance (p=0.050) and metabolic syndrome (p=0.003); while those with elevated us-CRP showed a lower concentration of HDL3 (p=0.011). HDL-C subfractions show varying clinical-epidemiological behavior in adults from Maracaibo. Lower serum levels are observed in men, differences only in those with low HDL-C; and no predominance of any subclass was observed according to sociodemographic, clinical and biochemical characteristics.


Cervical lesions are associated with human papillomavirus type 16 intratypic variants that have high transcriptional activity and increased usage of common mammalian codons.
Human papillomavirus type 16 (HPV-16) is a major cause of cervical neoplasia, but only a minority of HPV-16 infections result in cancer. Whether particular HPV-16 variants are associated with cervical disease has not yet been clearly established. An investigation of whether cervical neoplasia is associated with infection with HPV-16 intratypic variants was undertaken by using RFLP analyses in a study of 100 HPV-16 DNA-positive women with or without neoplasia. RFLP variant 2 was positively associated [odds ratio (OR)=2.57] and variant 5 was negatively associated with disease (OR=0.2). Variant 1, which resembles the reference isolate of HPV-16, was found at a similar prevalence among those with and without neoplasia. Variants 1 and 2 were also more likely to be associated with detectable viral mRNA than variant 5 (respectively P=0.03 and P=0.00). When HPV-16 E5 ORFs in 50 clones from 36 clinical samples were sequenced, 19 variant HPV-16 E5 DNA sequences were identified. Twelve of these DNA sequences encoded variant E5 amino acid sequences, 10 of which were novel. Whilst the associations between HPV-16 E5 RFLP variants and neoplasia could not be attributed to differences in amino acid sequences, correlation was observed in codon usage. DNA sequences of RFLP variant 2 (associated with greatest OR for neoplasia) had a significantly greater usage of common mammalian codons compared with RFLP pattern 1 variants.


Cyclocryotherapy for glaucoma.
CCT is a simple, noninvasive, short, ablative surgical procedure that has been effectively used to treat advanced uncontrolled glaucoma. A specific protocol is recommended and the rationale for strict adherence is presented. The long-term benefits of CCT in patients with open-angle glaucoma following cataract extraction have been well established. However, although patients with neovascular glaucoma may have adequate pressure control following CCT, the serious complications of progression to no light perception and phthisis bulbi have discouraged its use. CCT can be effective for neovascular glaucoma when other methods of surgical management prove unsuccessful and visual prognosis is very poor. The loss of functional vision occurred in fewer than 10 percent of eyes treated with CCT, and it is important to emphasize that only eyes with greatest risk and poorest prognosis were treated with this modality. CCT has become an important addition to the surgical armamentarium for the treatment of some specific types of glaucoma.


Effects of Safety Zone Implementation on Perceptions of Safety and Well-being When Caring for COVID-19 Patients.
In March 2020, the caseload of patients positive for COVID-19 in hospitals began increasing rapidly, creating fear and anxiety among health care workers and concern about supplies of personal protective equipment. To determine if implementing safety zones improves the perceptions of safety, well-being, workflow, and teamwork among hospital staff caring for patients during a pandemic. A safety zone process was implemented to designate levels of contamination risk and appropriate activities for certain areas. Zones were designated as hot (highest risk), warm (moderate risk), or cold (lowest risk). Caregivers working in the safety zones were invited to complete a survey regarding their perceptions of safety, caregiver well-being, workflow, and teamwork. Each question was asked twice to obtain caregiver opinions for the periods before and after implementation of the zones. Significant improvements were seen in perceptions of caregiver safety (P < .001) and collaboration within a multidisciplinary staff (P < .001). Significant reductions in perceived staff fatigue (P = .03), perceived cross contamination (P < .001), anxiety (P < .001), and fear of exposure (P < .001) were also seen. Teamwork (P = .23) and workflow (P = .69) were not significantly affected. Safety zone implementation improved caregivers' perceptions of their safety, their well-being, and collaboration within the multidisciplinary staff but did not improve their perceptions of teamwork or workflow.


DNA polymerases alpha, delta, and epsilon localize and function together at replication forks in Saccharomyces cerevisiae.
Early in eukaryotic cell cycle, a pre-RC is assembled at each replication origin with ORC, Cdc6, Cdt1 and Mcm2-7 proteins to license the origin for use in the subsequent S phase. Licensed origin must then be activated by S-Cdk and Ddk. At the onset of S phase, RPA is loaded on to the ARS in a reaction stimulated by S-Cdk and Ddk, followed by Cdc45-dependent loading of pol alpha, -delta, and -epsilon. This study examines cell cycle-dependent localization of pol alpha, -delta and -epsilon in Saccharomyces cerevisiae using immuno-histochemical and chromatin immuno-precipitation methods. The results show that pol alpha, -delta, or -epsilon localizes on chromatin as punctate foci at all stages of the cell cycle. However, some foci overlap with or are adjacent to foci pulse-labeled with bromodeoxyuridine during S phase, indicating these are replicating foci. DNA microarray analysis localized pol alpha, -delta, and -epsilon to early firing ARSs on yeast chromosome III and VI at the beginning of S phase. These data collectively suggest that bidirectional replication occurs at specific foci in yeast chromosomes and that pol alpha, -delta, and -epsilon localize and function together at multiple replication forks during S phase.


Impact of patient selection criteria and treatment history on comparisons of alternative therapies: a case study of atypical antipsychotics.
Comparative effectiveness analyses using retrospective databases may be highly sensitive to common design decisions employed by researchers. To test the sensitivity of statistical results to common research methods in retrospective database analyses. Comparisons of time to all-cause discontinuation (TTAD) across antipsychotic drug therapies are used to illustrate these effects. Data from the California Medicaid Program were used to identify 231,635 episodes of antipsychotic drug therapy. Four sequential analyses of TTAD were performed on all patients, patients with 1 year of post-treatment data, and patients with schizophrenia and using models that included variables documenting drug treatment history. Patients using atypical antipsychotics consistently achieve longer TTAD than patients treated with conventional antipsychotics. Nevertheless, estimated differences narrowed when analyses included only patients with schizophrenia. Risperidone performed better than olanzapine when diagnosis was not limited to schizophrenia, and quetiapine outperformed olanzapine and risperidone when the analysis did not control for treatment history. This latter result reflects the disproportionate use of quetiapine in long-duration augmentation episodes. There were no statistical differences across alternative atypical antipsychotics once the analysis excluded patients without a diagnosis of schizophrenia and included patient treatment history in the analysis. Comparative effectiveness analyses of alternative drug therapies are sensitive to diagnosis and patient drug treatment history. Data on these factors can be derived from paid claims data and should be used to provide more accurate comparisons of effectiveness across drugs and to provide results that cover the full range of clinical scenarios that clinicians face.


