Telemedicine and the delivery of health services to veterans with multiple sclerosis.
Telemedicine involves the provision of health care and sharing of medical knowledge using telecommunications technologies. Preventive, diagnostic, and therapeutic services, as well as patient education and assistance with self-management of health, can be provided via telemedicine. The Veterans Health Administration (VHA) has a wide range of telemedicine capabilities. Given limitations on studying its effectiveness, telemedicine is often applied to new patient populations without explicit evaluation of efficacy. Evaluating the potential use of telemedicine services through supporting literature from other disorders may be possible. This paper discusses applying telemedicine to the care of individuals with multiple sclerosis (MS) when few published evaluations exist in MS. In this paper, we (1) provide a background on the use of telemedicine in the private sector and in the VHA, (2) discuss the use of current telemedicine literature to management of individuals with MS, and (3) review the strengths and limitations of telemedicine as a care delivery vehicle.


Neurotransplantation-induced plasticity in the recipient CNS: focusing on the recipient response.
In the last two decades, neurotransplantation has gained the status of a potentially valuable treatment option in various central nervous system (CNS) disorders. This technique has provided considerable functional improvement in animal models of neurodegenerative diseases, stroke and trauma. In order to make the best therapeutic use of this treatment option, mechanisms of neurotransplantation-induced recovery need to be better understood. Specific interactions of transplants with the recipient brain, which are prominent in embryonic neural cell grafts, include formation of synapses between grafted neurons and recipient neuronal population with controlled release of neurotransmitters. Production and release of specific trophic substances for the recipient neurons by the grafted cells also play a considerable role in some transplants. In the above cases, the functional recovery seems to correlate well with the number of surviving cells in the transplant. There is, however, another component to the graft-induced recovery, best revealed in those graft recipients who display functional improvement although only few or no grafted cells can be found at the post mortem analysis. While psychological factors (placebo effect) have been proposed to play a central role in human graft recipients with functional recovery in the absence of surviving grafts, animal models of neurodegenerative disease have consistently shown the same phenomenon. Our recent results point to the local inflammatory and immune response to transplantation as a key element which induces a trophic response in the CNS parenchyma and stimulates plastic changes of the recipient neural connections. Findings by other investigators, who studied the connections between the inflammatory and neurotrophic responses in vitro and in vivo, and glial reaction to CNS trauma and trophic factor synthesis in vivo, support such conclusions. Accumulated evidence point to the need for further studies that would elucidate the role of the immune response in connection with CNS transplantation outcome.


New lipophilic glycomimetic DC-SIGN ligands: Stereoselective synthesis and SPR-based binding inhibition assays.
The design and synthesis of efficient ligands for DC-SIGN is a topic of high interest, because this C-type lectin has been implicated in the early stages of many infection processes. DC-SIGN membrane-protein presents four carbohydrate-binding domains (CRD) that specifically recognize mannose and fucose. Therefore, antagonists of minimal disaccharide epitope Manα(1,2)Man, represent potentially interesting antibacterial and antiviral agents. In the recent past, we were able to develop efficient antagonists, mimics of the natural moiety, characterized by the presence of a real d-carbamannose unit which confers greater stability to enzymatic breakdown than the corresponding natural disaccharide ligand. Herein, we present the challenging stereoselective synthesis of four new amino or azide glycomimetic DC-SIGN antagonists with attractive orthogonal lipophilic substituents in C(3), C(4) or C(6) positions of the real carba unit, which were expected to establish crucial interactions with lipophilic areas of DC-SIGN CRD. The activity of the new ligands was evaluated by SPR binding inhibition assays. The interesting results obtained, allow to acquire important information about the influence of the lipophilic substituents present in specific positions of the carba scaffold. Furthermore, C(6) benzyl C(4) tosylamide pseudodisaccharide displayed a good affinity for DC-SIGN with a more favorable IC50 value than those of the previously described real carba-analogues. This study provides valuable knowledge for the implementation of further structural modifications towards improved inhibitors.


Early glycemic control, age at onset, and development of microvascular complications in childhood-onset type 1 diabetes: a population-based study in northern Sweden.
The aim of this work was to study the impact of glycemic control (HbA(1c)) early in disease and age at onset on the occurrence of incipient diabetic nephropathy (MA) and background retinopathy (RP) in childhood-onset type 1 diabetes. All children, diagnosed at 0-14 years in a geographically defined area in northern Sweden between 1981 and 1992, were identified using the Swedish Childhood Diabetes Registry. From 1981, a nationwide childhood diabetes care program was implemented recommending intensified insulin treatment. HbA(1c) and urinary albumin excretion were analyzed, and fundus photography was performed regularly. Retrospective data on all 94 patients were retrieved from medical records and laboratory reports. During the follow-up period, with a mean duration of 12 +/- 4 years (range 5-19), 17 patients (18%) developed MA, 45 patients (48%) developed RP, and 52% had either or both complications. A Cox proportional hazard regression, modeling duration to occurrence of MA or RP, showed that glycemic control (reflected by mean HbA(1c)) during the follow-up was significantly associated with both MA and RP when adjusted for sex, birth weight, age at onset, and tobacco use as potential confounders. Mean HbA(1c) during the first 5 years of diabetes was a near-significant determinant for development of MA (hazard ratio 1.41, P = 0.083) and a significant determinant of RP (1.32, P = 0.036). The age at onset of diabetes significantly influenced the risk of developing RP (1.11, P = 0.021). Thus, in a Kaplan-Meier analysis, onset of diabetes before the age of 5 years, compared with the age-groups 5-11 and >11 years, showed a longer time to occurrence of RP (P = 0.015), but no clear tendency was seen for MA, perhaps due to lower statistical power. Despite modern insulin treatment, >50% of patients with childhood-onset type 1 diabetes developed detectable diabetes complications after approximately 12 years of diabetes. Inadequate glycemic control, also during the first 5 years of diabetes, seems to accelerate time to occurrence, whereas a young age at onset of diabetes seems to prolong the time to development of microvascular complications.


Attenuation of free radical production and paracrystalline inclusions by creatine supplementation in a patient with a novel cytochrome b mutation.
Mitochondrial cytopathies are associated with increased free radical generation and paracrystalline inclusions. Paracrystalline inclusions were serendipitously found in a young male athlete with a very high respiratory exchange ratio during steady-state exercise; he also had an unusually low aerobic capacity. Direct sequencing of the mitochondrial DNA (mtDNA) coding regions revealed a novel missense mutation (G15497A) resulting in a glycine-->serine conversion at a highly conserved site in the cytochrome b gene in the subject, his mother, and sister. Cybrids, prepared by fusion of the subject's platelets with either U87MG rho degrees or SH-SY5Y rho degrees cells, generated higher basal levels of reactive oxygen species (ROS), had a lower adenosine triphosphate (ATP) content, and were more sensitive to oxygen and glucose deprivation and peroxynitrite generation compared to control cybrids with wild-type mtDNA. Cell survival was significantly enhanced with 50 mmol/L creatine monohydrate (CM) administration. The subject was also treated with CM (10 g/d) for a period of 5 weeks and a repeat muscle biopsy showed no paracrystalline inclusions. The results suggest that the development of exercise-induced paracrystalline inclusions may be influenced by the G15497A mtDNA mutation, and that CM mitigates against the pathological consequences of this mutation.


London's medieval hospitals and the reformation.
Pre Reformation London was well provided with hospitals. However, with the dissolution of the monasteries, these establishments (all of which were linked to religious foundations) suffered. Most closed their doors permanently and their inmates were cast onto the streets. At least ten hospitals ceased to exist. St Bartholomew's Hospital and the Savoy survived the tumultuous years of the 1540s. In 1553 The 'Royal Group' of five hospitals was founded, eventually comprising St Bartholomew's Hospital, St Thomas's Hospital, the Bethlehem, the Bridewell and Christ's Hospital. This was achieved more by pressure from the citizens of London led by Sir Richard Gresham than by Royal beneficence.


Sensitive analysis of ethanolamine- and serine-containing phosphoglycerides by high-performance liquid chromatography.
A highly sensitive method for the separation and quantitative measurement of phospholipids containing primary amino groups, such as phosphatidylethanolamine, phosphatidylserine and lysophosphatidylethanolamine, is described. The method involves a simple and quantitative derivative formation of the phospholipids containing amino groups to their u.v.-absorbing biphenylcarbonyl derivatives. These have molar extinction coefficients of about 23,000 at 268nm. The phospholipid derivatives are then separated and non-destructively determined by high-performance liquid chromatography. The amino phospholipids containing vinyl ether bonds (plasmalogens) can be determined separately from the diacyl- and alkylacyl-amino phospholipids. The lower limit of detection by high-performance liquid-chromatographic analysis of the phospholipid derivatives is about 10-13pmol or 0.3-0.4ng of phospholipid P. The quantitative range of derivative formation and analysis by high-performance liquid chromatography of the phospholipids containing amino groups was shown to be 10-500nmol. The method was shown to be applicable to the analysis of phospholipids containing amino groups in tissue samples.


Relativistic effects at the Cu2O2 core - a density functional theory study.
This work presents for the first time the impact of relativistic effects on the Cu2O2 peroxide dicopper(ii)-bis(μ-oxo) dicopper (iii) equilibrium bonding motif in existing tyrosinase model complexes [Cu2(btmgp)2(μ-O)2]2+ and [Cu2{HC(tBuPz)2Py}2(O2)]2+ [S. Herres et al., Inorg. Chim. Acta, 2005, 358, 1089; S. Herres-Pawlis et al., Eur. J. Inorg. Chem., 2005, 3815; A. Hoffmann et al., Angew. Chem., Int. Ed., 2013, 52, 5398]. We use density functional theory (TPSSh/cc-pVTZ+D3BJ) with various relativistic approaches (ECPs, DKH, ZORA) to tackle the question of impact and find, as already known for small model complexes in the literature, that the O core is more stabilized with respect to the P core by the relativistic influence [D. G. Liakos and F. Neese, J. Chem. Theory Comput., 2011, 7, 1511]. Whereas DKH and ZORA yield similar results, ECPs underestimate the predicted effect. By calculating the functional of the relativistic overlap change, we can exactly identify the relativistic changes at the molecular orbital level and narrow down the affected MOs. Thus, by performing a detailed bond analysis utilizing the overlap population, we are able to rationalize the effects at the chemical level by finding relativistic bond stabilization in both isomers, which is more dominating in the O core. In conclusion, relativistic effects already play an important role in dicopper cores and should be considered.


