A dissociation of dorso-lateral striatum and amygdala function on the same stimulus-response habit task.
This experiment tested the idea that the amygdala-based learning and memory system covertly acquires a stimulus-reward (stimulus-outcome) association during acquisition of a stimulus-response (S-R) habit task developed for the eight-arm radial maze. Groups of rats were given dorso-lateral striatal or amygdala lesions and then trained on the S-R habit task on the eight-arm radial maze. Rats with neurotoxic damage to the dorso-lateral striatum were severely impaired on the acquisition of the S-R habit task but showed a conditioned-cue preference for the stimulus reinforced during S-R habit training. Rats with neurotoxic damage to the amygdala were able to acquire the S-R habit task but did not show a conditioned-cue preference for the stimulus reinforced during S-R habit training. This pattern of results represents a dissociation of learning and memory functions of the dorsal striatum and amygdala on the same task.


A Randomized, Double-Blind, Placebo-Controlled Phase 2a Study of Tildrakizumab Efficacy and Safety in Patients With Active Ankylosing Spondylitis.
Tildrakizumab is an anti-interleukin-23p19 monoclonal antibody approved to treat moderate to severe plaque psoriasis. This study evaluated the efficacy and safety of tildrakizumab in patients with ankylosing spondylitis (AS). In this randomized, double-blind, parallel-group, multinational trial ( clinicaltrials.gov NCT02980705), patients with active AS, according to modified New York criteria and Bath Ankylosing Spondylitis Disease Activity Index Score ≥4, were randomized 1:1 to tildrakizumab 200 mg or placebo every 4 weeks until week 24. Thereafter, all patients received tildrakizumab 200 mg every 4 weeks until week 48. The primary outcome was proportion of patients achieving 20% improvement from baseline by Assessment in SpondyloArthritis International Society criteria (ASAS20) at week 24. This outcome was analyzed in subgroups defined by prior treatment experience, weight, age, and sex using the full analysis set. Safety was assessed through treatment-emergent adverse events. From December 5, 2017-September 3, 2019, 101 patients (76.2% male, 97% White) enrolled and were randomized to treatment. At week 24, the ASAS20 response rate was 74.0% in patients receiving tildrakizumab 200 mg (n = 50) versus 80.4% in placebo-treated patients (n = 51; treatment difference, -6.31%; 95% confidence interval, -22.34 to 9.71; p = 0.44). No difference in treatment effect by subgroups was observed. Tildrakizumab treatment was generally well tolerated, with no unexpected safety findings. The study was terminated after the week 24 interim analysis due to lack of efficacy. Tildrakizumab treatment was generally well tolerated but did not improve ASAS20 response rate versus placebo in patients with AS.


Carbon(sp(3))-fluorine bond-forming reductive elimination from palladium(IV) complexes.
Pd(IV)-fluoride complexes, some of which are remarkably insensitive to water, have been synthesized and used in the title reaction, which proceeds with high selectivity to give the product of the C(sp(3))-F coupling. Preliminary mechanistic studies implicate a pathway involving dissociation of pyridine followed by direct C-F coupling at the Pd center.


[Simultaneous lesion of the cervical lymph node by metastatic thyroid cancer and lymphosarcoma].
A combination of the thyroid carcinoma and diffuse lymphosarcomatosis in a patient of 56 with metastasis to the cervical lymph node with lymphosarcomatous changes is described. The diagnosis of primary multiple tumor was confirmed by the second biopsy (changes typical of lymphoblastic lymphosarcoma in the axillary lymph node).


Comparative effects of morphine on leukocytic antigenic markers of monkeys and humans.
Knowing the in vitro effects of morphine on monkey leukocytes would be helpful in extending the utility of a monkey model for psychoneuroimmunological investigations. Morphine effects on T11, Leu2a, and Leu3a antigenic markers on leukocytes from rhesus monkeys and humans were assessed by using single- and two-color cytofluorometric analyses. Kinetics of expression of these markers was determined after modulation of the original complement of T11 markers from the surface of T11(+) cells. Percentages of leukocytes detectable by directly staining these markers before modulation were within the expected range for monkey and human cells. Also, as expected, T11 modulation reduced the percentages of cells expressing T11. This reduction was particularly obvious for T11 in the single-color analyses, with reductions being greater for monkey than human cells. Furthermore, in the single-color analyses, the effects of morphine on kinetics of T11 expression were quite similar for both human and monkey cells. In the two-color analyses, the simultaneous expression of T11 and Leu3a markers was uniform for both monkey and human cells. The effects of morphine on kinetics of expression of these markers varied only slightly between species. On the other hand, the distribution of Leu2a on T11 cells was markedly different for monkey and human T-cells. Whereas all human Leu2a(+) cells expressed similar numbers of T11 receptors, monkey cells with high-density Leu2a expressed fewer T11 markers than those with low-density Leu2a. The effects of morphine on kinetics of Leu2a and T11 expression were at obvious variance between species.(ABSTRACT TRUNCATED AT 250 WORDS)


Safety of breast/chest-feeding by those infected by SARS-CoV-2.
One important question from the outset of the pandemic has been whether a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected person's milk might be a vehicle for SARS-CoV-2 transmission. This review summarizes the most recent data on this topic. A SARS-CoV-2 sIgA response in milk after infection is very common. To date, there has been no evidence that SARS-CoV-2 transmits via human milk. Though viral RNA has been identified in a minority of milk samples studied, infectious virus particles have not. The highly dominant transmission route for SARS-CoV-2 is via inhalation of respiratory droplets containing virus particles. Other routes of transmission are possible, including fecal-oral, trans-placental, and to a much lesser extent, via a contaminated surface. SARS-CoV-2 cannot transmit via human milk. There is no evidence that infants should be separated from SARS-CoV-2-infected mothers who are well enough to establish or continue breastfeeding.