Economic evaluations of occupational therapy approaches for people with cognitive and/or functional decline: A systematic review.
With the ageing of the world's population comes significant implications for nearly all sectors of society, including health and aged care spending. Health and aged care systems need to respond to the increasing need for services for older people. Occupational therapy is concerned with maintaining a person's functional independence and well-being from preventative and treatment perspectives. The aim of this systematic review was to identify the costs and outcomes of occupational therapy for people with cognitive and/or functional decline. The searches for this review were conducted on 23 September 2016 and updated on 20 April 2017. Full economic evaluation studies, partial economic evaluations, randomised trials reporting estimates of resource use or costs associated with intervention(s) and comparator(s) and studies with pre- and post-intervention cost comparators were included. Thirteen studies met the inclusion criteria. The type and duration of occupational therapy intervention in the included studies varied, ranging from one-off assessments through to systematic multicomponent programmes. Results suggested that structured occupational therapy interventions which comprised of multiple consultations and engaged caregivers delivered better functional and economic outcomes.


Impact of continuous pharmaceutical care led by clinical pharmacists during transitions of care on medication adherence and clinical outcomes for patients with coronary heart disease: a prospective cohort study.
Objectives: The study aimed to explore the impact of a continuous pharmaceutical care (CPC) program during care transitions on medication adherence and clinical outcomes for patients with coronary heart disease (CHD). Methods: A prospective cohort study was conducted from April 2020 to February 2021. Patients diagnosed with CHD were selected and divided into intervention (CPC) and usual care (UC) groups by nurses at equal intervals based on admission time. The intervention group received CPC services provided by clinical pharmacists (including medication reconciliation, disease education, medication guidance, lifestyle counseling, and follow-up services) and usual care. The UC group received only routine medical care. The study compared medication adherence, clinical indicators (low-density lipoprotein cholesterol [LDL-C], blood pressure [BP], glycated hemoglobin [HbA1c] control rates), the incidence of adverse drug reactions (ADRs), and readmission rates (overall, major adverse cardiovascular events [MACEs]-related, and CHD risk factors-related) at admission and 1, 3, and 6 months after discharge between the two groups. Results: A total of 228 patients with CHD completed the study, including 113 patients in the CPC group and 115 patients in the UC group. There were no significant differences (p > 0.05) in both groups in demographic and clinical characteristics at baseline. A total of 101 drug-related problems were identified in the CPC group (an average of 0.89 per person). The CPC group showed significantly higher medication adherence at 1, 3, and 6 months after discharge than the UC group (p < 0.05). At 3 and 6 months after discharge, the intervention group had significantly higher control rates of LDL-C (61.11% vs. 44.64% at 3 months, 78.18% vs. 51.43% at 6 months), and BP (91.15% vs. 77.39% at 3 months, 88.50% vs. 77.19% at 6 months). The CPC group had higher HbA1c control rates (53.85% vs. 34.21% at 3 months, 54.05% vs. 38.46% at 6 months) than the UC group. However, the differences were not statistically significant. The incidence of ADRs 6 months after discharge was significantly lower in the CPC group than in the UC group (5.13% vs. 12.17%, p < 0.05). The CPC group had a lower overall readmission rate (13.27% vs. 20.00%), MACE-related readmission rate (5.31% vs. 12.17%), and readmission rate related to CHD risk factors (0.88% vs. 2.61%) 6 months after discharge compared to the UC group. However, these differences were not statistically significant (p > 0.05). Conclusion: CPC led by clinical pharmacists during care transitions effectively improved medication adherence, safety, and risk factor control in patients with CHD.


Drosophila aPKC regulates cell polarity and cell proliferation in neuroblasts and epithelia.
Cell polarity is essential for generating cell diversity and for the proper function of most differentiated cell types. In many organisms, cell polarity is regulated by the atypical protein kinase C (aPKC), Bazooka (Baz/Par3), and Par6 proteins. Here, we show that Drosophila aPKC zygotic null mutants survive to mid-larval stages, where they exhibit defects in neuroblast and epithelial cell polarity. Mutant neuroblasts lack apical localization of Par6 and Lgl, and fail to exclude Miranda from the apical cortex; yet, they show normal apical crescents of Baz/Par3, Pins, Inscuteable, and Discs large and normal spindle orientation. Mutant imaginal disc epithelia have defects in apical/basal cell polarity and tissue morphology. In addition, we show that aPKC mutants show reduced cell proliferation in both neuroblasts and epithelia, the opposite of the lethal giant larvae (lgl) tumor suppressor phenotype, and that reduced aPKC levels strongly suppress most lgl cell polarity and overproliferation phenotypes.


Challenges in dynamic mode decomposition.
Dynamic mode decomposition (DMD) is a powerful tool for extracting spatial and temporal patterns from multi-dimensional time series, and it has been used successfully in a wide range of fields, including fluid mechanics, robotics and neuroscience. Two of the main challenges remaining in DMD research are noise sensitivity and issues related to Krylov space closure when modelling nonlinear systems. Here, we investigate the combination of noise and nonlinearity in a controlled setting, by studying a class of systems with linear latent dynamics which are observed via multinomial observables. Our numerical models include system and measurement noise. We explore the influences of dataset metrics, the spectrum of the latent dynamics, the normality of the system matrix and the geometry of the dynamics. Our results show that even for these very mildly nonlinear conditions, DMD methods often fail to recover the spectrum and can have poor predictive ability. Our work is motivated by our experience modelling multilegged robot data, where we have encountered great difficulty in reconstructing time series for oscillatory systems with intermediate transients, which decay only slightly faster than a period.