Morphometry and abnormalities of the feet of Kaimanawa feral horses in New Zealand.
The present study investigated the foot health of the Kaimanawa feral horse population and tested the hypotheses that horses would have a large range of foot morphology and that the incidence of foot abnormality would be significantly high. Abnormality was defined as a variation from what the two veterinarian assessors considered as optimal morphology and which was considered to impact negatively on the structure and/or function of the foot. Fifteen morphometric variables were measured on four calibrated photographic views of all four feet of 20 adult Kaimanawa feral horses. Four morphometric variables were measured from the lateromedial radiographs of the left forefoot of each horse. In addition, the study identified the incidence of gross abnormality observed on the photographs and radiographs of all 80 feet. There was a large variation between horses in the morphometric dimensions, indicating an inconsistent foot type. Mean hoof variables were outside the normal range recommended by veterinarians and hoof care providers; 35% of all feet had a long toe conformation and 15% had a mediolateral imbalance. Abnormalities included lateral (85% of horses) and dorsal (90% of horses) wall flares, presence of laminar rings (80% of horses) and bull-nose tip of the distal phalanx (75% of horses). Both hypotheses were therefore accepted. The Kaimanawa feral horse population demonstrated a broad range of foot abnormalities and we propose that one reason for the questionable foot health and conformation is lack of abrasive wearing by the environment. In comparison with other feral horse populations in Australia and America there may be less pressure on the natural selection of the foot of the Kaimanawa horses by the forgiving environment of the Kaimanawa Ranges. Contrary to popular belief, the feral horse foot type should not be used as an ideal model for the domestic horse foot.


Intraocular penetration of periocular ketorolac and efficacy in experimental uveitis.
To determine in rabbits whether periocular injection of ketorolac tromethamine effectively delivers the drug to the eye and, if so, whether this is efficacious in the treatment of experimental uveitis. Ketorolac was administered by anterior subconjunctival injection, posterior periocular injection, intramuscular injection, or topical eye drops. The aqueous and vitreous were assayed for ketorolac. Anterior subconjunctival and topical ketorolac were compared to control as well as topical and anterior subconjunctival steroid treatments in uveitis induced by the intravitreal injection of tumor necrosis factor. Anterior subconjunctival injection led to high, though short-lived, levels of drug in the aqueous and vitreous. Posterior periocular injection led to much lower levels. Topical dosing led to relatively low aqueous and undetectable vitreous levels. No ocular levels were detected after intramuscular dosing. All tested antiinflammatory treatments were similarly effective in controlling uveitis. Anterior subconjunctival injection of ketorolac produced high intraocular concentrations of drug and was beneficial in controlling the inflammation in this animal model of uveitis.


Do vitamin D levels affect antibody titers produced in response to HPV vaccine?
In addition to its well-known effects on bone metabolism, vitamin D is an immunomodulating hormone. Serum vitamin D levels in males 18-25 years were measured at baseline, and HPV antibody titers were measured one month following the third quadrivalent HPV vaccine dose. Vitamin D levels were ≥ 30 ng/ml (normal) in 60 males and <30 ng/ml (low) in 113 males. Reverse cumulative distribution curves and scatter plots showed higher antibody titers with low vitamin D for all vaccine strains (P < 0.05). In linear regression analyses, antibody titers for all HPV strains were significantly higher among those with lower vitamin D levels and among younger participants (P < 0.05). These relationships add to the body of knowledge of the complex role of vitamin D in immunoregulation.


Synthesis of symmetrical multichromophoric Bodipy dyes and their facile transformation into energy transfer cassettes.
Multichromophoric boron-dipyrromethene (Bodipy) dyes synthesized on phenylene-ethynylene platforms have been be converted to energy transfer cassettes in a one-step chemical transformation. Excitation energy transfer processes in these highly symmetrical derivatives were studied in detail, including time-resolved fluorescence spectroscopy techniques. Excitation spectra and the emission lifetimes suggest efficient energy transfer between the donor and acceptor chromophore. These novel energy transfer cassettes, while highlighting a short-cut approach to similar energy transfer systems, could be useful as large pseudo-Stokes shift multichromophoric dyes with potential applications in diverse applications.


[Chemotherapy of head and neck carcinomas].
In most cases head and neck tumors manifest themselves on a local-regional level giving rise to highly mutilating pathologies with psycho-social repercussions. Surgery and radiotherapy are effective treatments for limited neoplasms (stage I-II). On the other hand, after surgery and/or radiotherapy, the treatment of locally advanced tumors (stage III-IV) or local recurrences and/or distant metastases is still problematic. For this reason chemotherapy, initially used only as a palliative, is today associated with other treatments to achieve better results both in terms of survival and disease-free time spans. Hence chemotherapy must be considered part of any multimodal primary treatment for advanced squamous cell carcinoma of the head and neck. In fact, numerous clinical studies have clearly demonstrated that adjuvant or neoadjuvant chemotherapy has a highly relative affect on survival in locally advanced diseases and that the incidence of distant metastases is reduced. This is not, however, followed by a similar reduction in local recurrences which are often the cause of death in such patients. It would, on the other hand, appear that survival is improved with integrated radio-chemotherapy. Immunochemotherapy, which has not as yet provided significant clinical results in cases of advanced tumors and/or metastases, must still be evaluated in the treatment of locally limited neoplasms. Organ preservation, which proves feasible in the larynx, leads one to hope it can be applied in other head and neck sites. The future balance leans in favor of the multidisciplinary approach and multi-center studies must be performed so that an adequate number of cases can be gathered over a brief period. This will make it possible to answer those questions and, at times, illusions which accompany chemotherapy in the treatment of advanced head and neck tumors.


Experiences of immigrant women who self-petition under the Violence Against Women Act.
Undocumented immigrant women who are abused and living in the United States are isolated in a foreign country, in constant fear of deportation, and feel at the mercy of their spouse to gain legal status. To ensure that immigration law does not trap women in abusive relationships, the Violence Against Women Act (VAWA, 1994) enabled immigrant women to self-petition for legal status. Qualitative research methods were used in this participatory action research to investigate the experiences of Mexican immigrant women filing VAWA self-petitions. Emotional, financial, and logistic barriers in applying are identified, and recommendations for practice research and policy are provided.


The Effectiveness of Resisted Sled Training (RST) for Sprint Performance: A Systematic Review and Meta-analysis.
Sprinting is key in the development and final results of competitions in a range of sport disciplines, both individual (e.g., athletics) and team sports. Resisted sled training (RST) might provide an effective training method to improve sprinting, in both the acceleration and the maximum-velocity phases. However, substantial discrepancies exist in the literature regarding the influence of training status and sled load prescription in relation to the specific components of sprint performance to be developed and the phase of sprint. Our objectives were to review the state of the current literature on intervention studies that have analyzed the effects of RST on sprint performance in both the acceleration and the maximum-velocity phases in healthy athletes and to establish which RST load characteristics produce the largest improvements in sprint performance. We performed a literature search in PubMed, SPORTDiscus, and Web of Science up to and including 9 January 2018. Peer-reviewed studies were included if they met all the following eligibility criteria: (1) published in a scientific journal; (2) original experimental and longitudinal study; (3) participants were at least recreationally active and towed or pulled the sled while running at maximum intensity; (4) RST was one of the main training methods used; (5) studies identified the load of the sled, distance covered, and sprint time and/or sprint velocity for both baseline and post-training results; (6) sprint performance was measured using timing gates, radar gun, or stopwatch; (7) published in the English language; and (8) had a quality assessment score > 6 points. A total of 2376 articles were found. After filtering procedures, only 13 studies were included in this meta-analysis. In the included studies, 32 RST groups and 15 control groups were analyzed for sprint time in the different phases and full sprint. Significant improvements were found between baseline and post-training in sprint performance in the acceleration phase (effect size [ES] 0.61; p = 0.0001; standardized mean difference [SMD] 0.57; 95% confidence interval [CI] - 0.85 to - 0.28) and full sprint (ES 0.36; p = 0.009; SMD 0.38; 95% CI - 0.67 to - 0.10). However, non-significant improvements were observed between pre- and post-test in sprint time in the maximum-velocity phase (ES 0.27; p = 0.25; SMD 0.18; 95% CI - 0.49 to 0.13). Furthermore, studies that included a control group found a non-significant improvement in participants in the RST group compared with the control group, independent of the analyzed phase. RST is an effective method to improve sprint performance, specifically in the early acceleration phase. However, it cannot be said that this method is more effective than the same training without overload. The effect of RST is greatest in recreationally active or trained men who practice team sports such as football or rugby. Moreover, the intensity (load) is not a determinant of sprint performance improvement, but the recommended volume is > 160 m per session, and approximately 2680 m per total training program, with a training frequency of two to three times per week, for at least 6 weeks. Finally, rigid surfaces appear to enhance the effect of RST on sprint performance.


High-pass resolution perimetry in uncomplicated myopia.
Fifteen subjects (28 eyes) with uncomplicated myopia (3-9 D) were examined using high-pass resolution and Goldmann perimetry. In the central 30 degree field a slight increase was observed in mean resolution threshold significantly correlated to the degree of myopia. In the Goldmann visual fields threshold increase was observed in the area around the blind spot in eight subjects (10 eyes). In the resolution fields only one subject (one eye) showed a corresponding abnormality.


The presence of gonadotropin receptors in nonpregnant human uterus, human placenta, fetal membranes, and decidua.
The possible presence of gonadotropin receptors in nonpregnant human uterus and human fetoplacental unit was investigated by light microscope immunocytochemistry using a monoclonal antibody to rat luteal hCG/LH receptors. The receptor antibody cross-reacted with human and bovine hCG/LH receptors and appears to be directed against the receptor rather than other proteins, including HLA class I antigens. Uterus and fetoplacental unit contained receptor antibody-binding sites, which indicates the presence of hCG/LH receptors. In the endometrium these receptors were present in glandular and luminal epithelial cells as well as in stromal cells. In the myometrium the receptors were detected in circular and elongated myometrial smooth muscle and vascular smooth muscle. Comparison of immunostaining intensities, which indicates the presence of different amounts of receptors, revealed that luminal and glandular epithelial cells contained more receptors than stromal cells. These cells, in turn, contained more receptors than myometrial and vascular smooth muscle. All cells in secretory phase uterine specimens contained more receptors than corresponding cells from the proliferative phase of the cycle. Midpregnancy placenta, amniotic epithelium, chorionic cytotrophoblasts, and decidual cells contained hCG/LH receptors. At term pregnancy, while receptors in fetal membranes and decidua continue to be detected, placental tissues did not show any detectable receptors unless the tissues were pretreated with neuraminidase. This indicated that term pregnancy placenta contain hCG/LH receptors masked by sialic acid residues. Comparison of immunostaining intensities suggested that syncytiotrophoblasts contained more receptors than cytotrophoblasts at midpregnancy; mesenchymal cells or blood vessels contained no detectable receptors. There were more receptors in decidua than in fetal membranes at mid- and term pregnancy. While the amniotic epithelial receptors decreased, the receptors in chorionic cytotrophoblasts and decidual cells increased from mid- to term pregnancy. In summary, hCG/LH receptors were demonstrated in the nonpregnant human uterus, human placenta, fetal membranes, and decidua. This indicates that hCG/LH may directly regulate functions of these tissues by endocrine, autocrine, or paracrine mechanisms.