Modified calcium accumulation after controlled cortical impact under cyclosporin A treatment: a 45Ca autoradiographic study.
As a neuroprotective drug, cyclosporin A (CsA) has been subject of multiple experimental works in traumatic brain injury (TBI) research. It is well known that CsA inhibits calcium (Ca2+) induced mitochondrial permeability transition (mPT). The aim of this study was to investigate the influence of CsA on the alteration of Ca2+ homeostasis after experimental brain injury. Sprague-Dawley male rats (n = 36) with a mean weight of 330 g (280-350 g) were general anesthetized with isofluran through gas mask. The anesthetized animals (n = 24) were subjected to a controlled cortical impact (CCI) over the left parietotemporal cortex using round-tip impounder with a 5 mm diameter at a velocity of approximately 3.7 m/s and a penetration depth of 2 mm. The sham group (n = 12) underwent anesthesia and craniotomy without CCI. In the CCI groups, CsA (n = 12) or vehicle (n = 12) was administered 15 minutes post-injury with a subsequent i.p. injection after 24 hours. Thirty-three hours after injury or sham craniotomy, 45calcium (45Ca) suspended in physiologic saline solution was injected in the left femoral vein. Five hours after isotope administration, animals were killed and the brain was quickly removed and placed in powdered dry ice. Coronal plane sections (20 microm thick) taken every 400 microm from the frontal cortex through the occipital cortex, were exposed to cyclotron films for 14 days at -18 degrees C. Relative optical density was utilized to provide a relative measure of 45Ca accumulation within seven different structures. The difference of 45Ca accumulation (measured by relative optical density) in the CsA group was greater by 30-70% in the following structures compared to vehicle treated traumatized animals: temporal cortex, CA1, anteromedial and posteromedial thalamus (p < 0.05). Post-traumatic 45Ca accumulation is modified under CsA. The crucial neuroprotective effect of CsA might be unrelated to a reduction of post-traumatic Ca2+ accumulation, especially with regard to the importance of Ca2+ as an intracellular messenger governing a large number of cellular functions.


The use of single case studies by academic general practitioners.
To compare the use of the single case for teaching, clinical, and research by academic general practitioners (GPs) with other academic specialists. A questionnaire study involving all four departments of general practice in New Zealand and other academic departments from the Wellington School of Medicine. The main outcome measures were respondents' publication history, details of the last single case they published, the use of single cases for teaching, and opinion of the usefulness of the single case in teaching, clinical, and research work. 33 academic GPs and 41 other academic specialists (response rate was 97% versus 79%). All doctors reported 3.6% of all their publications were as single cases. General practitioners were less likely to publish at least one single case compared to specialist (24% versus 59%). The characteristics of the single cases published varied widely with 70% categorised as 'rare' or 'first ever' cases of a disease or problem. More GPs compared to specialists thought cases encountered in clinical work could influence subsequent cases (100% versus 83%). All doctors considered single cases to be useful for teaching and clinical uses, but only a little useful for research. However, 23% of all doctors stated that a single case had been a stimulus for their own research work. Furthermore, a textual analysis found doctors used single cases as examples of research possibilities and to influence other doctors. Single cases had important teaching and clinical uses among academic doctors. However, GPs were less likely to publish single cases than their specialist colleagues. This may reflect the smaller pool of academic GPs in New Zealand. Single cases were ranked low among research methodologies, but were considered to have an important triggering role for doctors doing research.


Racial and Ethnic Disparities in Seasonal Influenza Vaccination among Dialysis Facilities in the United States.
Racial and ethnic disparities in vaccination rates for seasonal influenza exist. Whether such disparities extend to patients with ESKD, who simultaneously are at risk for complications of infection and have extensive contact with health care providers, has not been investigated. To determine whether the proportion of patients vaccinated at a dialysis facility differs according to the facility's racial and ethnic composition, we examined dialysis facility data reported to the Centers for Medicare and Medicaid Services. The main outcome was the proportion of facility patients vaccinated for influenza among 6735 Medicare-certified facilities operating between 2014 and 2017. Among dialysis facilities, the mean percentage of patients vaccinated during the influenza season was 72.1%. Facilities with higher proportions of Black and Hispanic patients had significantly lower vaccination percentages than less diverse facilities. The average proportion of patients vaccinated at each facility decreased significantly from 2014 to 2017 (a decrease of 1.05% vaccinated per year) and decreased significantly more so among facilities with higher minority proportions. The share of vaccinated patients in facilities in the quartile with the highest proportion of Black patients decreased 1.21% per year compared with a decrease of 0.88% per year in facilities in the quartile with the lowest proportion of Black patients. We found similar trends for Hispanic patients. Rates of seasonal influenza vaccination are modestly but significantly lower among dialysis facilities with larger proportions of minority patients, and the gap seems to be widening over time. As wide-scale vaccination efforts grow more urgent amid the current COVID-19 pandemic, these disparities must be addressed to protect patients and communities equitably.


Nitrogen-rich g-C3N4@AgPd Mott-Schottky heterojunction boosts photocatalytic hydrogen production from water and tandem reduction of NO3- and NO2.
Developing an effective photocatalytic denitrification technology for NO3- and NO2- in water is urgently needed. In this paper, we synthesized a nitrogen-rich g-C3N4, and in-situ grown AgPd nanowires (NWs) on the surface of nitrogen-rich g-C3N4 to build AgyPd10-y/g-CxN4 Mott-Schottky heterojunction. Compared with g-CxN4, AgyPd10-y/g-CxN4 exhibits the enhanced photocatalytic hydrogen production from water and tandem reduction of NO3- and NO2- without the addition of other hydrogen source under 365 nm irradiation. The catalytic activity and selectivity of AgyPd10-y/g-CxN4 were studied by combination of the nitrogen-rich g-C3N4 and the different component of AgyPd10-y nanowires (NWs). Among the AgyPd10-y/g-CxN4 catalyst, the Ag3Pd7/g-C1.95N4 catalyst exhibited the highest photocatalytic activity and selectivity for photocatalytic reduction of NO3- and NO2-, and the removal rate of NO3- and NO2- are 87.4% and 61.8% under 365 nm irradiation at 25 °C, respectively. The strategy opens a new way for making the photocatalytic hydrogen production in tandem with reduction of NO3- and NO2- in water, also extending it to remove metal ion.


Diagnosis of Factor XI deficiency following congenital cataract extraction.
Factor XI deficiency is a rare coagulopathy that requires a specific approach to preoperative planning. Herein we report a case where ophthalmic surgery led to this diagnosis in a 4-month old boy and review the warranted prophylactic measures prior to operative intervention.