T2 Relaxation Study to Evaluate the Crystalline State of Indomethacin Containing Solid Dispersions Using Time-Domain NMR.
The aim of this study was to demonstrate the usefulness of T2 measurements conducted with a time-domain NMR (TD-NMR) for the characterization of active pharmaceutical ingredients (APIs) containing solid dosage forms. A solid dispersion (SD) and a physical mixture (PM) consisting of indomethacin (IMC) and polyvinylpyrrolidone (PVP) were prepared at different weight ratios as test samples, and then their T2 relaxation curves were measured by TD-NMR. The T2 relaxation curve of IMC was quite different from that of PVP by nature. T2 values of the SD and PM samples became gradually shortened with increasing IMC content. No difference in T2 relaxation curves was observed between SD and PM. By analyzing the T2 relaxation curves in detail, we succeeded in precisely quantifying the IMC contents incorporated in the samples. Next, this study evaluated the T2 relaxation curves of amorphous and crystalline states of powdered IMC. T2 relaxation rate of crystalline IMC was slightly but significantly higher than that of amorphous IMC, proving that the T2 measurement was sensitive enough to detect these differences. Finally, a thermal stress was imposed on SD and PM samples at 60°C for 7 d, and then an amorphous-to-crystalline transformation occurred in IMC in the PM sample and was successfully monitored by T2 measurement. We believe that T2 measurement by TD-NMR is a promising analysis for the characterization of APIs in solid dosage forms, including SD-based pharmaceuticals.


Suicide in custody: case-control study.
Few risk factors and indicators of vulnerability for suicide in custody are known so far. A case-control study was conducted to investigate the relevance of criminal history, psychiatric morbidity and social integration to suicide in prison. For every suicide that occurred in an Austrian correctional institution between 1975 and 1999, two controls matched for correctional institution, gender, nationality, age, custodial status and time of admission were selected. Psychiatric characteristics, previous suicidal behaviour, criminal history and indicators of social integration were compared. Of 250 recorded suicides, 220 personal files were available and matched to 440 controls. The most important predictors for suicide in custody were a history of suicidality (status following attempted suicide and suicide threat), psychiatric diagnosis, psychotropic medication, a highly violent index offence and single- cell accommodation. A significant finding is the importance of suicidal behaviour as an indicator of risk of suicide in correctional institutions, which until now has been a matter of debate. This study demonstrates the need for staff to take suicidal behaviour as seriously in custodial settings as in any other circumstances.


Levels of oxidative stress markers: correlation with hepatic function and worm burden patients with schistosomiasis.
Schistosomiasis is caused by Schistosoma mansoni and is a public health problem in Brazil. The typical granulomatous lesion is associated with the increase in the oxidative damage by generation of free radicals. The aim of this work was to correlate some oxidative stress markers with the worm burden on carriers of schistosomiasis (n = 30) in the acute phase in comparison to healthy subjects (n = 30). The pro-oxidant parameter used was the colorimetric quantification of reactive substances to thiobarbituric acid, while the antioxidant markers used were blood content of reduced glutathione and determination of the activity of catalase. The worm burden was assessed by Kato-Katz method. The results pointed out that initially there was no difference in the catalase activity. However, there was a positive correlation between the increase in parasitic load and intensity of lipid peroxidation, and decrease in the content of reduced glutathione. Additionally, only the aspartate aminotransferase levels presented to be high, while there was a decrease in bilirubin level. Therefore, a possible association between the establishment of the oxidative stress in tissue and the parasitic load of Schistosoma mansoni is suggested.


Stroke: acute stroke receiving facilities and management.
Management of ischemic stroke is challenging. No prehospital treatment option exists, and the only approved pharmacologic therapy, that is, systemic thrombolysis, requires brain imaging and initiation of therapy within a narrow therapeutic window. This review provides an overview of recent efforts to optimize management of suspected stroke patients by reducing the interval from symptom onset to reperfusion therapy. There is clear evidence that stroke patients have a favorable outcome when treated with thrombolysis in specialized stroke centers. Data from the European Cooperative Acute Stroke Study-III trial, coupled with improved patient selection by advanced imaging technologies will expand future therapeutic options. However, major obstacles remain in consistently translating scientific advances into clinical practice with only a small percentage of potentially eligible patients receiving thrombolysis. Integrated systems of prehospital management and clinical pathways are necessary to reduce this treatment gap. The dogma 'time is brain' is as relevant now as it was at the inauguration of recombinant tissue plasminogen activator for acute stroke treatment in 1996. Knowledge of stroke symptoms and treatment options by the public and first responders, along with integrated stroke systems of care are crucial to ensure rapid access to stroke expertise and treatment.


Sertraline as a first-line treatment for cholestatic pruritus.
Pruritus is frequently the most debilitating symptom of cholestatic liver diseases. Moreover, existing therapies are often ineffective. Recent small, retrospective case series reports suggest that serotonin reuptake inhibitors can improve pruritus. This study was undertaken to establish the dose of sertraline and to evaluate its efficacy for cholestatic pruritus. Twenty one subjects with chronic pruritus due to liver disease (including primary biliary cirrhosis, primary sclerosing cholangitis, chronic hepatitis C, and postnecrotic cirrhosis) initially underwent an open-label, dose escalation to determine the dose with optimal efficacy and tolerability. After a washout period, 12 of the subjects entered a randomized, double-blind, placebo-controlled trial. Participants quantified their pruritus using a 0-10 visual analog scale, and pruritus was assessed for distribution, timing, degree of disability, and physical evidence of scratching. The optimum sertraline dose (75-100 mg/day) was well tolerated. In the controlled portion of the study, itch scores improved in patients taking sertraline, but worsened in patients taking placebo (P=0.009). Changes in itch distribution, duration, direction, and physical evidence of scratching paralleled changes in the visual analog pruritus score. Sertraline seems to be an effective, well-tolerated treatment for pruritus due to chronic liver disease. These results suggest that serotonergic pathways are important in the perception of itch.