Mössbauer studies of Escherichia coli sulfite reductase complexes with carbon monoxide and cyanide. Exchange coupling and intrinsic properties of the [4Fe-4S] cluster.
Mössbauer studies of the hemoprotein subunit (SiR) of E. coli sulfite reductase have shown that the siroheme and the [4Fe-4S] cluster are exchange-coupled. Here we report Mössbauer studies of SiR complexed with either CO or CN- and of SiR in the presence of the chaotropic agent dimethyl sulfoxide (Me2SO). The spectra of one-electron-reduced SiR X CN show that all five iron atoms reside in a diamagnetic environment; the ferroheme X CN complex is low spin and the [4Fe-4S] cluster is in the 2+ oxidation state. Titration with ferricyanide affords a CN- complex of oxidized SiR in which the siroheme iron is low spin ferric, with the cluster remaining in the 2+ state. At low temperatures, paramagnetic hyperfine interactions are observed for the iron sites of the cluster, suggesting that it is exchange-coupled to the heme iron. Reduction of one-electron-reduced SiR X CN and SiR X CO yields complexes with "g = 1.94"-type EPR signals showing that the second electron is accommodated by the iron-sulfur cluster. The fully reduced complexes yield well resolved Mössbauer spectra which were analyzed in the spin Hamiltonian formalism. The analysis shows that the cluster subsites are equivalent in pairs, one pair having properties reminiscent of ferric sites whereas the other pair has features more typical of ferrous sites. The Mössbauer spectra of oxidized SiR kept in 60% (v/v) Me2SO are virtually identical with those observed for SiR in standard buffer, implying that the coupling is maintained in the presence of the chaotrope. Fully reduced SiR displays an EPR signal with g values of g = 2.53, 2.29, and 2.07. In 60% Me2SO, this signal vanishes and a g = 1.94 signal develops; this transition is accompanied by a change in the spin state of the heme iron from S = 1 (or 2) to S = O.


Efficacy and safety of gemcitabine plus S-1 vs. gemcitabine plus nab-paclitaxel in treatment-naïve advanced pancreatic ductal adenocarcinoma.
Gemcitabine plus nab-paclitaxel (GnP) is the standard first-line therapy for advanced pancreatic ductal adenocarcinoma (PDAC). S-1, an oral fluoropyrimidine derivative, as compared with gemcitabine, is non-inferior in terms of overall survival (OS) and is associated with lower hematologic toxicity. Accordingly, S-1 is a convenient oral alternative treatment for advanced PDAC. This study was aimed at comparing the efficacy and safety of gemcitabine plus S-1 (GS) vs. GnP as first-line chemotherapy for advanced PDAC. Patients with advanced PDAC who received first-line GS or GnP at the Peking Union Medical College Hospital between March 2011 and November 2022 were evaluated. A total of 300 patients were assessed, of whom 84 received GS and 216 received GnP. The chemotherapy completion rate was higher with GS than GnP (50.0% vs. 30.3%, P = 0.0028). The objective response rate (ORR) was slightly higher (14.3% vs. 9.7%, P = 0.35), and the median OS was significantly longer (17.9 months vs. 13.3 months, P = 0.0078), in the GS group than the GnP group. However, the median progression-free survival (PFS) did not significantly differ between groups. Leukopenia risk was significantly lower in the GS group than the GnP group (14.9% vs. 28.1%, P = 0.049). As first-line chemotherapy for advanced PDAC, the GS regimen led to a significantly longer OS than the GnP regimen. The PFS, ORR, and incidence of severe adverse events were comparable between the GS and GnP groups.


Persistence profile to nucleos(t)ide analogue treatment for patients with chronic hepatitis B.
There are currently five approved nucleos(t)ide analogues (NUCs) for the management of chronic hepatitis B (CHB): lamivudine, adefovir dipivoxil, telbivudine, entecavir, and tenofovir disoproxil fumarate. To determine the persistence rates among patients receiving NUCs for CHB at weeks 48, 96 and 144, compare them in these periods, and analyse the evolution of treatment persistence. We conducted a retrospective study that included patients with CHB who initiated antiviral therapy and were attended to by the pharmaceutical care office between January 2002 and December 2011. Patients included in a clinical trial or patients who did not collect their medication personally were excluded. There were two different analyses: a comparative analysis of the persistence rates in three periods (weeks 1-48, weeks 48-96, and weeks 96-144); and a Kaplan-Meier analysis to evaluate the evolution of persistence. A total of 102 patients were included. Persistence rates were different in the three periods. They decreased during the course of the different periods, and the decline was more rapid between the first and second period. There were statistically significant differences in the non-persistence of the five drugs (p<0.005). Entecavir had the best profile of persistence, followed by tenofovir. This study showed that high genetic barrier drugs had a better profile of persistence in the initial treatment of patients with CHB. Data seem to suggest entecavir may offer better persistence rates than tenofovir, and the persistence rates for all five medications dropped in weeks 48-96.


R659X mutation in the MLH1 gene in hereditary non-polyposis colorectal cancer(HNPCC) in an Indian extended family.
Hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome), is a genetically heterogeneous disorder that is believed to account for 2-10 per cent of all the colorectal cancer cases. The disease follows autosomal dominant inheritance pattern with high penetrance (85%) and younger age of onset when compared to patients with sporadic tumours. HNPCC is associated with germ-line mutations in the DNA mismatch repair (MMR) genes namely MLH1, MSH2, MSH6, and PMS2. The present study was aimed at analyzing mismatch repair gene(s) in an extended Indian family satisfying the Amsterdam criteria, and extending the analysis to general population to estimate frequency of the mutations/polymorphisms observed. A total 12 members of the HNPCC family were studied for genetic investigation. Ethnically matched 250 normal individuals were also included as controls to study the observed mutations/polymorphisms at population level. The analysis resulted in identification of a 1975C>T mutation in exon 17, resulting in substitution of arginine residue with stop codon at codon 659. 655A>G substitution was also observed, resulting in replacement of isoleucine with valine at codon 219. Similar analysis on 250 ethnically matched control subjects revealed complete absence of R659X mutation, while I219V variant was found in 9.8 per cent of the controls. R659X mutation correlates with disease phenotype, and 655A>G locus is highly polymorphic. Our study suggested that R659X substitution was prime cause for the disease phenotype in this family. I219V substitution is a polymorphism having no association with the disease onset or segregation. The family members harbouring this mutation were advised to be under regular medical surveillance.


Probing the binding of indolactam-V to protein kinase C through site-directed mutagenesis and computational docking simulations.
Protein kinase C (PKC) comprises a family of ubiquitous enzymes transducing signals by the lipophilic second messenger sn-1, 2-diacylglycerol (DAG). Teleocidin and its structurally simpler congener indolactam-V (ILV) bind to PKC with high affinity. In this paper, we report our computational docking studies on ILV binding to PKC using an automatic docking computer program, MCDOCK. In addition, we used site-directed mutagenesis to assess the quantitative contribution of crucial residues around the binding site of PKC to the binding affinity of ILV to PKC. On the basis of the docking studies, ILV binds to PKC in its cis-twist conformation and forms a number of optimal hydrogen bond interactions. In addition, the hydrophobic groups in ILV form "specific" hydrophobic interactions with side chains of a number of conserved hydrophobic residues in PKC. The predicted binding mode for ILV is entirely consistent with known structure-activity relationships and with our mutational analysis. Our mutational analysis establishes the quantitative contributions of a number of conserved residues to the binding of PKC to ILV. Taken together, our computational docking simulations and analysis by site-directed mutagenesis provide a clear understanding of the interaction between ILV and PKC and the structural basis for design of novel, high-affinity, and isozyme-selective PKC ligands.


Activated Braf induces esophageal dilation and gastric epithelial hyperplasia in mice.
Germline mutations in BRAF are a major cause of cardio-facio-cutaneous (CFC) syndrome, which is characterized by heart defects, characteristic craniofacial dysmorphology and dermatologic abnormalities. Patients with CFC syndrome also commonly show gastrointestinal dysfunction, including feeding and swallowing difficulties and gastroesophageal reflux. We have previously found that knock-in mice expressing a Braf Q241R mutation exhibit CFC syndrome-related phenotypes, such as growth retardation, craniofacial dysmorphisms, congenital heart defects and learning deficits. However, it remains unclear whether BrafQ241R/+ mice exhibit gastrointestinal dysfunction. Here, we report that BrafQ241R/+ mice have neonatal feeding difficulties and esophageal dilation. The esophagus tissues from BrafQ241R/+ mice displayed incomplete replacement of smooth muscle with skeletal muscle and decreased contraction. Furthermore, the BrafQ241R/+ mice showed hyperkeratosis and a thickened muscle layer in the forestomach. Treatment with MEK inhibitors ameliorated the growth retardation, esophageal dilation, hyperkeratosis and thickened muscle layer in the forestomach in BrafQ241R/+ mice. The esophageal dilation with aberrant skeletal-smooth muscle boundary in BrafQ241R/+ mice were recovered after treatment with the histone H3K27 demethylase inhibitor GSK-J4. Our results provide clues to elucidate the pathogenesis and possible treatment of gastrointestinal dysfunction and failure to thrive in patients with CFC syndrome.