Different Effects of Interleukin 21 and Interleukin 15 on In Vitro Expanded CD8+ T Cells Stimulated by Alloantigen.
To investigate the effects of IL (interleukin) 21 on CD8+ T cells stimulated by alloantigen in the presence of IL-15 in vitro. CD8+ T cells sorted with MicroBeads from fresh human peripheral blood mononuclear cells were cocultured with antigen-presenting cells derived from HLA-A, -B, and -DR full-mismatched individuals for 9 days without any cytokines, in the presence of IL-15, IL-21, and IL-15 combined with IL-21, respectively. The proliferation and phenotypic characteristics of CD28+ and CD28- subsets were measured after 9 days of culture. The proliferation of CD8+ T cells can be promoted either by IL-15 alone or in combination with IL-21 compared with IL-21. Cells expanded in the presence of IL-15 are mainly CD8+CD28- T cells, while those expanded in the presence of IL-15 combined with IL-21 are mostly CD8+CD28+ T cells. In the presence of IL-15, most CD8+CD28+ T cells shifted to CD8+CD28- T cells during the process of proliferation, but In the presence of IL-15 combined with IL-21, CD8+CD28+ T cells didn't shift to CD8+CD28- T cells during proliferation, moreover, CD8+CD28- T cells cannot transform in reverse to CD8+CD28+ T cells. IL-21 combined with IL-15 can promote the expression of granzyme B and perforin in CD8+CD28+ and/or CD8+CD28- T cells compared with IL-15 alone. IL-21 cannot promote the proliferation of CD8+ T cells under allogeneic stimulation unless combined with IL-15. IL-21 prevents the loss of CD28 molecules caused by IL-15 but cannot promote its re-expression in CD28- T cells. CD8+ T cells expanded by IL-21 combined with IL-15 is characterized by cytotoxic phenotype.


Can acetate via FFA receptors contribute to the diabetogenic effect of statins?
Despite the proven effects of statins in preventing cardiovascular disease, their diabetogenic effect has caused concern. The mechanism of this diabetogenic effect is unknown. We suggest a novel mechanism that may contribute to the diabetogenic effect of statins, through an effect of statins that has apparently escaped previous consideration. Briefly, by inhibiting HMG-CoA reductase, statins may cause accumulation of acetate, which through FFA2 and FFA3 stimulation may inhibit insulin secretion.


Peripheral neurophysins changes under mild stress conditions.
Total immunoreactive neurophysins levels increased significantly in rats after they had been trained in a situation based on the innate light-dark avoidance principle. These levels varied according to the amount of 'familiarisation cues' which characterised the situation. The results are discussed in terms of arousal/stress-neurophysins relationships.


Electron microscopic observation of gastric mucosal capillaries in diabetics--relationship between diabetic microangiopathy and complications following gastrectomy.
An electron microscopic study was made of the gastric mucosal capillaries (GMC) of diabetic patients. Ultrastructural findings, including diabetic microangiopathy (DMA), and clinical features of these diabetic patients were investigated in relation to anastomotic leakage after gastrectomy. The gastric mucosa of resected stomachs from 12 diabetics and 10 nondiabetics were examined. Ultrastructurally, DMA was demonstrated in the stomachs of diabetics, in which the basement membrane of GMC was thicker. The degree of this DMA in the stomach significantly correlated with the duration of diabetes and the degree of DMA found in the skin, but not with age and fasting plasma glucose (FPG) level. Marked DMA was observed with significant frequency in diabetics with anastomotic leakage after gastrectomy. In our hospital, anastomotic leakage after gastrectomy occurred in 9 out of 53 diabetics. Diabetics with anastomotic leakage had severe FPG, a long duration of diabetes and diabetic retinopathy. It seems reasonable to presume that anastomotic leakage after gastrectomy occurs more frequently in diabetics with ultrastructurally severe DMA, clinically severe FPG and relatively long duration of diabetes.


Intra-familial transmission of hepatitis B virus in Italy: phylogenetic sequence analysis and amino-acid variation of the core gene.
Transmission of hepatitis B virus (HBV) in countries of intermediate endemicity, such as Italy, is thought to be primarily horizontal and, to a lesser extent, vertical. Most chronic carriers therefore become infected in infancy or at a very young age. The index cases in such events have been assumed to come from within the family unit or from sources outside the immediate family, with whom the affected person is in close contact. We studied a number of Italian families with multiple members chronically infected with HBV. The precore/core region of the virus was amplified from serum derived HBV-DNA, and the sequences subjected to phylogenetic tree analysis. In addition, the extent of amino-acid variation within the core region was correlated to HLA type, determined by allele-specific PCR. The phylogenetic tree analysis provided strong evidence of intra-familial transmission of the virus. Analysis of amino-acid substitutions in the core region in relation to HLA class II alleles from members of the same family showed that these substitutions were restricted in siblings with concordant, and more diverse in those with discordant HLA haplotypes. This is consistent with major histocompatibility complex class II mediated selection pressure on the virus.


Application of the theory of transition probability in "ageing" WI 38 cells; similar behaviour of clonogenic cells from early and late passage cultures.
Analysis of genealogies of WI 38 clones reveals: 1. The proliferation behaviour of the cells can be adequately described in terms of the transition probability model, despite non-steady state kinetics. 2. Early and late clones show nearly identical behaviour.