The Protective Action of Metformin against Pro-Inflammatory Cytokine-Induced Human Islet Cell Damage and the Mechanisms Involved.
Metformin, a drug widely used in type 2 diabetes (T2D), has been shown to protect human β-cells exposed to gluco- and/or lipotoxic conditions and those in islets from T2D donors. We assessed whether metformin could relieve the human β-cell stress induced by pro-inflammatory cytokines (which mediate β-cells damage in type 1 diabetes, T1D) and investigated the underlying mechanisms using shotgun proteomics. Human islets were exposed to 50 U/mL interleukin-1β plus 1000 U/mL interferon-γ for 48 h, with or without 2.4 µg/mL metformin. Glucose-stimulated insulin secretion (GSIS) and caspase 3/7 activity were studied, and a shotgun label free proteomics analysis was performed. Metformin prevented the reduction of GSIS and the activation of caspase 3/7 induced by cytokines. Proteomics analysis identified more than 3000 proteins in human islets. Cytokines alone altered the expression of 244 proteins (145 up- and 99 down-regulated), while, in the presence of metformin, cytokine-exposure modified the expression of 231 proteins (128 up- and 103 downregulated). Among the proteins inversely regulated in the two conditions, we found proteins involved in vesicle motility, defense against oxidative stress (including peroxiredoxins), metabolism, protein synthesis, glycolysis and its regulation, and cytoskeletal proteins. Metformin inhibited pathways linked to inflammation, immune reactions, mammalian target of rapamycin (mTOR) signaling, and cell senescence. Some of the changes were confirmed by Western blot. Therefore, metformin prevented part of the deleterious actions of pro-inflammatory cytokines in human β-cells, which was accompanied by islet proteome modifications. This suggests that metformin, besides use in T2D, might be considered for β-cell protection in other types of diabetes, possibly including early T1D.


RASA1 analysis guides management in a family with capillary malformation-arteriovenous malformation.
Capillary malformation-arteriovenous malformation (CM-AVM; MIM 60354) is an autosomal dominant disorder characterized by multifocal cutaneous capillary malformations, often in association with fast-flow vascular lesions, which may be cutaneous, subcutaneous, intramuscular, intraosseus, or cerebral arteriovenous malformations or arteriovenous fistulas. CM-AVM results from heterozygous mutations in the RASA1 gene. Capillary malformations of the skin are common, and clinical examination alone may not be able to definitively diagnose-or exclude- CM-AVM. We report a family in which the proband was initially referred for a genetic evaluation in the neonatal period because of the presence of a cardiac murmur and minor dysmorphic features. Both he and his mother were noted to have multiple capillary malformations on the face, head, and extremities. Echocardiography revealed dilated head and neck vessels and magnetic resonance imaging and angiography of the brain revealed a large infratentorial arteriovenous fistula, for which he has had two embolization procedures. RASA1 sequence analysis revealed a heterozygous mutation, confirming his diagnosis of CM-AVM. We established targeted mutation analysis for the proband's mother and sister, the latter of whom is a healthy 3-year-old whose only cutaneous finding is a facial capillary malformation. This revealed that the proband's mother is also heterozygous for the RASA1 mutation, but his sister is negative. Consequently, his mother will undergo magnetic resonance imaging and angiography screening for intracranial and spinal fast-flow lesions, while his sister will require no imaging or serial evaluations. Targeted mutation analysis has been offered to additional maternal family members. This case illustrates the benefit of molecular testing in diagnosis and making screening recommendations for families with CM-AVM.


Antagonism between two mechanisms of antifungal drug resistance.
This study tested for interaction between two independently evolved mechanisms of fluconazole resistance in Saccharomyces cerevisiae. One set of strains was from a 400-generation evolution experiment, during which the concentration of fluconazole was increased from 16 to 256 microg/ml in four increments. At 100 generations, populations became fixed for resistance mutations in either of two transcriptional regulators, PDR1 or PDR3. At 400 generations, replicate populations became fixed for another resistance mutation in UNK1, an unmapped gene further increasing resistance. Another genotype used in this study came from a population placed initially in 128 microg/ml of fluconazole; this environment selects for resistance through loss of function at ERG3, resulting in altered sterol metabolism. Mutant strains carrying PDR1(r) or PDR3(r) were crossed with the erg3(r) mutant strain, and the doubly mutant, haploid offspring were identified. The double-mutant strains grew less well than the parent strains at all concentrations of fluconazole tested. In genome-wide assays of gene expression, several ABC transporter genes that were overexpressed in one parent and several ERG genes that were overexpressed in the other parent were also overexpressed in the double mutants. Of the 43 genes that were consistently overexpressed in the PDR1(r) parents at generation 100, however, 31 were not consistently overexpressed in the double mutants. Of these 31 genes, 30 were also not consistently overexpressed after a further 300 generations of evolution in the PDR1(r) parent populations. The two independently evolved mechanisms of fluconazole resistance are strongly antagonistic to one another.


The uncertain primary diagnosis of inflammatory bowel diseases.
The purpose of this study is to re-evaluate our series of patients affected by a colonic non-neoplastic disease, in order to measure the percentage in whom we were unable to make a correct diagnosis after the first clinical and histological approach and to single-out the reasons for our inability to reach the correct diagnosis. During the period 1985-1999 we observed 1228 patients affected by chronic inflammatory colonic diseases. In 859 patients (69.9%) an ulcerative colitis was diagnosed for the first time, and 248 patients (20.1%) were affected by Crohn's colitis. One hundred and twenty-one patients (9.8%) were defined as being affected by an undetermined colitis. Forty-three patients of these had a definite diagnosis, afterwards: 27 patients were affected by ulcerative colitis and 16 by Crohn's colitis. Differential diagnosis between inflammatory large bowel diseases (ILBD) and other forms of colitis was set out as follows: 62 cases out of 1228 were consequent on a bacterial infection or parasitosis; in 28 patients a colitis pseudomembranosus was diagnosed. Eighteen cases of ischemic colitis are reported and 14 patients were affected by NSAID-related colitis. In another 6 patients we diagnosed a postradiation colitis. In 22 cases mimicking a Crohn's colitis we ascertained 9 patients affected by intestinal lymphoma, 11 mycobacterium tuberculosis related intestinal infections and 2 cytomegalovirus related colitis. Despite progress in scientific acquisitions and in diagnostic methods, correct initial diagnosis of ILBD is still difficult, even though it will be defined with time.