Finding the right hip implant for patient and surgeon: the Dutch strategy--empowering patients.
We describe the implementation process of hip prostheses selection in the Netherlands. The recent problems with large head metal-on-metal hip prostheses resulted in substantial damage to the surgeons' credibility and reputation in the media. This led to a true sense of urgency among orthopaedic surgeons to increase their activities to secure patient safety. The board of the Dutch Orthopaedic Association (NOV) in the Netherlands established a Dutch Hip Task Force (DHTF) with the explicit assignment of formulating criteria to classify the quality of total hip implants on the Dutch market based on survivorship. The aim was to offer unequivocal information enabling a balanced choice of total hip prosthesis. The ultimate goal of the NOV is that all implanted total hip prostheses implanted in the Netherlands are based on reliable clinical evidence. The DHTF decided to adapt the principles of the National Institute for Health and Care Excellence (NICE, UK) (www.nice.org.uk). The taskforce uses data from the registries as well as the Orthopaedic Data Evaluation Panel (ODEP). If the ODEP guidelines had been chosen as standard alone, one quarter of our listed hip components would not have been included. In our view this underlines the strength in the Dutch approach where high quality registry data and ODEP ratings are complementary and result in a list of reliable hip prostheses. Most importantly we offer patients insights into the known quality of the implants by sharing the results of our implant review. This will facilitate shared decision making by empowering patients in their knowledge on available hip arthroplasties.


The International Caries Detection and Assessment System - ICDAS: A Systematic Review.
The aims of this study were: (1) to evaluate the overall reproducibility and accuracy of the International Caries Detection and Assessment System (ICDAS) for assessing coronal caries lesions, and (2) to investigate the use of systems associated with the ICDAS for activity assessment of coronal caries lesions. Specific search strategies were adopted to identify studies published up to 2016. For the first objective, we selected studies that assessed primary coronal caries lesions using the ICDAS as a reference standard. A total of 54 studies were included. Meta-analyses summarized the results concerning reproducibility and accuracy (correlation with histology, summary ROC curves [SROC], and diagnostic odds ratio [DOR]). The latter 2 were expressed at D1/D3 levels. The heterogeneity of the studies was also assessed. Reproducibility values (pooled) were > 0.65. The ICDAS mostly presented a good overall performance as most areas under SROC were > 0.75 at D1 and > 0.90 at D3; DOR ≥6. For the second objective, we selected studies investigating activity assessment associated with the ICDAS. The meta-analyses pooled results based on the same methodology and parameters as above. Longitudinal findings regarding caries progression were described to estimate the validity of these systems. On average, the systems for activity assessment of caries lesions showed moderate values concerning reproducibility and overall performance. Active caries lesions were more prone to progress than inactive ones after 2 years. In conclusion, the ICDAS presented a substantial level of reproducibility and accuracy for assessing primary coronal caries lesions. Additional systems associated with the ICDAS that classify caries lesion activity can be useful as they are moderately reproducible and accurate.


Association between the homeostasis model assessment of insulin resistance and coronary artery calcification: a meta-analysis of observational studies.
Insulin resistance (IR), a risk factor for cardiovascular diseases, has garnered significant attention in scientific research. Several studies have investigated the correlation between IR and coronary artery calcification (CAC), yielding varying results. In light of this, we conducted a systematic review to investigate the association between IR as evaluated by the homeostasis model assessment (HOMA-IR) and CAC. A comprehensive search was conducted to identify relevant studies in PubMed, Embase, Scopus, and Web of Science databases. In addition, preprint servers such as Research Square, BioRxiv, and MedRxiv were manually searched. The collected data were analyzed using either fixed or random effects models, depending on the heterogeneity observed among the studies. The assessment of the body of evidence was performed using the GRADE approach to determine its quality. The current research incorporated 15 studies with 60,649 subjects. The analysis revealed that a higher category of HOMA-IR was associated with a greater prevalence of CAC in comparison to the lowest HOMA-IR category, with an OR of 1.13 (95% CI: 1.06-1.20, I2 = 29%, P < 0.001). A similar result was reached when HOMA-IR was analyzed as a continuous variable (OR: 1.27, 95% CI: 1.14-1.41, I2 = 54%, P < 0.001). In terms of CAC progression, a pooled analysis of two cohort studies disclosed a significant association between increased HOMA-IR levels and CAC progression, with an OR of 1.44 (95% CI: 1.04-2.01, I2 = 21%, P < 0.05). It is important to note that the strength of the evidence was rated as low for the prevalence of CAC and very low for the progression of CAC. There is evidence to suggest that a relatively high HOMA-IR may be linked with an increased prevalence and progression of CAC.


Ankyrin repeat proteins comprise a diverse family of bacterial type IV effectors.
Specialized secretion systems are used by many bacteria to deliver effector proteins into host cells that can either mimic or disrupt the function of eukaryotic factors. We found that the intracellular pathogens Legionella pneumophila and Coxiella burnetii use a type IV secretion system to deliver into eukaryotic cells a large number of different bacterial proteins containing ankyrin repeat homology domains called Anks. The L. pneumophila AnkX protein prevented microtubule-dependent vesicular transport to interfere with fusion of the L. pneumophila-containing vacuole with late endosomes after infection of macrophages, which demonstrates that Ank proteins have effector functions important for bacterial infection of eukaryotic host cells.


Metabolic changes after prior treatment with ethanol. Evidence against in involvement of the Na+ + K+-activated ATPase in the increase in ethanol metabolism.
In perfused rat liver, the inhibition of ethanol uptake by ouabain does not follow the rapid inhibition of the Na+ K+- activated ATPase as assessed by changes in perfusate [K+] (half-time, t 1/2 = 2--3 min), but correlated rather with the slow inhibition of oxygen uptake (maximal inhibition = 40% in 20 min). The data indicate that ouabain exerts its effect on ethanol metabolism via the following sequence of events; inhibition of the sodium pump is followed gradually by a perturbation of the intracellular cation milieu; this leads to an inhibition of the mitochondrial respiratory chain, resulting in diminished rate of NADH oxidation, which in turn causes in inhibition of ethanol metabolism.


Maximum Constrained Directivity of Oversteered End-Fire Sensor Arrays.
For linear arrays with fixed steering and an inter-element spacing smaller than one half of the wavelength, end-fire steering of a data-independent beamformer offers better directivity than broadside steering. The introduction of a lower bound on the white noise gain ensures the necessary robustness against random array errors and sensor mismatches. However, the optimum broadside performance can be obtained using a simple processing architecture, whereas the optimum end-fire performance requires a more complicated system (because complex weight coefficients are needed). In this paper, we reconsider the oversteering technique as a possible way to simplify the processing architecture of equally spaced end-fire arrays. We propose a method for computing the amount of oversteering and the related real-valued weight vector that allows the constrained directivity to be maximized for a given inter-element spacing. Moreover, we verify that the maximized oversteering performance is very close to the optimum end-fire performance. We conclude that optimized oversteering is a viable method for designing end-fire arrays that have better constrained directivity than broadside arrays but with a similar implementation complexity. A numerical simulation is used to perform a statistical analysis, which confirms that the maximized oversteering performance is robust against sensor mismatches.


The pseudorabies virus Us2 protein, a virion tegument component, is prenylated in infected cells.
The Us2 gene is conserved among alphaherpesviruses, but its function is not known. We demonstrate here that the pseudorabies virus (PRV) Us2 protein is synthesized early after infection and localizes to cytoplasmic vesicles and to the plasma membrane, despite the lack of a recognizable signal sequence or membrane-spanning domain. Us2 protein is also packaged as part of the tegument of mature virions. The Us2 carboxy-terminal four amino acids comprise a CAAX motif, a well-characterized signal for protein prenylation. Treatment of infected cells with lovastatin, a drug that disrupts protein prenylation, changed the relative electrophoretic mobility of Us2 in sodium dodecyl sulfate-polyacrylamide gels. In addition, lovastatin treatment caused a dramatic relocalization of Us2 to cytoplasmic punctate structures associated with microtubules, which appeared to concentrate over the microtubule organizing center. When the CAAX motif was changed to GAAX and the mutant protein was synthesized from an expression plasmid, it concentrated in punctate cytoplasmic structures reminiscent of Us2 localization in infected cells treated with lovastatin. We suggest that prenylation of PRV Us2 protein is required for proper membrane association. Curiously, the Us2 protein isolated from purified virions does not appear to be prenylated. This is the first report to describe the prenylation of an alphaherpesvirus protein.


Oligonucleotide-based theranostic nanoparticles in cancer therapy.
Theranostic approaches, combining the functionality of both therapy and imaging, have shown potential in cancer nanomedicine. Oligonucleotides such as small interfering RNA and microRNA, which are powerful therapeutic agents, have been effectively employed in theranostic systems against various cancers. Nanoparticles are used to deliver oligonucleotides into tumors by passive or active targeting while protecting the oligonucleotides from nucleases in the extracellular environment. The use of quantum dots, iron oxide nanoparticles and gold nanoparticles and tagging with contrast agents, like fluorescent dyes, optical or magnetic agents and various radioisotopes, has facilitated early detection of tumors and evaluation of therapeutic efficacy. In this article, we review the advantages of theranostic applications in cancer therapy and imaging, with special attention to oligonucleotide-based therapeutics.


Regulation of intracellular pH in proximal tubules of avian long-looped mammalian-type nephrons.
In nonperfused proximal tubules isolated from chicken long-looped mammalian-type nephrons, intracellular pH (pHi), measured with the pH-sensitive fluorescent dye 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein, was approximately 7.3 under control conditions (HEPES-buffered medium with pH 7.4 at 37 degrees C) and was reduced to approximately 7.0 in response to NH4Cl pulse. The rate of recovery of pHi from this level to the resting level was 1) significantly reduced by the removal of Na+ from the bath, 2) significantly increased by the removal of Cl- from the bath, 3) unchanged by the removal of both Na+ and Cl- from the bath, 4) significantly reduced by the addition of either ethylisopropylamiloride or DIDS to the bath, 5) significantly increased by a high bath K+ concentration, and 6) unchanged by the addition of Ba2+ to the bath. These data suggest that both Na+-coupled and Cl--coupled basolateral acid-base fluxes are involved in determining the rate of recovery of pHi after acidification. The most likely ones to be important in regulating pHi are a Na+/H+ exchanger and a Na+-coupled Cl-/HCO-3 exchanger. In birds, long-looped mammalian-type nephrons resemble short-looped transitional nephrons but differ markedly from superficial loopless reptilian-type nephrons.


When cognitive control is not adaptive.
In order to engage in goal-directed behavior, cognitive agents have to control the processing of task-relevant features in their environments. Although cognitive control is critical for performance in unpredictable task environments, it is currently unknown how it affects performance in highly structured and predictable environments. In the present study, we showed that, counterintuitively, top-down control can impair and interfere with the otherwise automatic integration of statistical information in a predictable task environment, and it can render behavior less efficient than it would have been without the attempt to control the flow of information. In other words, less can sometimes be more (in terms of cognitive control), especially if the environment provides sufficient information for the cognitive system to behave on autopilot based on automatic processes alone.