Validation of a clinical prediction score to target viral load testing in adults with suspected first-line treatment failure in resource-constrained settings.
Although routine viral load (VL) monitoring currently is too costly for poor countries, clinical failure criteria perform poorly. We previously developed an algorithm combining a clinical predictor score (CPS) with targeted VL testing in a Cambodian patient population (derivation population). We now prospectively validate the algorithm in the same clinical setting (validation population), assess its operational performance, and explore its cost-saving potential. We performed a cross-sectional study in a tertiary hospital in Phnom Penh, Cambodia, applying the CPS in adults on first-line antiretroviral treatment for at least 1 year. Treatment failure was defined as a VL >1000 copies per milliliter. The area under the receiver-operating characteristic (AUROC) curve of the CPS to detect treatment failure in the current study population (validation population) was compared with the AUROC of the CPS obtained in the patient population where the CPS was derived from in 2008 in the same study setting (derivation population). Costs related to VL testing and second-line regimens with the different testing strategies were compared. One thousand four hundred ninety individuals {56.6% female, median age 38 years [interquartile range (IQR): 33-44]} were included, with a median baseline CD4 cell count of 94 cells per microliter (IQR: 28-205). Median time on antiretroviral treatment was 3.6 years (IQR: 2.1-5.1), 45 (3.0%) individuals had treatment failure. The AUROC of the CPS in validation was 0.75 (95% confidence interval: 0.67 to 0.83), relative to an AUROC of 0.70 in the derivation population. At the CPS cutoff ≥ 2, VL was indicated for 164 (11%) individuals, preventing inappropriate switching to second line in 143 cases. Twenty-four cases of treatment failure would be missed. When applied in routine care, the AUROC was 0.69 (95% confidence interval: 0.60 to 0.77). Overall 1-year program costs with targeted VL testing were 4-fold reduced. The algorithm performed well in validation and has cost-saving potential. Further studies to assess its performance, feasibility, and impact in different settings are warranted.


Vigabatrin in the treatment of childhood epilepsy: a retrospective chart review of efficacy and safety profile.
To review the efficacy, cognitive outcome and safety profile in children treated with vigabatrin (VGB) for infantile spasms (IS) and partial epilepsies related to tuberous sclerosis complex (TSC) and other etiologies. Retrospective review of children followed in the Pediatric Epilepsy Program of Massachusetts General Hospital for Children between May 2001 and March 2006 who were treated with VGB. Eighty-four children were treated with VGB, 68 of them were treated for IS, and 59 were treated for partial seizures (PS). Etiology (TSC or other) was the only predictive factor for IS control with VGB (p < 0.0003). IS control was achieved in 73% of children with TSC and 27% of children with other etiologies (combined 56%). Partial onset seizures were controlled in 34% of all children, (17% seizure free,17%reduction in seizure frequency >50%) and no predictive factor was found. Shorter time from seizure onset to VGB treatment (p < 0.027) and longer total time on VGB (p < 0.045) was associated with better IQ-developmental quotient (DQ) outcome in children treated for IS, but not with IS control. Adverse events were seen in 13%. Electroretinogram and/or behavioral visual field (VF) testing was done in 52%. VGB was discontinued in one case due to abnormal electroretinogram (ERG) findings. We confirm the efficacy of VGB in the treatment of IS and PS in an American population. VGB may improve cognitive outcome in the absence of complete IS control, but this finding is of uncertain clinical significance. VGB was well tolerated, and ophthalmologic side effects were uncommon.


The expressions and clinical significances of tissue and serum galectin-3 in pancreatic carcinoma.
Galectin-3, a member of the beta-galactoside-binding protein family, is involved in many biological processes, including cell proliferation, regulating cell cycle, angiogenesis, tumorigenesis, metastasis, etc. The aim of this study is to elucidate the relationship between galectin-3 and clinicopathological variables and to evaluate the clinical significance of serum galectin-3 in the diagnosis of pancreas carcinoma. Galectin-3 expression in 78 pairs of pancreatic carcinoma tissues and the adjacent nontumorous tissues was tested by immunohistochemistry. The relationship between galectin-3 expression and clinical variables was analyzed. A sensitive method of time-resolved fluorescence immunological assay (TRFIA) for the detection of galectin-3 was established, and serum galectin-3 in cases with different pancreatic diseases was measured by TRFIA and ELISA. Further we compared the sensitivity and specificity of determining galectin-3, carcinoembryonic antigen (CEA) and carbohydrate antigen199 (CA199) for diagnosis of pancreatic carcinoma and assessed the complementary diagnostic value of galectin-3, CEA and CA199 for pancreatic carcinoma. Immunohistochemistry showed that galectin-3 expression was significantly higher in the human pancreatic carcinoma tissues than in the adjacent nontumorous tissues. The expression levels were correlated with the differentiation degree with the higher expression in poor differentiation tissues. Serum galectin-3 detected by both TRFIA and ELISA was much higher in patients with pancreatic carcinoma than in other groups. Serum galectin-3 was not correlated with CEA and CA199. Combined determination of these three markers has the complementary diagnostic value for human pancreatic carcinoma and may increase the diagnostic sensitivity to 97.5%. Galectin-3 is overexpressed in pancreatic carcinoma tissues, and it is correlated with the tumor differentiation. Serum galectin-3 is higher in cases with pancreatic carcinoma than in benign pancreatic diseases and healthy persons. Combined determination of serum galectin-3, CEA and CA199 may improve the diagnostic power for pancreatic carcinoma.


Ca2+, Mg2+-dependent endonuclease activity in different subpopulations of spleen cells from normal and erythroleukemic mice.
We have detected Ca2+, Mg2+-dependent endonuclease activity in spleen cells of normal, Friend erythroleukemic, and phenylhydrazine-treated mice. When nuclei were isolated and incubated in the presence of Ca2+ and Mg2+ ions, the activity resulted in the production of 3'-OH termini in the cellular DNA and the release of chromatin due to internucleosomal DNA fragmentation. This enzyme activity was chromatin-bound and could be extracted from chromatin in an active form in 0.35 M KCl. The majority of endonuclease activity from erythroleukemic spleens was present in nuclei of precursor erythroid cells of low buoyant density (1.025-1.05 g/ml). Uninfected normal splenic tissue contained an endonuclease activity which was almost entirely confined to a B-lymphocyte population of high buoyant density (greater than 1.07 g/ml). Erythroid cell-enriched spleens from phenylhydrazine-treated mice exhibited a distribution of endonuclease activity in cells at low and high densities reflecting a mixture of erythroid and lymphoid cells. Cloned erythroleukemic cell lines propagated in vitro lacked cells of low density and showed no detectable endonuclease activity. However, nuclei from these cell lines were susceptible to exogenously added endonuclease extracted from erythroleukemic spleen cells. These same cell lines propagated as subcutaneous tumors contained endonuclease activity and a morphologically-similar low-density cell population which accounted for the endonuclease activity in these tumors. Nuclei from cloned lymphoid cell lines, representing different B-lymphocyte phenotypes, showed differences in the presence of endonuclease activity. Among the cell lines tested, only those expressing late B-cell markers showed detectable endonuclease activity.