Craniofacial Characteristics and Orthodontic Treatment of Diamond Blackfan Syndrome: Two Case Reports.
Diamond Blackfan anemia (DBA) is a chronic congenital form of erythrocytic hypoplasia in which erythroid precursor cell levels are low. DBA reflects ribosomal dysfunction and is accompanied by hematopoietic cell apoptosis, anemia, and various somatic symptoms. We report the characteristic symptoms of the craniofacial region and the orthodontic treatments of two DBA cases. Case 1 was a 12-year-old female. The typical physical and facial characteristics of DBA were lacking. On initial examination, she exhibited a skeletal Class II jaw and end to end molar relationships and a large overjet. An edgewise appliance was placed after extraction of the first maxillary premolars. After 3 years and 11 months, an appropriate overjet and overbite, rigid intercuspation, and an acceptable profile were evident without any clinical adverse effects. Case 2 was a 13-year-old female. She exhibited a skeletal Class I jaw relationship, a spaced dental arch, the maxillofacial dysplasia characteristic of Binder syndrome, hypoplasia of the right mandibular condyle, and labial protrusions of the maxillary and mandibular incisors. We placed an edgewise appliance and after 1 year and 7 months, the occlusion was optimal in the absence of any adverse effects. Our two DBA cases exhibited a broad spectrum of physical and dentofacial symptoms. Patients with DBA are often prescribed combined steroid/bisphosphonate therapies. Both agents are likely to affect alveolar bone remodeling after tooth extraction and orthodontic tooth movement. Careful consideration of medication with reference to various dentofacial characteristics is necessary.


[Functional changes in hematopoiesis in healthy subjects during adaptation to a high altitude hypoxia].
In the article, findings of the studies of white blood in healthy subjects during a short-term adaptation to high altitude (per. Tuya-Ashu, 3200 m), are discussed. A 40-day adaptation of healthy people has led to positive shifts: an increase of the number of leukocytes with prevalence of the absolute count of neutrophiles and lymphocytes, as well as an activation of the latter during the first days of stay at high altitude. An effect of the high-altitude hypoxia resulted in intensification of erythropoiesis that manifests itself in an improvement of red cell hemoglobinization and a decrease of the degree of non-effective erythropoiesis. The data obtained support the data of the myelograms demonstrating an improvement of differentiation of white hematopoiesis.


Strain in Silica-Supported Ga(III) Sites: Neither Too Much nor Too Little for Propane Dehydrogenation Catalytic Activity.
Well-defined Ga(III) sites on SiO2 are highly active, selective, and stable catalysts in the propane dehydrogenation (PDH) reaction. In this contribution, we evaluate the catalytic activity toward PDH of tricoordinated and tetracoordinated Ga(III) sites on SiO2 by means of first-principles calculations using realistic amorphous periodic SiO2 models. We evaluated the three reaction steps in PDH, namely, the C-H activation of propane to form propyl, the β-hydride (β-H) transfer to form propene and a gallium hydride, and the H-H coupling to release H2, regenerating the initial Ga-O bond and closing the catalytic cycle. Our work shows how Brønsted-Evans-Polanyi relationships are followed to a certain extent for these three reaction steps on Ga(III) sites on SiO2 and highlights the role of the strain of the reactive Ga-O pairs on such sites of realistic amorphous SiO2 models. It also shows how transition-state scaling holds very well for the β-H transfer step. While highly strained sites are very reactive sites for the initial C-H activation, they are more difficult to regenerate. The corresponding less strained sites are not reactive enough, pointing to the need for the right balance in strain to be an effective site for PDH. Overall, our work provides an understanding of the intrinsic activity of acidic Ga single sites toward the PDH reaction and paves the way toward the design and prediction of better single-site catalysts on SiO2 for the PDH reaction.


Alendronate-induced Perturbation of the Bone Proteome and Microenvironmental Pathophysiology.
Objectives: Bisphosphonates (BPs) are powerful inhibitors of osteoclastogenesis and are used to prevent osteoporotic bone loss and reduce the risk of osteoporotic fracture in patients suffering from postmenopausal osteoporosis. Patients with breast cancer or gynecological malignancies being treated with BPs or those receiving bone-targeted therapy for metastatic prostate cancer are at increased risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Although BPs markedly ameliorate osteoporosis, their adverse effects largely limit the clinical application of these drugs. This study focused on providing a deeper understanding of one of the most popular BPs, the alendronate (ALN)-induced perturbation of the bone proteome and microenvironmental pathophysiology. Methods: To understand the molecular mechanisms underlying ALN-induced side-effects, an unbiased and global proteomics approach combined with big data bioinformatics was applied. This was followed by biochemical and functional analyses to determine the clinicopathological mechanisms affected by ALN. Results: The findings from this proteomics study suggest that the RIPK3/Wnt/GSK3/β-catenin signaling pathway is significantly perturbed upon ALN treatment, resulting in abnormal angiogenesis, inflammation, anabolism, remodeling, and mineralization in bone cells in an in vitro cell culture system. Conclusion: Our investigation into potential key signaling mechanisms in response to ALN provides a rational basis for suppressing BP-induced adverse effect and presents various therapeutic strategies.


Reporting on methods in clinical trials.
A clinical trial cannot be adequately interpreted without information about the methods used in the design of the study and the analysis of the results. To determine the frequency of reporting what we consider 11 important aspects of design and analysis, we surveyed all 67 clinical trials published in the New England Journal of Medicine, the Lancet, and the British Medical Journal from July through December 1979 and in the Journal of the American Medical Association from July 1979 through June 1980. Of all 11 items in the 67 trials published in all four journals, 56 per cent were clearly reported, 10 per cent were ambiguously mentioned, and 34 per cent were not reported at all. At least 80 per cent of the 67 trials reported information about statistical analyses, statistical methods used, and random allocation of subjects, yet only 19 per cent reported the method of randomization. Loss to follow-up was discussed in 79 per cent of the articles, treatment complications in 64 per cent, and admission of subjects before allocation in 57 per cent, but eligibility criteria for admission to the trial appeared in only 37 per cent. Although information about whether patients were blind to treatment was given in 55 per cent, information about whether there was blind assessment of outcome was reported in only 30 per cent. The statistical power of the trial to detect treatment effects was discussed in only 12 per cent of the articles. The clinical trials published in The New England Journal of Medicine reported 71 per cent of the 11 items, those in the Journal of the American Medical Association 63 per cent, those in the British Medical Journal 52 per cent, and those in the Lancet 46 per cent. These rates are significantly different (P less than 0.001). We recommend that editors improve the reporting of clinical trials by giving authors a list of the important items to be reported.