Modeling Natural Killer Cell Targeted Immunotherapies.
Animal models have extensively contributed to our understanding of human immunobiology and to uncover the underlying pathological mechanisms occurring in the development of diseases. However, mouse models do not reproduce the genetic and molecular complexity inherent in human disease conditions. Human immune system (HIS) mouse models that are susceptible to human pathogens and can recapitulate human hematopoiesis and tumor immunobiology provide one means to bridge the interspecies gap. Natural killer cells are the founding member of the innate lymphoid cell family. They exert a rapid and strong immune response against tumor and pathogen-infected cells. Their antitumor features have long been exploited for therapeutic purposes in the context of cancer. In this review, we detail the development of highly immunodeficient mouse strains and the models currently used in cancer research. We summarize the latest improvements in adoptive natural killer (NK) cell therapies and the development of novel NK cell sources. Finally, we discuss the advantages of HIS mice to study the interactions between human NK cells and human cancers and to develop new therapeutic strategies.


Cost-benefit analysis of a school health education program: one method.
Health education professionals within the school setting must respond to the increasing challenge of satisfying the popular question of program accountability. The purpose of this paper is to suggest a method by which school health education programs can be evaluated in cost-benefit terms. The methodology presented utilizes a cost-effective model that has been altered so that monetary values can be assigned to health outcomes or benefits. The procedure is demonstrated to show that school health education programs can be shown to have a positive cost benefit ratio. The model can be used in any school health setting.


Plasma Rich in Growth Factors in Macular Hole Surgery.
The aim of this study was to evaluate the use of PRGF (plasma rich in growth factors) as an adjuvant to PPV (pars plana vitrectomy) in recurrent, persistent, or poor prognosis MH (macular hole). Patients with MH were treated with PPV plus adjuvant therapy (PRGF membrane (mPRGF) and injectable liquid PRGF (iPRGF)). The anatomical closure of MH and postoperative BCVA (best-corrected visual acuity) were evaluated. Eight eyes (eight patients) were evaluated: myopic MH (MMH, n = 4), idiopathic MH (IMH, n = 2), iatrogenic n = 1, traumatic n = 1. The mean age was 53.1 ± 19.3 years. Hence, 66.7% (n = 4) of patients previously had internal limiting membrane peeling. Five patients (62.5%) received mPRGF and iPRGF, and three patients (37.5%) received iPRGF. Gas tamponade (C3F8) was placed in seven cases and one case of silicone oil. Anatomic closure of MH was achieved in seven eyes (87.5%) and BCVA improved in six cases. In the MMH group, visual acuity improved in two lines of vision. Follow-up time was 27.2 ± 9.0 months. No adverse events or MH recurrences were recorded during follow-up. The use of PRGF as an adjuvant therapy to PPV can be useful to improve anatomical closure and visual acuity in MH surgery.


Analgesic and antispasmodic activities of 2-(2-nitro-phenyl)-1H-benzimidazole 5-carboxylic acid: evidence for the importance of the 2-(o-substituted phenyl) group.
Benzimidazole 5-carboxylic acid derivatives were investigated for analgesic activity in this study. Of the benzimidazole compounds tested, 2-(2-nitro-phenyl)-1H-benzimidazole 5-carboxylic acid showed remarkable naloxone sensitive analgesic activity in the tail clamp but not in the tail immersion analgesia tests. This centrally active compound showed antispasmodic activity only on KCl induced contractions of isolated rat ileum and not on acetylcholine induced contractions. Acute toxicity of the compounds were >100 mg/kg i.p. mice. It was concluded that substitution of the 2(o-phenyl) by nitro- but not by chloro- or methoxy groups is important for naloxone sensititive analgesic activity of benzimidazole compounds and it was hypothetized that new imidazole compounds having a 2-(o-substituted phenyl) moiety needs to be investigated.


A closed loop ML algorithm for phase aberration correction in phased array imaging systems. I. Algorithm synthesis and experimental results [Ultrasound medical imaging].
A new closed loop algorithm is described, based on the maximum likelihood theory, that corrects phase aberrations in phased array coherent imaging systems using phase estimates which are directly obtained from measured data (and not from estimated correlation functions). It has the advantage of estimating phase differences with respect to the same reference, and not phase differences between signals in adjacent array elements, eliminating the need to perform an integration to get the phase aberration profile. It allows for a real time implementation, in the sense that corrected data flows out of the circuit at the same rate that input data is fed into it. Being a closed loop algorithm, it is able to track time variations that may occur in the phase aberrations and, as in any phase lock loop circuit, it shows a trade-off between acquisition time and phase jitter.


Patient Portals: Objectives, Acceptance, and Effects on Health Outcome - A Scoping Review of Reviews.
Patient portals provide patients access to their electronic health record and other functions as secure messaging. For over a decade, more and more patient portals are developed for various settings. The aim of this scoping review of reviews is to systematically search the literature for existing reviews to provide an overview of patient portals' objectives, acceptance and effects on outcome. We followed the PRISMA Statement and its extension for scoping reviews, and searched for articles published in 2011-2021. The 19 included articles were considerably heterogeneous concentrating on health outcome or patient portal facilitators and barriers.


Bond strengths of an epoxy resin-based fiber post with four adhesive systems.
To investigate the push-out bond strengths of one epoxy resin-based quartz-fiber post with four adhesive systems. Forty-four single-rooted, single-canal teeth were randomly divided into four groups (n = 11): One-step (One-Step + Duo-link; Bisco), Variolink II (Excite DSC + Variolink II; Ivoclar Vivadent), Panavia F (ED primer + Panavia F; Kuraray), and RelyX (RelyX Unicem; 3M ESPE). All teeth crowns were removed, and the roots were treated with root canal therapy. Four adhesive systems were employed for bonding of one type of quartz-fiber post, strictly according to the manufacturers' instructions. Ten roots in each group were transversely sectioned into cervical, middle, and apical third slices 2 mm thick, and the bond strengths were measured with the push-out test. The other root was processed for SEM analysis. Two-way ANOVA, one-way ANOVA, and Student-Newman-Keuls test were used for statistical analysis. The push-out bond strengths were 7.15 +/- 3.43 MPa (RelyX), 12.48 +/- 9.33 MPa (One-step), 2.96 +/- 2.76 MPa (Panavia F), and 13.43 +/- 6.14 MPa (Variolink II). Two-way ANOVA showed statistically significant differences among adhesive systems (P < .05) and root regions (P < .05). The bond strengths of One-step and Variolink II groups were statistically higher than those of RelyX and Panavia F groups. The bond strengths of the cervical region of One-step and Panavia F groups were statistically significantly higher than those of the other two regions. The SEM images showed uniform and long resin tags in One-step and Variolink II groups, whereas few or no resin tags were visible in the other two groups. The type of adhesive system and root region had a significant influence on the bond strengths of the adhesively luted fiber posts. Total-etching technique achieved better bond strength than did the self-etching technique.


Gait Speed and Mobility Disability: Revisiting Meaningful Levels in Diverse Clinical Populations.
To investigate the heterogeneity of clinically meaningful levels of gait speed relative to self-reported mobility disability (SR-MD). Five longitudinal studies with older adults in different health states (onset of acute event, presence of chronic condition, sedentary, community living) were used to explore the relationship between gait speed and SR-MD. Lifestyle Interventions and Independence for Elders Pilot (LIFE-P), LIFE, Trial of Angiotensin-Converting Enzyme Inhibition and Novel Cardiovascular Risk Factors (TRAIN), Baltimore Hip Fracture Study (BHS2), Invecchiare in Chianti (InCHIANTI). Individuals aged 65 and older (N=3,540): sedentary, community dwelling (LIFE-P/LIFE), with hip fracture (BHS2), random population-based sample (InCHIANTI), high cardiovascular risk (TRAIN). Usual-pace gait speed across 3 to 4 m and SR-MD, defined as inability to walk approximately 1 block or climb 1 flight of stairs. The mean gait speed of participants without SR-MD was greater than 1.0 m/s in InCHIANTI and TRAIN, 0.79 m/s in LIFE-P/LIFE, and 0.46 m/sec in BHS2. Of individuals with SR-MD, mean gait speed was 0.08 m/s slower in LIFE-P/LIFE, 0.19 m/s slower in TRAIN, 0.22 m/s slower in BHS2, and 0.36 m/s slower in InCHIANTI. The optimal gait speed cutpoint for minimizing SR-MD misclassification rates ranged from 0.3 m/s in BHS2 to 1.0 m/s in TRAIN. In longitudinal analyses, development of SR-MD was dependent on initial gait speed and change in gait speed (p<.001). The relationship between absolute levels of gait speed and SR-MD may be context specific, and there may be variations between populations. Across diverse clinical populations, clinical interpretations of how change in usual pace gait speed relates to development of SR-MD depend on where on the gait speed continuum change occurs.


Free to visit all hours.
Helping patients keep in touch with relatives and friends is the objective of justvisiting.com, a website being piloted in Gateshead.


The nonstress test: the false negative test.
The nonstress test (NST) has been shown to be a reliable technique for the evaluation of fetal status. As a rule, a reactive NST, as opposed to a nonreactive NST, has been associated with a good pregnancy outcome. Nonetheless, fetal death has followed a reactive test. Because of the uncommon occurrence of a false negative NST, a retrospective investigation of the 2,226 patients who had undergone 4,500 NSTs was undertaken. Of these high-risk pregnancies, 1,564 women were delivered within 7 days of a reactive NST and there were four fetal deaths (0.026%). The presumed etiology for the four deaths was cord accident in three cases and abruptio placentae in one case. As with the false negative contraction stress test, the false negative NST appears to be associated with cord accidents, congenital anomalies, and abruptio placentae. Even though a reactive NST is associated with a low incidence of fetal death, close attention to the presence of fetal heart rate decelerations on the NST may be helpful in identifying those patients at risk for a cord accident and, theoretically, in reducing the incidence of fetal death. Even then, certain unavoidable situations can occur soon after a reactive NST, and, at present, no test of fetal well-being offers complete reassurance.