Massive Pulmonary Embolism after a Short Episode of Physical Restraint in an Adolescent Psychiatric Patient.
Medical restraints, when used for short periods of time, can pose additional risk for deep vein thrombosis in adolescent psychiatric patients. The problem is often unrecognized, and there is a lack of awareness of this potential risk. However, as associated major adverse events may result in fatal outcomes, an individual patient's risk for deep vein thrombosis should be assessed and prophylactic anticoagulation may be indicated.


Competencies for Physiotherapists Working to Facilitate Rehabilitation, Work Participation and Return to Work for Workers with Musculoskeletal Disorders: A Scoping Review.
Purpose The aim of this scoping review was to synthesize the literature addressing the competencies that physiotherapists in a clinical setting need to facilitate the rehabilitation, work participation, and return to work of workers with musculoskeletal disorders.Methods We conducted a scoping review in accordance with Arksey & O'Malley's five-step method. The following categories of keywords were used during searches in Embase, Medline and CINAHL in May 2020: (1) physiotherapy/physical therapy; (2) return to work, work participation or occupational health; and (3) education/professional competencies/guidelines. Two authors reviewed the full-text papers and agreed on the selection of articles for inclusion. The selected articles were then charted in an Excel grid and descriptively analyzed.Results Three main categories of competencies were identified: (1) Understanding and interacting with patients who are workers; (2) Planning rehabilitation with other stakeholders; and (3) Reaching out to the workplace. The fourth category named "Obstacles to the development of work-related competencies", regroups several obstacles that were identified as potentially impeding the development of work-related competencies by physiotherapists.Conclusion The findings of this scoping review inform physiotherapy clinicians, educators and regulators on the specific knowledge, skills, abilities, and attitudes that appear to play a role in facilitating the rehabilitation of workers with musculoskeletal disorders. We trust that this study will lead to new initiatives that will define, implement and evaluate the effectiveness of these competencies in practice, along with rekindling the discussions about the place of work rehabilitation in the physiotherapy profession.


Paraneoplastic limbic encephalitis in a patient with adenocarcinoma of the colon: a case report.
Paraneoplastic limbic encephalitis is a rare clinical entity characterized by the development of neuropsychiatric symptoms associated with malignancies. A case of a woman who presented to the Emergency Department with abdominal pain, hyperglycemia, and altered mental status is presented. After initial stabilization and correction of hyperglycemia the patient underwent emergency surgery. Laparotomy showed marked dilatation and gangrenous changes of the colon and tumor in the sigmoid colon. She was mechanically ventilated and remained ventilator-dependent for 42 days. Most of the time she was febrile; fever persisted with peaks up to 40° C despite various antibiotic treatments. On neurological examination, the patient was somnolent with left-sided hemiparesis. Magnetic resonance imaging (MRI) showed hyperintensities in both hippocampal areas, and electroencephalography (EEG) showed sharp-wave activity in the temporal lobes. Cerebrospinal fluid (CSF) examination showed slightly elevated protein levels, and laboratory assessments showed an elevated titer of anti-Yo antibodies. Although we do not have pathological confirmation of limbic encephalitis, the diagnosis of paraneoplastic limbic encephalitis was presumed on the basis of MRI findings, EEG abnormality, elevated CSF protein, positive anti YO antibodies, and neurological findings.


Efficiency of visual selection in duplex and conjunction conditions in partial report.
Factors that determine the efficiency of visual selection were investigated in two precued partial-report experiments. There were four selection conditions: a color condition (e.g., selecting purple letters among blue letters), a class condition (e.g., selecting letters among digits), a duplex condition (e.g., selecting purple letters among blue digits; that is, the targets differed from the distractors both in color and in alphanumeric class), and a conjunction condition (e.g., selecting purple letters among blue letters and purple digits; that is, the targets differed from the distractors either in color or in alphanumeric class). The efficiency of visual selection was highest in the duplex condition and lowest in the conjunction condition. The difference in performance across the different selection conditions within subjects was accounted for by variation in the value of a single parameter of the fixed-capacity independent race model (FIRM) proposed by Shibuya and Bundesen (1988), which assumes independent parallel processing, limitations in both processing capacity and storage capacity, and time-invariant selectivity. By assuming that the factors that determine the efficiency of selection in the color and class conditions also underlie the efficiency of selection in the duplex and conjunction conditions, an extension of FIRM, FIRM+, accounted for the relationship with respect to efficiency of selection among the different conditions.


Metagenomics as a Tool for Enzyme Discovery: Hydrolytic Enzymes from Marine-Related Metagenomes.
This chapter discusses metagenomics and its application for enzyme discovery, with a focus on hydrolytic enzymes from marine metagenomic libraries. With less than one percent of culturable microorganisms in the environment, metagenomics, or the collective study of community genetics, has opened up a rich pool of uncharacterized metabolic pathways, enzymes, and adaptations. This great untapped pool of genes provides the particularly exciting potential to mine for new biochemical activities or novel enzymes with activities tailored to peculiar sets of environmental conditions. Metagenomes also represent a huge reservoir of novel enzymes for applications in biocatalysis, biofuels, and bioremediation. Here we present the results of enzyme discovery for four enzyme activities, of particular industrial or environmental interest, including esterase/lipase, glycosyl hydrolase, protease and dehalogenase.


Haemangioendothelioma (Kupffer cell angiosarcoma), myelofibrosis, splenic atrophy, and myeloma paraproteinaemia after parenteral thorotrast administration.
A case of thorotrastosis occurred 25 years after thorotrast angiography, with the previously unrecorded association of myeloma type paraproteinaemia. The relationship between haemangioendothelioma due to thorotrast and other vascular sarcomas of the liver is briefly reviewed.