Factors influencing intraocular pressure, corneal thickness and corneal biomechanics after congenital cataract surgery.
This study aims to compare intraocular pressure (IOP), central corneal thickness (CCT) and corneal biomechanics among patients with aphakia, patients with primary and secondary pseudophakia and matched controls following congenital cataract surgery and to investigate the factors influencing these variables. This study included 36 aphakic eyes, 47 primary pseudophakic eyes and 30 secondary pseudophakic eyes. Thirty-four normal eyes of matched volunteers were recruited for comparisons. Postoperative IOP measured with a Goldmann applanation tonometer (IOPGAT), CCT, corneal hysteresis (CH), corneal resistance factor (CRF) and cornea-compensated IOP (IOPCC) were compared among the groups. Univariate analyses and multiple linear regression analyses were used to investigate the influences of independent factors on IOPGAT, CCT, CH, CRF and IOPCC, considering all the operated eyes as one group. IOPGAT was 12.5±0.92, 14.7±1.9, 13.4±2.3 and 15.7±2.0 mm Hg in normal, aphakic, primary pseudophakic and secondary pseudophakic eyes, respectively (p<0.001). CCT was 559.5±42.7, 628.0±61.7, 566.8±35.3 and 585.2±41.1 µm, respectively (p<0.001). CH was 10.87±2.47, 10.42±2.20, 11.84±2.13 and 9.74±1.94 mm Hg, respectively (p=0.019). IOPCC was 15.91±3.74, 18.40±4.35, 14.58±4.36 and 19.05±4.54 mm Hg, respectively (p<0.001). There was no significant difference in CRF among the groups (p=0.06). Regression analyses revealed that the type of operation was significantly associated with IOPGAT (p=0.04), CCT (p<0.001) and CH (p=0.006). IOPGAT, CCT, CH and IOPCC were significantly different in treated eyes compared with normal eyes after congenital cataract surgery. These variables were primarily affected by the type of surgery. Primary intraocular lens implantation preserved corneal structure and function of the anterior chamber angle.


The metabolic topography of idiopathic torsion dystonia.
We used [18F]fluorodeoxyglucose (FDG) and PET with a statistical model of regional metabolic covariation to study brain topographic organization in idiopathic torsion dystonia (ITD). We studied 11 patients with predominantly right-sided ITD and 11 age-matched controls, and measured global, regional cerebral and normalized metabolic rates for glucose (GMR, rCMRGlc, rCMRGlc/GMR). The Scaled Subprofile Model was applied to the combined rCMRGlc dataset to identify topographic covariance profiles associated with ITD. We found that global and regional metabolic rates were normal in ITD. The SSM analysis of the combined groups of ITD patients and normals revealed a significant topographic profile characterized by relative bilateral increases in the metabolic activity of the lateral frontal and paracentral cortices, associated with relative covariate hypermetabolism of the contralateral lentiform nucleus, pons and midbrain. Subject scores for this profile correlated significantly with Fahn-Marsden disease severity ratings (r = 0.67, P < 0.02). In contrast to parkinsonism, lentiform and thalamic metabolism were dissociated in dystonia. We conclude that ITD is characterized by relative metabolic overactivity of the lentiform nucleus and premotor cortices. The presence of lentiform thalamic metabolic dissociation suggests that in this disorder hyperkinetic movements may arise through excessive activity of the direct putameno-pallidal inhibitory pathway.


Adolescent dating violence: a national assessment of school counselors' perceptions and practices.
Adolescent dating violence (ADV) is a significant public health problem that, according to various estimates, affects 9% to 34% of adolescents in the United States. Schools can play an important role in preventing ADV. However, little is known about school personnel's practices and perceptions regarding ADV. This study assessed high school counselors' knowledge, training, perceptions, and practices on dealing with ADV incidents. A national random sample (n = 550) of high school counselors who were members of the American School Counselors Association were sent a valid and reliable questionnaire on ADV. A 3-wave mailing procedure was used to increase the response rate, which was 58%. Statistically significant differences (P < .05) were calculated by using t tests, χ(2) tests, analysis of variance, and logistic regression. A majority of the school counselors reported that they did not have a protocol in their schools to respond to an incident of ADV (81.3%). Additionally, the majority (90%) of counselors reported that in the past 2 years, training to assist survivors of teen dating abuse has not been provided to personnel in their schools, their school did not conduct periodic student surveys that include questions on teen dating abuse behaviors (83%), and their school did not have a committee that meets periodically to address health and safety issues that include teen dating abuse (76%). The results of this study indicate that schools do not find ADV a high-priority issue to be addressed in their student populations.


Surgical treatment of acute and chronic anterior and posterior cruciate ligament and lateral side injuries of the knee.
Combined anterior cruciate ligament, posterior cruciate ligament, and lateral-sided injuries of the knee most often occurs secondary to a forced varus moment or after knee dislocation. Management controversies include the optimal timing of surgery, operative techniques, and postoperative rehabilitation. Recent systematic literature reviews have demonstrated higher rates of failure with repair of the lateral and posterolateral corner structures, as opposed to reconstruction. However, the ideal ligament reconstruction techniques remain unclear. This chapter will review the combined anterior cruciate ligament/posterior cruciate ligament/lateral-sided injury pattern, including the physical examination findings, imaging, timing of surgery, graft selection, operative techniques, and postoperative rehabilitation protocols.


Silica core-shell particles for the dual delivery of gentamicin and rifamycin antibiotics.
Increasing bacterial resistance calls for the simultaneous delivery of multiple antibiotics. One strategy is to design a unique pharmaceutical carrier that is able to incorporate several drugs with different physico-chemical properties. This is highly challenging as it may require the development of compartmentalization approaches. Here we have prepared core-shell silica particles allowing for the dual delivery of gentamicin and rifamycin. The effect of silica particle surface functionalization on antibiotic sorption was first studied, enlightening the role of electrostatic and hydrophobic interactions. This in turn dictates the chemical conditions for shell deposition and further sorption of these antibiotics. In particular, the silica shell deposition was favored by the positively charged layer of gentamicin coating on the core particle surface. Shell modification by thiol groups finally allowed for rifamycin sorption. The antibacterial activity of the core-shell particles against Staphylococcus aureus and Pseudomonas aeruginosa demonstrated the dual release and action of the two antibiotics.