Hyperferritinaemia in dengue virus infected patients is associated with immune activation and coagulation disturbances.
During a dengue outbreak on the Caribbean island Aruba, highly elevated levels of ferritin were detected in dengue virus infected patients. Ferritin is an acute-phase reactant and hyperferritinaemia is a hallmark of diseases caused by extensive immune activation, such as haemophagocytic lymphohistiocytosis. The aim of this study was to investigate whether hyperferritinaemia in dengue patients was associated with clinical markers of extensive immune activation and coagulation disturbances. Levels of ferritin, standard laboratory markers, sIL-2R, IL-18 and coagulation and fibrinolytic markers were determined in samples from patients with uncomplicated dengue in Aruba. Levels of ferritin were significantly increased in dengue patients compared to patients with other febrile illnesses. Moreover, levels of ferritin associated significantly with the occurrence of viraemia. Hyperferritinaemia was also significantly associated with thrombocytopenia, elevated liver enzymes and coagulation disturbances. The results were validated in a cohort of dengue virus infected patients in Brazil. In this cohort levels of ferritin and cytokine profiles were determined. Increased levels of ferritin in dengue virus infected patients in Brazil were associated with disease severity and a pro-inflammatory cytokine profile. Altogether, we provide evidence that ferritin can be used as a clinical marker to discriminate between dengue and other febrile illnesses. The occurrence of hyperferritinaemia in dengue virus infected patients is indicative for highly active disease resulting in immune activation and coagulation disturbances. Therefore, we recommend that patients with hyperferritinaemia are monitored carefully.


Illness intrusiveness in individuals with panic disorder, obsessive-compulsive disorder, or social phobia.
To measure the extent to which anxiety disorders interfere with various domains of functioning, the Illness Intrusiveness Ratings Scale (IIRS) was completed by individuals with a DSM-IV principal diagnosis of panic disorder (PD; N = 35), obsessive-compulsive disorder (OCD; N = 51), or social phobia (SP; N = 49). Although the three groups did not differ on total IIRS scores, group differences did emerge for particular domains of functioning. Patients with OCD reported significantly more interference with respect to passive recreation (e.g., reading) than did SP patients and with respect to religious expression compared with both PD and SP patients. Patients with SP reported more impairment with respect to social relationships and self-expression/self-improvement compared with the other two groups. When compared with populations with a variety of other chronic illnesses, patients in the present study reported much higher levels of illness intrusiveness. The implications of these findings and future directions for research are discussed.


Bioinspired Soft Robotics: How Do We Learn From Creatures?
Soft robotics has opened a unique path to flexibility and environmental adaptability, learning from nature and reproducing biological behaviors. Nature implies answers for how to apply robots to real life. To find out how we learn from creatures to design and apply soft robots, in this Review, we propose a classification method to summarize soft robots based on different functions of biological systems: self-growing, self-healing, self-responsive, and self-circulatory. The bio-function based classification logic is presented to explain why we learn from creatures. State-of-art technologies, characteristics, pros, cons, challenges, and potential applications of these categories are analyzed to illustrate what we learned from creatures. By intersecting these categories, the existing and potential bio-inspired applications are overviewed and outlooked to finally find the answer, that is, how we learn from creatures.


An algorithm for determination of ideal location of interdental osteotomies in presurgical orthodontic treatment planning.
Treatment-planning patients with dentofacial deformities begins with the desired final occlusal results in mind. Examination of occlusal models and subsequent feasibility model surgery determine whether segmentalization of one or both arches is necessary to accomplish the final occlusal scheme desired. Segmentalization of the maxilla and/or mandible may be used to resolve transverse or arch configuration discrepancies, level occlusal plane(s), correct dentoalveolar inclination, and/or remove extraction spaces by osteotomy. With so many variables to consider, it is often difficult even for an experienced clinician to systematically evaluate and select the ideal location of interdental osteotomies prior to presurgical orthodontics. This manuscript describes an algorithmic approach to diagnosis and treatment planning that will assist the clinician in determining the most favorable location(s) for interdental osteotomy(ies).


Role of epigenetic mechanisms in differential regulation of the dioxin-inducible human CYP1A1 and CYP1B1 genes.
The aryl hydrocarbon receptor (AhR) mediates induction of CYP1A1 and CYP1B1 by 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (dioxin) via binding to xenobiotic-responsive elements (XREs) in their enhancer regions. CYP1A1 and CYPIB1 were both inducible by dioxin in human MCF-7 cells. However, only CYP1A1 was inducible in human HepG2 cells. Further experiments focused on providing an explanation for this last observation. Dioxin induced the recruitment of AHR and the transcriptional coactivators p300 and p300/cAMP response element-binding protein binding protein-associated factor (PCAF) to the CYP1B1 enhancer in HepG2 cells but failed to induce recruitment of RNA polymerase II (polII) or the TATA binding protein (TBP) and acetylations of histones 3 and 4 or methylation of histone 3 at the promoter. Because p300 was required for dioxin induction of the aforementioned histone modifications at the CYP1B1 promoter and for induction of CYP1B1 transcription (in MCF-7 cells), the recruitments of p300 and AhR, although necessary, are not sufficient for eliciting the above responses to dioxin. Cytosine residues within CpG dinucleotides at the enhancer, including those within the XREs, were partially methylated, whereas those at the promoter were fully methylated. Treatment of HepG2 cells with 5-aza-2'-deoxycytidine led to partial demethylation of the promoter, restored polII and TBP binding, and CYP1B1 inducibility. Thus, the deficiency of CYP1B1 induction in HepG2 cells is ascribable to cytosine methylation at the promoter, which prevents recruitment of TBP and polII. It is noteworthy that our data indicate that stable recruitment of p300 and PCAF to the CYP1B1 gene does not require their tethering to the promoter and to the enhancer.


Fully-primed slowly-recovering vesicles mediate presynaptic LTP at neocortical neurons.
Pre- and postsynaptic forms of long-term potentiation (LTP) are candidate synaptic mechanisms underlying learning and memory. At layer 5 pyramidal neurons, LTP increases the initial synaptic strength but also short-term depression during high-frequency transmission. This classical form of presynaptic LTP has been referred to as redistribution of synaptic efficacy. However, the underlying mechanisms remain unclear. We therefore performed whole-cell recordings from layer 5 pyramidal neurons in acute cortical slices of rats and analyzed presynaptic function before and after LTP induction by paired pre- and postsynaptic neuronal activity. LTP was successfully induced in about half of the synaptic connections tested and resulted in increased synaptic short-term depression during high-frequency transmission and a decelerated recovery from short-term depression due to an increased fraction of a slow recovery component. Analysis with a recently established sequential two-step vesicle priming model indicates an increase in the abundance of fully-primed and slowly-recovering vesicles. A systematic analysis of short-term plasticity and synapse-to-synapse variability of synaptic strength at various types of synapses revealed that stronger synapses generally recover more slowly from synaptic short-term depression. Finally, pharmacological stimulation of the cyclic adenosine monophosphate and diacylglycerol signaling pathways, which are both known to promote synaptic vesicle priming, mimicked LTP and slowed the recovery from short-term depression. Our data thus demonstrate that LTP at layer 5 pyramidal neurons increases synaptic strength primarily by enlarging a subpool of fully-primed slowly-recovering vesicles.


[PPARs: structure, mechanisms of action and control. Note I].
PPARs (peroxisome proliferator activated receptors) are proteine receptors that act as transcription factors activated by ligands. There are three known isoforms of PPARs (alpha, beta/delta, gamma) with similar modulated structure, consisting of distinct regions with specific functions. PPARs activate transcription of their target genes by forming cytoplasmatic heterodimers (PPARs:RXR) with his partner RXR (retinoid X receptor), and once translocated into the nucleus bind to specific DNA sequence called PPRE (peroxisome proliferator response elements) and modulate the expression of genes. Each PPAR is differently expressed in various tissues. Modulatory function of PPARs is induced by natural or synthetic ligand binding. Additional activator proteins are recruited to form a complex that coordinates and regulates the expression of many genes. Moreover, nuclear receptors' activity is also regulated by posttranslational changes.


Enrichment of carotenoids in flaxseed (Linum usitatissimum) by metabolic engineering with introduction of bacterial phytoene synthase gene crtB.
Linseed flax (Linum usitatissimum L.) is an industrially important oil crop, which includes large amounts of alpha-linolenic acid (18:3) and lignan in its seed oil. We report here the metabolic engineering of flax plants to increase carotenoid amount in seeds. Agrobacterium-mediated transformation of flax was performed to express the phytoene synthase gene (crtB) derived from the soil bacterium Pantoea ananatis (formerly called Erwinia uredovora 20D3) under the control of the cauliflower mosaic virus (CaMV) 35S constitutive promoter or the Arabidopsis thaliana fatty acid elongase 1 gene (FAE1) seed-specific promoter. As a result, eight transgenic flax plants were generated. They formed orange seeds (embryos), in which phytoene, alpha-carotene, and beta-carotene were newly accumulated in addition to increased amounts of lutein, while untransformed flax plants formed light-yellow seeds, in which only lutein was detected. Interestingly, despite the control of the CaMV 35S promoter, the expression of crtB was not observed in the leaves but in the seeds in the transgenic flax plants. Total carotenoid amounts in these seeds were 65.4-156.3 microg/g fresh weight, which corresponded to 7.8- to 18.6-fold increase, compared with those of untransformed controls. These results suggest that the flux of phytoene synthesis from geranylgeranyl diphosphate was first promoted by the expressed crtB gene product (CrtB), and then phytoene was consecutively decomposed to the downstream metabolites alpha-carotene, beta-carotene, and lutein, as catalyzed by endogenous carotenoid biosynthetic enzymes in seeds. The transgenic flaxseeds enriched with the carotenoids could be valuable as nutritional sources for human health.


Ingestion, cytotoxicity, and early morphological effects of asbestos on Tetrahymena.
Crocidolite asbestos fibers are rapidly ingested in large amounts by Tetrahymena. This varies little with incubation time of fibers in the culture medium or with dilution of the medium. The ingested fibers form large, oblong bundles in the cell rather than the normal spherical food vacuoles. In addition, crocidolite results in a rapid dose dependent induction of various minor morphological abnormalities. At 0.1-3 mg/ml these are observed in approximately one third of the population. Crocidolite is, however, not cytotoxic to Tetrahymena even in these high concentrations as measured by cell death and population doubling time. Phagocytosis and cytotoxicity are thus not related in this cell. Preliminary studies indicate that all the U.I.C.C. standard reference asbestos samples have largely similar effects but that their ability to induce abnormalities depends on the species of Tetrahymena used. For studies of the effects of asbestos Tetrahymena should be a suitable model system because the massive ingestion of fibers and its short generation time should facilitate rapid detection of adverse effects. Among such effects is the induction of heterogenous cell lines. This may involve modification of non-nucleic acid carried hereditary (cytotactic) information.