Effect of denervation and nerve extract on ultrastructure of muscle.
Changes in denervated skeletal muscle result both from disuse and loss of neurogenic trophic substances. It had been shown that administration of nerve extract intramuscularly in rats or systemically in mice prevented the nondisuse component of atrophy in denervated muscle. Amelioration of atrophy was manifested as reduced losses of weight, protein, and cross-sectional areas of fiber in denervated hind-limb muscles. The present study assessed the effects of nerve extract on ultrastructural changes in different types of fiber (as classified by activity of ATPase) in mouse skeletal muscle denervated for 7 days. Denervated and contralateral innervated muscles of treated and untreated mice were examined by electron microscopy, and morphological parameters were quantitated by stereological techniques. Denervated muscles exhibited smaller reductions of several ultrastructural changes in treated than in untreated mice including sizes of mitochondria, and percentage volume per fiber of mitochondria, sarcoplasmic reticulum, and t-tubules. The magnitude of the myotrophic effects varied in the different types of fiber, with amelioration of between 50 and 95% of the postdenervation changes.


Experience of Thai women in Bangkok with Norplant-2 implants.
A prospective study of the Norplant-2 contraceptive subdermal implant system was conducted in Bangkok, Thailand. The objective of the study was to evaluate the efficacy, adverse effects, and overall acceptability of Norplant-2 implants. A total of 140 women were enrolled in a 3-year clinical trial. The mean age was 29 years. Of all the acceptors, 70% had completed primary school. The continuation rates at years 1, 2, and 3 were, respectively, 94%, 89%, and 83%. No accidental pregnancies occurred throughout the 3 years of use in this study. Personal reasons were the leading cause for termination of Norplant-2 implant use. The 3-year cumulative termination rate for personal reasons was 7.2%. These personal reasons were divorce, husband having vasectomy, and moving away from the study area. The other leading cause for termination was medical reasons; acne, headache, and pain at the implant site were the complaints. The termination rate for medical reasons in year 3 of the study was 4.6%. Prolonged menstrual flow was the other main reason for termination. The 3-year cumulative termination rate for menstrual irregularities was 3.8%. In this study, the cumulative termination for planned pregnancy at the end of the year 3 was only 1.6%. The incidence of difficult removals was 8%. Breakage of the rods on removal was encountered in the majority of these cases. The study findings presented suggest that the Norplant-2 implants are highly effective with high continuation rates. The Norplant-2 system could become another choice of long acting reversible contraception for Thai women.


The elementary forms of care: an empirical approach to ethics in a South African Hospital.
Ethics is generally seen as the application of universal and intangible principles. Empirical studies then consist in verifying the degree of adequacy of practices to the norms. Here, conversely, ethics is considered as everyday practice: professionals, whether nurses or doctors, act within routines and under constraints, and later give an account of their action. Fieldwork was conducted during one year in the emergency and admission wards of a large South African hospital. It was based on interviews and observation and included feedback meetings for health professionals and focus group discussions with inhabitants of the neighbouring township. Ten elementary forms of care were identified in terms of patients' expectations. Five concerned the person as patient: ailment, problem, pain, agitation, life. Five concerned the patient as person: recognition, sovereignty, respect, privacy, interest. Discrepancies between claimed norms and actual practices were justified by health professionals in terms of workload, lack of resources and social deviance of patients. Ethnography suggests a more complex interpretation: on the one hand, technique-oriented professional ethos and efficiency-oriented organizational imperative are consequences of both historical territorial segregation and present resource inequalities. On the other hand, the lack of social recognition felt by nurses and doctors is in turn reflected in their moral evaluation of patients, which goes beyond concepts of values and worthiness. Although inscribed in the specific context of post-apartheid South Africa, the present description and analysis of practices has a broader scope as it proposes a way of approaching the elementary forms of care.


Iodine-129 concentrations in marginal seas of the north Pacific and Pacific-influenced waters of the Arctic Ocean.
Water sampling during the 1993 IV Russian-US Joint Expedition to the Bering and Chukchi Seas (BERPAC) indicates that Pacific Ocean burdens of the long-lived radionuclide 129I are relatively low in the Pacific-influenced Arctic, particularly compared to high latitude waters influenced by the North Atlantic. These low concentrations occur despite the presence of potential submerged anthropogenic sources in the East Sea (Sea of Japan), and in the northwest Pacific Ocean, east of the Kamchatka Peninsula. The concentration of 129I entering the Arctic Ocean through Bering Strait, approximately 0.7 x 10(8) atoms kg(-1), is only slightly higher than observed in deep Pacific waters. Similar concentrations (0.44-0.76 x 10(8) atoms kg(-1)) measured in Long Strait indicate no significant transfer of 129I eastward into the Chukchi Sea in the Siberian Coastal Current from the Siberian marginal seas to the west. However, the concentrations reported here are more than an order of magnitude higher than the Bering Strait input concentration estimated (1.0 x 10(6) atoms kg(-1)) from bomb fallout mass balances, which supports other existing evidence for a significant atmospheric deposition term for this radionuclide in surface ocean waters. Near-bottom water samples collected in productive waters of the Bering and Chukchi Seas also suggest that sediment regeneration may locally elevate 129I concentrations, and impact its utility as a water mass tracer. As part of this study, two deep 129I profiles were also measured in the East Sea in 1993-1994. The near-surface concentration of 129I ranged from 0.12 to 0.31 x 10(8) atoms kg(-1). The 129I concentration showed a steady decrease with depth, although because of active deep water ventilation, the entire 3000 m water column exceeded natural concentrations of the radionuclide. Atom ratios of 129I/137Cs in the East Sea also suggest an excess of 129I above bomb fallout estimates, also possibly resulting from atmospheric deposition ultimately originating from nuclear facilities.


SOX3 can promote the malignant behavior of glioblastoma cells.
Glioblastoma is the most common and lethal adult brain tumor. Despite current therapeutic strategies, including surgery, radiation and chemotherapy, the median survival of glioblastoma patients is 15 months. The development of this tumor depends on a sub-population of glioblastoma stem cells governing tumor propagation and therapy resistance. SOX3 plays a role in both normal neural development and carcinogenesis. However, little is known about its role in glioblastoma. Thus, the aim of this work was to elucidate the role of SOX3 in glioblastoma. SOX3 expression was assessed using real-time quantitative PCR (RT-qPCR), Western blotting and immunohistochemistry. MTT, immunocytochemistry and Transwell assays were used to evaluate the effects of exogenous SOX3 overexpression on the viability, proliferation, migration and invasion of glioblastoma cells, respectively. The expression of Hedgehog signaling pathway components and autophagy markers was assessed using RT-qPCR and Western blot analyses, respectively. Higher levels of SOX3 expression were detected in a subset of primary glioblastoma samples compared to those in non-tumoral brain tissues. Exogenous overexpression of this gene was found to increase the proliferation, viability, migration and invasion of glioblastoma cells. We also found that SOX3 up-regulation was accompanied by an enhanced activity of the Hedgehog signaling pathway and by suppression of autophagy in glioblastoma cells. Additionally, we found that SOX3 expression was elevated in patient-derived glioblastoma stem cells, as well as in oncospheres derived from glioblastoma cell lines, compared to their differentiated counterparts, implying that SOX3 expression is associated with the undifferentiated state of glioblastoma cells. From our data we conclude that SOX3 can promote the malignant behavior of glioblastoma cells.