Envelope glycoprotein nucleotide sequence and genetic characterization of North American ovine lentiviruses.
Ovine lentiviruses (OvLV) resemble human immunodeficiency viruses in genomic organization, viral heterogeneity, and spectrum of cytophenotypic expression. To gain a better understanding of the relationship of North American OvLV isolates with other characterized OvLV strains, the complete DNA nucleotide sequence of the env region of a highly lytic (rapid/high) OvLV strain (85/34) was determined and compared with the sequence of amplicons within env of three other OvLV strains of varying cytophenotype and isolated from the same flock of sheep. LTR and pol regions also were compared among these strains. The env region of 85/34 was 986 codons in length and the reported nucleotide sequence showed features shared by other OvLV including heavy glycosylation and conserved and hypervariable regions within the surface membrane protein region. Phylogenetic analyses of regions within LTR, reverse transcriptase, and env grouped the four virus strains together and similar to the maedi-visna OvLV strains, including visna virus, South African ovine maedi visna virus, and EV1 (British OvLV isolate), but they were distinct from caprine arthritis encephalitis virus.


Health insurance for low-income working families. Effect on the provision of immunizations to preschool-age children.
The out-of-pocket cost for immunizations is a cause for referral to public health department clinics and is associated with delayed immunization. In 1991, New York State started Child Health Plus (CHPlus), an insurance program that covers ambulatory care and immunization services for children of families earning less than 222% of the poverty level. To determine the effect of CHPlus on the provision of immunizations. A before-and-after design was used to compare the year immediately before enrollment in CHPlus with the first year after enrollment in CHPlus. A mixed-model analysis of variance was used to control for the effects of age. All area primary care practices (n = 164) and public health department clinics (n = 6). Children (n = 1730) younger than 6 years who were enrolled in CHPlus. Number of immunization visits; types of providers (public health department clinics or primary care providers [pediatricians and family physicians]); and series-complete immunization coverage, including the diphtheria toxoid, tetanus toxoid, and pertussis vaccine, the oral poliovirus vaccine, and the measles, mumps, and rubella vaccine. The average age of the children was 37.7 months, 85% were white, 50% had been uninsured for immunizations before enrollment in CHPlus, and 16% previously received Medicaid. For infants, CHPlus decreased immunization visits to public health department clinics by 37% (from 0.14 to 0.09 visits per child, P = .009), increased immunization visits to primary care providers' offices by 15% (from 2.3 to 2.7 visits per child, P = .001), and increased immunization coverage by 7% (from 76% to 83%, P = .03). For children aged 1 to 5 years, CHPlus decreased visits to public health department clinics by 67% (from 0.06 to 0.02 visits per child, P < .001), increased visits to primary care providers' offices by 27% (from 0.46 to 0.59 visits per child, P < .001), and increased immunization coverage by 5% (from 83% to 88%, P < .001). The effects were greatest among previously uninsured children and among those with a gap in insurance coverage that was longer than 6 months. Insurance coverage for low-income working families resulted in a shift in the provision of immunizations from the health department to primary care providers and in increased immunization coverage.


Mixed model segregation analysis of LDL-C concentration with genotype-covariate interaction.
Mixed model complex segregation analyses have in the past ignored the possibility of genotype-covariate interaction. Only in the nonmixed model with polygenic heritability equal to zero have segregation analyses been performed that allowed for genotype specific regression of the phenotype on covariates. We present an extension of Hasstedt's [1982] mixed model likelihood approximation which does allow for genotype-covariate interaction in the mixed model. Following description of this approximation, we validate the likelihood calculation by a Monte Carlo procedure based on the actual pedigree and missing data structure used in a complex segregation analysis of low density plus very low density lipoprotein cholesterol (LDL-C + VLDL-C) in baboons. The observed averages of the bootstrap parameter estimates adequately recover the generating values, which included parameters specifying genotype-covariate interaction. We then applied both a traditional complex segregation analysis and an analysis with genotype-covariate interaction to test for the presence of a major locus affecting LDL-C levels in baboons. The model including genotype-covariate interaction was significantly different from the model without interactions, and strongly supported the hypothesis that there is a segregating Mendelian locus as opposed to a random environmental factor. This major locus accounts for approximately 46% of the variance in LDL-C levels, as compared to 40% explained by a locus with no genotype-covariate interaction.


Comparison of spectral-domain and time-domain optical coherence tomography in solar retinopathy.
The purpose of this article is to compare spectral-domain (SD) and time-domain (TD) optical coherence tomography (OCT) findings in patients with solar retinopathy. Complete ocular examinations and OCT were performed in two patients presenting with acute solar retinopathy soon after observation of an eclipse. Both patients were evaluated with SD-OCT and TD-OCT at the same time. SD-OCT demonstrated characteristic defects at the level of the inner and outer segment junction of the photoreceptors in all the affected eyes and decreased reflectiveness of the retinal pigment epithelium layer. TD-OCT images showed unremarkable findings in two eyes with deteriorated visual acuity. SD-OCT improves diagnosis and assessment of the degree and nature of foveal damage in patients with solar retinopathy and may be an important tool for use in identifying foveal damage not detected by TD-OCT. SD-OCT may be preferable to TD-OCT for confirmation or assessment of the degree of foveal damage in patients with solar retinopathy.


1000 Norms Project: protocol of a cross-sectional study cataloging human variation.
Clinical decision-making regarding diagnosis and management largely depends on comparison with healthy or 'normal' values. Physiotherapists and researchers therefore need access to robust patient-centred outcome measures and appropriate reference values. However there is a lack of high-quality reference data for many clinical measures. The aim of the 1000 Norms Project is to generate a freely accessible database of musculoskeletal and neurological reference values representative of the healthy population across the lifespan. In 2012 the 1000 Norms Project Consortium defined the concept of 'normal', established a sampling strategy and selected measures based on clinical significance, psychometric properties and the need for reference data. Musculoskeletal and neurological items tapping the constructs of dexterity, balance, ambulation, joint range of motion, strength and power, endurance and motor planning will be collected in this cross-sectional study. Standardised questionnaires will evaluate quality of life, physical activity, and musculoskeletal health. Saliva DNA will be analysed for the ACTN3 genotype ('gene for speed'). A volunteer cohort of 1000 participants aged 3 to 100 years will be recruited according to a set of self-reported health criteria. Descriptive statistics will be generated, creating tables of mean values and standard deviations stratified for age and gender. Quantile regression equations will be used to generate age charts and age-specific centile values. This project will be a powerful resource to assist physiotherapists and clinicians across all areas of healthcare to diagnose pathology, track disease progression and evaluate treatment response. This reference dataset will also contribute to the development of robust patient-centred clinical trial outcome measures.