Glycemic instability and spontaneous energy intake: association with knowledge-based work.
To further document the impact of knowledge-based work (KBW) on spontaneous energy intake and glucose homeostasis. We used a within-subjects experimental design, in which each participant was engaged in each of the three 45-minute conditions followed by an ad libitum buffet, 1) resting in a sitting position; 2) reading a document and writing a summary; or 3) performing a battery of computerized tests. Fourteen female students (mean age: 22.8 +/- 2.3 years, mean body mass index: 22.4 +/- 2.5 kg/m(2)) were recruited to participate. Plasma glucose, insulin, and cortisol levels at seven time-points, and appetite sensation markers were measured at each experimental condition. The mean ad libitum energy intake after the reading-writing and the automated test-battery conditions exceeded that measured after rest by 848 kJ and 1057 kJ, respectively (p < .05). No specific dietary preference was detected, as reflected by the comparable percent of energy from each macronutrient in the three conditions. No significant difference in appetite sensation markers was observed among the three conditions. Mean cortisol level over 45 minutes in the two KBW conditions was significantly higher (p < .05) compared with the control condition. Finally, a significant increase in variations in plasma glucose and insulin levels was observed as compared with the control condition (p < .01). This study showed that KBW acutely induces an increase in spontaneous energy intake, and promotes an increased fluctuation in plasma glucose and insulin levels. This study contributes to the documentation of a new risk factor for a positive energy balance, with the potential to lead to overweight in the long-term.


Role of curved planar reformations using multidetector spiral CT in diagnosis of pancreatic and peripancreatic diseases.
To investigate the role of curved planar reformations using multidetector spiral CT (MSCT) in diagnosis of pancreatic and peripancreatic diseases. From October 2001 to September 2003, 47 consecutive patients with pancreatic or peripancreatic diseases, which were confirmed by operation, endoscopic retrograde cholangiopancreatography and clinical follow-up, were enrolled in this study. CT scanning was performed at a MSCT with four rows of detector. A set of images with an effective thickness of 1.0-2.0 mm and a gap of 0.5-1.0 mm (50% overlap) were acquired in all patients for post-processing. Curved planar reformations were carried out by drawing a curved line on transverse source images, coronal or sagittal multiplanar reformations according to certain anatomic structures (such as cholangiopancreatic ducts or peripancreatic vessels) and the position of lesion. With thin collimation, MSCT could acquire high-quality curved planar reformations to display the profile of the whole pancreas, to trace the cholangiopancreatic ducts and peripancreatic vessels, and to show the relationship of lesions with pancreas and peripancreatic anatomic structures in one curved plane, which facilitates diagnosis and rapid communication of diagnostic information with referring physicians. MSCT with thin collimation could be used to create high-quality curved planar reformations in evaluating pancreatic and peripancreatic diseases with pertinent anatomic information and relative pathologic signs to facilitate the diagnosis and enhance communication with the referring physician. Curved planar reformations can serve as supplements for transverse images in diagnosis and management of pancreatic and peripancreatic diseases.


Needlestick injuries: causes, preventability and psychological impact.
Needlestick injuries (NSI) pose a significant health hazard among healthcare personnel (HCP). The aim of our prospective observational study was to evaluate the psychological impact of NSI and assess measures to prevent NSI. The target group was the medical staff and students of Frankfurt University Hospital who had experienced a NSI (n = 370) during the 12-month study period. Data were retrieved from accident insurance reports, occupational follow-up examinations and a standardized anonymous questionnaire sent to the affected HCP. Analysis of the completed questionnaires (232/370) revealed that stress (48.3 %) and tiredness (36.6 %) were common factors contributing to the NSI and that >80 % of the respondents were concerned about the consequences of the NSI. Higher levels of anxiety were reported when the patient was known to have a chronic virus infection. Stressful working conditions, lack of adequate protective medical/technical equipment and poor work routines were suggested as factors contributing to NSI.


The asparagine residue in the FRNK box of potyviral helper-component protease is critical for its small RNA binding and subcellular localization.
The multifunctional potyviral helper-component protease (HcPro) contains variable regions with some functionally conserved domains, such as the FRNK box. Natural variants occur at the FRNK box, a conserved central domain, known for its role in RNA binding and RNAi suppression activities, although no dominant natural variants for the N(182) residue are known to occur. Here, a mutant at HcPro(N182L) was developed to investigate its role in natural populations. Using in vitro studies, we found an increase in the small RNA (sRNA) binding potential of HcPro(N182L) without affecting its protein-protein interaction properties, suggesting that the presence of N(182) is critical to maintain threshold levels of sRNAs, but does not interfere in the self-interaction of HcPro. Furthermore, we found that expression of HcPro(N182L) in Nicotiana benthamiana affected plant growth. Transient expression of HcPro(N182L) induced reporter gene expression in 16c GFP transgenic plants more than HcPro did, suggesting that replacement of asparagine in the FRNK box favours RNA silencing suppression. HcPro was found to be distributed in the nucleus and cytoplasm, whereas HcPro(N182L) was observed only in cytoplasmic inclusion bodies in N. benthamiana leaves, when fused to a GFP tag and expressed by agro-infiltration, suggesting mutation favours oligomerization of HcPro. These findings suggest that amino acid N(182) of the conserved FRNK box may regulate RNA silencing mechanisms, and is required for maintenance of the subcellular localization of the protein for its multi-functionality. Hence, the N(182) residue of the FRNK box seems to be indispensable for potyvirus infection during evolution.


[Cardinal problems of the regional bacteriological laboratories of tuberculosis facilities].
Restructuring the health care system and the epidemiological situation associated with tuberculosis result in an increased burden on the bacteriological laboratories (BLs) of tuberculosis facilities. At present, there are no statistical data that enable one to estimate the capacity of a laboratory service to assure the adequate quality and efficiency of bacteriological diagnosis. To assess the state of the headquarters BLs of tuberculosis facilities, the authors have worked out a questionnaire to glean necessary information on the activity of the laboratories to such an extent that suffices to reveal cardinal problems in the work of individual laboratories and the laboratory network as a whole. Out of the 48 questionnaires sent from the regional BLs, the data available from 22 laboratories that had fully answered all the questions were analyzed. The data obtained are referred to as of 2004, i.e. when the current antituberculous care projects were launched, which is of significance in organizing the monitoring of a laboratory service and in assessing the progress of the projects. The authors have identified the following cardinal problems: inadequate readiness of most laboratories to fully perform their incumbent functions; no coordination in providing data at the regional and federal levels; inefficient laboratory diagnosis that is associated with the disintegration of the curatorial institution, with neither reference relations no united external or internal quality control programs, with the lack of expertise and the undermanning of the laboratories, with the obsolete list of staff members and the obsolete standards for calculation of their loads, with the deterioration of a material and technical base, and with the unconformity of equipment to the state-of-the-art technologies. In order to solve the above problems, the authors offer a laboratory service monitoring system based on the proposed questionnaire, followed by the computerization of data collection and the compulsory supervision of regional laboratories by the officials of district and federal BLs.


Immunogenicity and Safety of Reduced-Dose Intradermal vs Intramuscular Influenza Vaccines: A Systematic Review and Meta-analysis.
Low-dose intradermal influenza vaccines could be a suitable alternative to full intramuscular dose during vaccine shortages. To compare the immunogenicity and safety of the influenza vaccine at reduced or full intradermal doses with full intramuscular doses to inform policy design in the event of vaccine shortages. MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched for studies published from 2010 until June 5, 2020. All comparative studies across all ages assessing the immunogenicity or safety of intradermal and intramuscular influenza vaccinations were included. Data were extracted by a single reviewer and verified by a second reviewer. Discrepancies between reviewers were resolved through consensus. Random-effects meta-analysis was conducted. Primary outcomes included geometric mean titer, seroconversion, seroprotection, and adverse events. A total of 30 relevant studies were included; 29 studies were randomized clinical trials with 13 759 total participants, and 1 study was a cohort study of 164 021 participants. There was no statistically significant difference in seroconversion rates between the 3-µg, 6-µg, 7.5-µg, and 9-µg intradermal vaccine doses and the 15-µg intramuscular vaccine dose for each of the H1N1, H3N2, and B strains, but rates were significantly higher with the 15-µg intradermal dose compared with the 15-µg intramuscular dose for the H1N1 strain (rate ratio [RR], 1.10; 95% CI, 1.01-1.20) and B strain (RR, 1.40; 95% CI, 1.13-1.73). Seroprotection rates for the 9-µg and 15-µg intradermal doses did not vary significantly compared with the 15-µg intramuscular dose for all the 3 strains, except for the 15-µg intradermal dose for the H1N1 strain, for which rates were significantly higher (RR, 1.05; 95% CI, 1.01-1.09). Local adverse events were significantly higher with intradermal doses than with the 15-µg intramuscular dose, particularly erythema (3-µg dose: RR, 9.62; 95% CI, 1.07-86.56; 6-µg dose: RR, 23.79; 95% CI, 14.42-39.23; 9-µg dose: RR, 4.56; 95% CI, 3.05-6.82; 15-µg dose: RR, 3.68; 95% CI, 3.19-4.25) and swelling (3-µg dose: RR, 20.16; 95% CI, 4.68-86.82; 9-µg dose: RR, 5.23; 95% CI, 3.58-7.62; 15-µg dose: RR, 3.47 ; 95% CI, 2.21-5.45). Fever and chills were significantly more common with the 9-µg intradermal dose than the 15-µg intramuscular dose (fever: RR, 1.36; 95% CI, 1.03-1.80; chills: RR, 1.24; 95% CI, 1.03-1.50) while all other systemic adverse events were not statistically significant for all other doses. These findings suggest that reduced-dose intradermal influenza vaccination could be a reasonable alternative to standard dose intramuscular vaccination.