Bridging the gap: interagency task force.
Admission of in-custody patients into an overtaxed emergency department is often frustrating for both law enforcement and ED staff. To facilitate collaboration between law enforcement and ED staff, it would be advantageous to initiate a professional interagency task force. To justify the need for such a task force, a random survey of hospital and law enforcement personnel was undertaken. Result of this survey revealed major misconceptions by both sides concerning the other's role. One common area of overwhelming agreement between the agencies was the need for such a task force. The data suggest the urgent need for mutually agreed upon policies and procedures for in-custody patients for both agencies to provide a safe environment for all involved.


Cyclic 3',5'-adenosine monophosphate phosphodiesterase (cAMP PDE) and cyclic 3',5'-guanosine monophosphate phosphodiesterase (cGMP PDE) in microvessels isolated from bovine cortex.
It was established that microvessels of a bovine cortex exhibit significant cyclic 3',5'-adenosine monophosphate phosphodiesterase (cAMP PDE) and cyclic 3',5'-guanosine monophosphate phosphodiesterase (cGMP PDE) activities. These activities are dependent on the presence of Mg2+. Absence of Ca2+ was virtually without effect. When both Mg2+ and Ca2+ were absent, PDE activities increased compared with activities observed in the absence of Mg2+. Xanthines (caffeine, theobromine, and theophylline) were better inhibitors of cAMP PDE than of cGMP PDE. Imidazole, in very high concentration (1 X 10(-2) M) only, exhibited PDE stimulatory activity at high concentrations of both substrates. Otherwise, it exhibited PDE-inhibitory properties.


Carbohydrate composition and taxonomy of the genus Dipodascus.
Carbohydrates released during acid hydrolysis of intact cells of Dipodascus were studied by gas-liquid chromatographic analysis as their trimethylsilyl derivatives. In addition, cells were characterized by pyrolysis gas-liquid chromatography and pyrolysis mass spectrometry. The data obtained support the classification of Dipodascus uninucleatus in a separate genus Dipodascopsis. Glucuronic acid is present in D. uninucleatus and, therefore, a possible affinity to fungi classified in the Zygomycetes is considered. Dipodascus aggregatus and Dipodascus australiensis were found to be rather different, but very close to Geotrichum candidum and related species.


Evidence for the association of dystrophin with the transverse tubular system in skeletal muscle.
Polyclonal antibodies to dystrophin (the protein product of the human Duchenne muscular dystrophy gene) were used to identify and characterize dystrophin in isolated triads from rabbit skeletal muscle. Anti-dystrophin antibodies recognize an approximately 400,000-Da protein in isolated triads or heavy microsomes from skeletal muscle. Treatment of heavy microsomes with buffers containing high salt or EDTA to remove peripheral or extrinsic membrane proteins does not remove dystrophin; however, treatment of intact triads with trypsin shows that dystrophin is extremely sensitive to mild proteolytic digestion. Isolation of junctional complexes from skeletal muscle triads indicates that dystrophin is tightly associated with the triadic junction. Fractionation of the triadic junction into junctional transverse tubular membranes and junctional sarcoplasmic reticulum membranes has shown that dystrophin is enriched in junctional transverse tubular membranes. Thus, our results suggest that dystrophin is a component of the triad junction which is exposed to the cytoplasm and embedded in or attached to the transverse tubular membrane.


Does biochar application in heavy metal-contaminated soils affect soil micronutrient dynamics?
Biochar has been practically used as a soil conditioner in degraded or contaminated soils. Whether biochar would simultaneously affect soil micronutrient bioavailability in heavy metal-contaminated soils warrants research. A 90-d incubation of rice straw biochar with either Pb- or Cd-contaminated soils was conducted to investigate the biochar effect on Fe, Mn, Cu and Zn bioavailability. Biochar amendment decreased the DTPA-extractable, acid extractable and reducible Pb and Cd but increased the oxidizable and residual Pb and Cd. It decreased the DTPA-extractable Fe by 73.8% and 23.1% but increased the DTPA-extractable Mn by 9.8% and 44.3% in the neutral and acidic soil, respectively. The lower Fe availability was attributed to the liming effect and the increased numbers of oxygen-containing groups and organic-mineral phases of biochar over time. Biochar amendment increased soil bacterial richness and diversity in both soils. Rice straw biochar can effectively immobilize heavy metals and reduce soil Fe bioavailability but increase Mn bioavailability, which would potentially affect soil micronutrient fertility and productivity.


3DDPDs: describing protein dynamics for proteochemometric bioactivity prediction. A case for (mutant) G protein-coupled receptors.
Proteochemometric (PCM) modelling is a powerful computational drug discovery tool used in bioactivity prediction of potential drug candidates relying on both chemical and protein information. In PCM features are computed to describe small molecules and proteins, which directly impact the quality of the predictive models. State-of-the-art protein descriptors, however, are calculated from the protein sequence and neglect the dynamic nature of proteins. This dynamic nature can be computationally simulated with molecular dynamics (MD). Here, novel 3D dynamic protein descriptors (3DDPDs) were designed to be applied in bioactivity prediction tasks with PCM models. As a test case, publicly available G protein-coupled receptor (GPCR) MD data from GPCRmd was used. GPCRs are membrane-bound proteins, which are activated by hormones and neurotransmitters, and constitute an important target family for drug discovery. GPCRs exist in different conformational states that allow the transmission of diverse signals and that can be modified by ligand interactions, among other factors. To translate the MD-encoded protein dynamics two types of 3DDPDs were considered: one-hot encoded residue-specific (rs) and embedding-like protein-specific (ps) 3DDPDs. The descriptors were developed by calculating distributions of trajectory coordinates and partial charges, applying dimensionality reduction, and subsequently condensing them into vectors per residue or protein, respectively. 3DDPDs were benchmarked on several PCM tasks against state-of-the-art non-dynamic protein descriptors. Our rs- and ps3DDPDs outperformed non-dynamic descriptors in regression tasks using a temporal split and showed comparable performance with a random split and in all classification tasks. Combinations of non-dynamic descriptors with 3DDPDs did not result in increased performance. Finally, the power of 3DDPDs to capture dynamic fluctuations in mutant GPCRs was explored. The results presented here show the potential of including protein dynamic information on machine learning tasks, specifically bioactivity prediction, and open opportunities for applications in drug discovery, including oncology.