Transinfection: a method to investigate Wolbachia-host interactions and control arthropod-borne disease.
The bacterial endosymbiont Wolbachia manipulates arthropod host biology in numerous ways, including sex ratio distortion and differential offspring survival. These bacteria infect a vast array of arthropods, some of which pose serious agricultural and human health threats. Wolbachia-mediated phenotypes such as cytoplasmic incompatibility and/or pathogen interference can be used for vector and disease control; however, many medically important vectors and important agricultural species are uninfected or are infected with strains of Wolbachia that do not elicit phenotypes desirable for disease or pest control. The ability to transfer strains of Wolbachia into new hosts (transinfection) can create novel Wolbachia-host associations. Transinfection has two primary benefits. First, Wolbachia-host interactions can be examined to tease apart the influence of the host and bacteria on phenotypes. Second, desirable phenotypes induced by Wolbachia in a particular insect can be transferred to another recipient host. This can allow the manipulation of insect populations that transmit pathogens or detrimentally affect agriculture. As such, transinfection is a valuable tool to explore Wolbachia biology and control arthropod-borne disease. The present review summarizes what is currently known about Wolbachia transinfection methods and applications. We also provide a comprehensive list of published successful and unsuccessful Wolbachia transinfection attempts.


Polymorphisms in MicroRNA Genes Associated with Schizophrenia Susceptibility but Not with Effectiveness of MECT.
Schizophrenia (SCZ) is a common and complex psychiatric disease associated with hereditary and environmental risk factors. MicroRNAs (miRNAs or miRs) are small, noncoding RNA molecules that endogenously regulate gene expression. Single nucleotide polymorphisms (SNPs) in related miRNA genes are associated with susceptibility of the disorder. We wonder if the SNPs have influence on the effectiveness of modified electroconvulsive therapy (MECT) for SCZ. rs1625579 within miR-137, rs6577555 within miR-34, and rs2296616 within miR-107 were sequenced in 150 cases and 150 controls to check the potential association between the SNPs and SCZ. Our results showed that allele G in rs1625579 (p = 0.005, adjusted OR = 1.379, 95%CI = 1.108 - 1.634), allele A in rs6577555 (p = 0.014, adjusted OR = 1.246, 95%CI = 1.045 - 1.463), allele G in rs2296616 (p < 0.001, adjusted OR = 1.646, 95%CI = 1.374 - 1.879) are positively associated with the disorder risk. MECT courses did significantly decrease the level of the miRNAs, except for the variant of rs2296616 with the AA genotype. Schizophrenic phenotypes assessed by the positive and negative syndrome scale (PANSS) were improved after MECT, and there was no significant relevance observed between the effectiveness of MECT and the variants of these loci. Thus, our findings indicate that polymorphisms within the loci may be involved in the pathogenesis of SCZ, and MECT is effective and unbiased for patients harboring different genotypes of the loci.


Histologic changes in skin implanted into the larynx and trachea by myocutaneous flap reconstruction.
Skin is the tissue most readily available for relining the walls of the reconstructed larynx or trachea. Its use has been condemned in the past because of potential contracture, complications have occurred when free, split-thickness grafts were used. We studied the changes that develop within skin that is transferred into the lumen of the airway as part of a vascularized sternohyoid myocutaneous flap. Twenty-one dogs underwent reconstruction of laryngotracheal defects by a vascularized myocutaneous flap. The closely shaved and chemically depilated skin included in this reconstruction was ultimately found to be well healed to the adjacent mucosa. Flaps as large as 8 cm2 survived with no evidence of scaling, crusting, or contracture. The cutaneous appendages in the flaps were compared with those found in adjacent skin near the donor site. After proper depilation there was involution of cutaneous appendages. Scarring of the dermis appeared to add support to the grafts. Our findings demonstrate that the rotary door sternohyoid myocutaneous flap is a reliable, well-vascularized flap that can have extensive application in laryngotracheal reconstruction.


Vaccination Status and Its Determinants Among Children Aged 12 to 23 Months in Mettu and Sinana Districts, Oromia Region, Ethiopia: A Comparative Cross Sectional Study.
Globally, more than 19 million children have not received all of their vaccination benefits, resulting in an estimated one million deaths worldwide each year. Vaccine-preventable diseases are becoming more common in Ethiopia, despite the fact that official vaccination coverage is sufficient to develop herd immunity locally for some diseases such as measles. This mistrust of the official report prompted us to conduct a community survey and compare it to other areas where there have been no reports of vaccine-preventable disease. A community-based comparative cross-sectional study was conducted from 20/01-20/02/2021 in Sinana and Mettu districts. Probability proportional to estimate size was used to select 23 clusters. We recruited 228 from Mettu and 436 from Sinana by systematic random sampling. We used a structured questionnaire to collected data from mother-child pair using card and history. We conducted independent t-tests to test coverage differences between districts. We identified determinants of full vaccination status by multivariate logistic regression analysis after bivariate candidate selection. Fully vaccinated children accounted for 62.7% in Sinana and 91.6% in Mettu, demonstrating a significant coverage difference (p<0.001). Being a resident of Mettu (AOR: 3.5, 95% CI [1.5, 6.9]), intended pregnancy (AOR 5.9, 95% CI [2.4, 11.3]), 4 or more antenatal care visits (AOR: 2.09, 95% CI [1.4, 3]), having postnatal care (AOR: 3.5, 95% CI [1.6, 7.9]), younger child age (AOR: 0.87, 95% CI [0.8, 0.9]), having up to three children (AOR 3, 95% CI [1.13, 8]) and good knowledge of vaccine schedule (AOR: 2.4, 95% CI [1.4, 4]) were associated positively with full vaccination status. Full vaccination status was 91.6% in Mettu and 62.7% in Sinana district. Place of residence, ANC, PNC, pregnancy intention, child number, age of child and knowledge of vaccination schedule were significantly associated with vaccination status of the children.