Accumulation of transactive response DNA binding protein 43 in mild cognitive impairment and Alzheimer disease.
Transactive response DNA binding protein 43 (TDP-43) plays a central role in the neuropathology of frontotemporal lobar degeneration and amyotrophic lateral sclerosis, but the relationship between TDP-43 abnormalities and Alzheimer disease (AD) remains unclear. To determine whether TDP-43 can serve as a neuropathologic marker of AD, we performed biochemical characterization and quantification of TDP-43 in homogenates from parietal neocortex of subjects with aclinical diagnosis of no cognitive impairment (NCI, n = 12), mild cognitive impairment (MCI, n = 12), or AD (n = 12). Immunoblots revealed increased detergent-insoluble TDP-43 in the cortex of 0, 3, and 6 of the 12 individuals with NCI, MCI, or AD, respectively. Detergent-insoluble TDP-43 was positively correlated with the accumulation of soluble Aβ42, amyloid plaques, and paired helical filamenttau. In contrast, phospho-TDP-43 was decreased in the cytosolic fraction and detergent-soluble membrane/nuclear fraction from AD patients and correlated with antemortem cognitive function.Immunofluorescence analysis confirmed that the frequencies of individuals with TDP-43 or phospho-TDP-43 cytoplasmic inclusions were higher in AD than in NCI, with MCI at an intermediate level. These data indicate that abnormalities of TDP-43 occur in an important subset of MCI and AD patients and that they correlate with the clinical and neuropathologic features of AD.


The Risks and Benefits of Myopia Control.
The prevalence of myopia is increasing around the world, stimulating interest in methods to slow its progression. The primary justification for slowing myopia progression is to reduce the risk of vision loss through sight-threatening ocular pathologic features in later life. The article analyzes whether the potential benefits of slowing myopia progression by 1 diopter (D) justify the potential risks associated with treatments. First, the known risks associated with various methods of myopia control are summarized, with emphasis on contact lens wear. Based on available data, the risk of visual impairment and predicted years of visual impairment are estimated for a range of incidence levels. Next, the increased risk of potentially sight-threatening conditions associated with different levels of myopia are reviewed. Finally, a model of the risk of visual impairment as a function of myopia level is developed, and the years of visual impairment associated with various levels of myopia and the years of visual impairment that could be prevented with achievable levels of myopia control are estimated. Assuming an incidence of microbial keratitis between 1 and 25 per 10 000 patient-years and that 15% of cases result in vision loss leads to the conclusion that between 38 and 945 patients need to be exposed to 5 years of wear to produce 5 years of vision loss. Each additional 1 D of myopia is associated with a 58%, 20%, 21%, and 30% increase in the risk of myopic maculopathy, open-angle glaucoma, posterior subcapsular cataract, and retinal detachment, respectively. The predicted mean years of visual impairment ranges from 4.42 in a person with myopia of -3 D to 9.56 in a person with myopia of -8 D, and a 1-D reduction would lower these by 0.74 and 1.21 years, respectively. The potential benefits of myopia control outweigh the risks: the number needed to treat to prevent 5 years of visual impairment is between 4.1 and 6.8, whereas fewer than 1 in 38 will experience a loss of vision as a result of myopia control.


Regional differences of myocyte hypertrophy and three-dimensional deformation of the heart.
Cross-sectional area was compared between the latitudinally and longitudinally oriented muscle fibers of the hypertrophied left ventricle of the rat heart under aortic banding and isoproterenol infusion. In addition, end-diastolic three-dimensional deformation of the left ventricle as expressed by cavity volume and eccentricity was examined in the early and chronic stages of these treatments. Under aortic banding, myocyte hypertrophy occurred to a greater extent in the latitudinally oriented fibers of the midwall layer than in the longitudinal fibers of the inner and outer layers. Such a regional difference of hypertrophy was not seen under isoproterenol infusion. At the early stage of aortic banding, the left ventricle at end diastole was more dilated and spherical, whereas at the acute stage of isoproterenol infusion, it was more decreased in size and prolate than that of the controls. The deformation of the left ventricle at the early stage of aortic banding is considered to cause, during diastole, axial stretching and increase in tensile stress more on the latitudinal fibers, leading them to the predominant hypertrophy.


Comparative efficacy and safety of multiple routes of direct CNS administration of adeno-associated virus gene transfer vector serotype rh.10 expressing the human arylsulfatase A cDNA to nonhuman primates.
Metachromatic leukodystrophy (MLD), a fatal disorder caused by deficiency of the lysosomal enzyme arylsulfatase A (ARSA), is associated with an accumulation of sulfatides, causing widespread demyelination in both central and peripheral nervous systems. On the basis of prior studies demonstrating that adeno-associated virus AAVrh.10 can mediate widespread distribution in the CNS of a secreted lysosomal transgene, and as a prelude to human trials, we comparatively assessed the optimal CNS delivery route of an AAVrh.10 vector encoding human ARSA in a large animal model for broadest distribution of ARSA enzyme. Five routes were tested (each total dose, 1.5 × 10(12) genome copies of AAVrh.10hARSA-FLAG): (1) delivery to white matter centrum ovale; (2) deep gray matter delivery (putamen, thalamus, and caudate) plus overlying white matter; (3) convection-enhanced delivery to same deep gray matter locations; (4) lateral cerebral ventricle; and (5) intraarterial delivery with hyperosmotic mannitol to the middle cerebral artery. After 13 weeks, the distribution of ARSA activity subsequent to each of the three direct intraparenchymal administration routes was significantly higher than in phosphate-buffered saline-administered controls, but administration by the intraventricular and intraarterial routes failed to demonstrate measurable levels above controls. Immunohistochemical staining in the cortex, white matter, deep gray matter of the striatum, thalamus, choroid plexus, and spinal cord dorsal root ganglions confirmed these results. Of the five routes studied, administration to the white matter generated the broadest distribution of ARSA, with 80% of the brain displaying more than a therapeutic (10%) increase in ARSA activity above PBS controls. No significant toxicity was observed with any delivery route as measured by safety parameters, although some inflammatory changes were seen by histopathology. We conclude that AAVrh.10-mediated delivery of ARSA via CNS administration into the white matter is likely to be safe and yields the widest distribution of ARSA, making it the most suitable route of vector delivery.


Voluntary Control of Epileptiform Spike-Wave Discharges in Awake Rats.
Genetically inherited absence epilepsy in humans is typically characterized by brief (seconds) spontaneous seizures, which involve spike-wave discharges (SWDs) in the EEG and interruption of consciousness and ongoing behavior. Genetic (inbred) models of this disorder in rats have been used to examine mechanisms, comorbidities, and antiabsence drugs. SWDs have also been proposed as models of complex partial seizures (CPSs) following traumatic brain injury (post-traumatic epilepsy). However, the ictal characteristics of these rat models, including SWDs and associated immobility, are also prevalent in healthy outbred laboratory rats. We therefore hypothesized that SWDs are not always associated with classically defined absence seizures or CPSs. To test this hypothesis, we used operant conditioning in male rats to determine whether outbred strains, Sprague Dawley and Long-Evans, and/or the inbred WAG/Rij strain (a rat model of heritable human absence epilepsy) could exercise voluntary control over these epileptiform events. We discovered that both inbred and outbred rats could shorten the duration of SWDs to obtain a reward. These results indicate that SWD and associated immobility in rats may not reflect the obvious cognitive/behavioral interruption classically associated with absence seizures or CPSs in humans. One interpretation of these results is that human absence seizures and perhaps CPSs could permit a far greater degree of cognitive capacity than often assumed and might be brought under voluntary control in some cases. However, these results also suggest that SWDs and associated immobility may be nonepileptic in healthy outbred rats and reflect instead voluntary rodent behavior unrelated to genetic manipulation or to brain trauma.SIGNIFICANCE STATEMENT Our evidence that inbred and outbred rats learn to control the duration of spike-wave discharges (SWDs) suggests a voluntary behavior with maintenance of consciousness. If SWDs model mild absence seizures and/or complex partial seizures in humans, then an opportunity may exist for operant control complementing or in some cases replacing medication. Their equal occurrence in outbred rats also implies a major potential confound for behavioral neuroscience experiments, at least in adult rats where SWDs are prevalent. Alternatively, the presence and voluntary control of SWDs in healthy outbred rats could indicate that these phenomena do not always model heritable absence epilepsy or post-traumatic epilepsy in humans, and may instead reflect typical rodent behavior.


Glenohumeral joint dynamics and shoulder muscle activity during geared manual wheelchair propulsion on carpeted floor in individuals with spinal cord injury.
This study investigated the effects of using geared wheels on glenohumeral joint dynamics and shoulder muscle activity during manual wheelchair propulsion. Seven veterans with spinal cord injury propelled their wheelchairs equipped with geared wheels over a carpeted floor in low gear (1.5:1) and standard gear (1:1) conditions. Hand-rim kinetics, glenohumeral joint dynamics, and muscle activity were measured using a custom instrumented geared wheel, motion analysis, and surface electromyography. Findings indicated that the propulsion speed and stroke distance decreased significantly during the low gear condition. The peak hand-rim resultant force and propulsive moment, as well as the peak glenohumeral inferior force and flexion moment, were significantly less during the low gear condition. The peak and integrated muscle activity of the anterior deltoid and pectoralis major decreased significantly, while the normalized integrated muscle activity (muscle activity per stroke distance) was not significantly different between the two conditions. Propulsion on carpeted floor in the low gear condition was accompanied by a reduced perception of effort. The notable decrease in the peak shoulder loading and muscle activity suggests that usage of geared wheels may be beneficial for wheelchair users to enhance independent mobility in their homes and communities while decreasing their shoulder demands.


The hallmarks of childhood abuse and neglect: A systematic review.
Studies on the impacts of child maltreatment (CM) have been conducted in diverse areas. Mechanistic understanding of the complex interplay between factors is lacking. Hallmarking is an approach which identifies common factors across studies and highlights the most robust findings. In a review of systematic reviews and meta-analyses, we addressed the following questions: 1) What are the hallmarks associated with exposure to CM across the bio-ecological spectrum? 2) What is the strength of evidence to support each hallmark? 3) What are the gaps that future research should address? A comprehensive literature search was carried out to find relevant systematic reviews or meta-analyses. 269 articles were read in full and 178 articles, encompassing more than 6000 original papers, were included in the final synthesis. All reviews were independently rated for quality by at least 2 reviewers using AMSTAR-2. Of 178 review articles, 6 were rated as high quality (all meta-analyses) and 46 were rated as medium quality. Most were from high income countries. Based on the most commonly reported high-quality research findings we propose that the hallmarks of exposure to child maltreatment are: Increased risk of psychopathology; Increased risk of obesity; Increased risk of high- risk sexual behaviours, Increased risk of smoking; and Increased risk of child maltreatment in children with disabilities. Research gaps include a lack of focus on complexity and resilience. Little can be concluded about directions of causality or mechanisms. Adequately powered prospective studies are required to move the field forward.