Direct lexical control of eye movements in reading: evidence from a survival analysis of fixation durations.
Participants' eye movements were monitored in an experiment that manipulated the frequency of target words (high vs. low) as well as their availability for parafoveal processing during fixations on the pre-target word (valid vs. invalid preview). The influence of the word-frequency by preview validity manipulation on the distributions of first fixation duration was examined by using ex-Gaussian fitting as well as a novel survival analysis technique which provided precise estimates of the timing of the first discernible influence of word frequency on first fixation duration. Using this technique, we found a significant influence of word frequency on fixation duration in normal reading (valid preview) as early as 145ms from the start of fixation. We also demonstrated an equally rapid non-lexical influence on first fixation duration as a function of initial landing position (location) on target words. The time-course of frequency effects, but not location effects was strongly influenced by preview validity, demonstrating the crucial role of parafoveal processing in enabling direct lexical control of reading fixation times. Implications for models of eye-movement control are discussed.


Applications of density functional theory in COVID-19 drug modeling.
The rapidly evolving Coronavirus 2019 (COVID-19) pandemic has led to millions of deaths around the world, highlighting the pressing need to develop effective antiviral pharmaceuticals. Recent efforts with computer-aided rational drug discovery have allowed detailed examination of drug-macromolecule interactions primarily by molecular mechanics (MM) techniques. Less widely applied in COVID-19 drug modeling is density functional theory (DFT), a quantum mechanics (QM) method that enables electronic structure calculations and elucidations of reaction mechanisms. Here, we review recent advances in applying DFT in molecular modeling studies of COVID-19 pharmaceuticals. We start by providing an overview of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs and targets, followed by a brief introduction to DFT. We then provide a discussion of different approaches by which DFT has been applied. Finally, we discuss essential factors to consider when incorporating DFT in future drug modeling research.


Effect of Mavacamten on Chinese Patients With Symptomatic Obstructive Hypertrophic Cardiomyopathy: The EXPLORER-CN Randomized Clinical Trial.
Mavacamten has shown clinical benefits in global studies for patients with obstructive hypertrophic cardiomyopathy (oHCM), but evidence in the Asian population is lacking. To evaluate the safety and efficacy of mavacamten compared with placebo for Chinese patients with symptomatic oHCM. This phase 3, randomized, double-blind, placebo-controlled clinical trial was conducted at 12 hospitals in China. Between January 4 and August 5, 2022, patients with oHCM and a left ventricular outflow tract (LVOT) gradient of 50 mm Hg or more and New York Heart Association (NYHA) class II or III symptoms were enrolled and received treatment for 30 weeks. Patients were randomized 2:1 to receive mavacamten (starting at 2.5 mg once daily) or placebo for 30 weeks. The primary end point was change in Valsalva LVOT peak gradient from baseline to week 30. Left ventricular outflow tract gradients and left ventricular ejection fraction (LVEF) were assessed by echocardiography, while left ventricular mass index (LVMI) was determined by cardiac magnetic resonance imaging. Analysis was performed on an intention-to-treat basis. A total of 81 patients (mean [SD] age, 51.9 [11.9] years; 58 men [71.6%]) were randomized. Mavacamten demonstrated a significant improvement in the primary end point compared with placebo (least-squares mean [LSM] difference, -70.3 mm Hg; 95% CI, -89.6 to -50.9 mm Hg; 1-sided P < .001). Similar trends were demonstrated for resting LVOT peak gradient (LSM difference, -55.0 mm Hg; 95% CI, -69.1 to -40.9 mm Hg). At week 30, more patients receiving mavacamten than placebo achieved a Valsalva LVOT peak gradient less than 30 mm Hg (48.1% [26 of 54] vs 3.7% [1 of 27]), less than 50 mm Hg (59.3% [32 of 54] vs 7.4% [2 of 27]), and NYHA class improvement (59.3% [32 of 54] vs 14.8% [4 of 27]). Greater improvements were also observed with mavacamten regarding the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (LSM difference, 10.2; 95% CI, 4.4-16.1), N-terminal pro-B-type natriuretic peptide level (proportion of geometric mean ratio, 0.18; 95% CI, 0.13-0.24), high-sensitivity cardiac troponin I level (proportion of geometric mean ratio, 0.34; 95% CI, 0.27-0.42), and LVMI (mean difference, -30.8 g/m2; 95% CI, -41.6 to -20.1 g/m2). Safety and tolerability were similar between mavacamten and placebo. No patients experienced LVEF less than 50%. Mavacamten significantly improved Valsalva LVOT gradient vs placebo for Chinese patients. All secondary efficacy end points were also improved. Mavacamten was well tolerated with no new safety signals. This study supports the efficacy and safety of mavacamten in diverse populations, including Chinese patients. ClinicalTrials.gov Identifier: NCT05174416.


Comparing the performance and coverage of selected in silico (liver) metabolism tools relative to reported studies in the literature to inform analogue selection in read-across: A case study.
Changes in the regulatory landscape of chemical safety assessment call for the use of New Approach Methodologies (NAMs) including read-across to fill data gaps. One critical aspect of analogue evaluation is the extent to which target and source analogues are metabolically similar. In this study, a set of 37 structurally diverse chemicals were compiled from the EPA ToxCast inventory to compare and contrast a selection of metabolism in silico tools, in terms of their coverage and performance relative to metabolism information reported in the literature. The aim was to build understanding of the scope and capabilities of these tools and how they could be utilised in a read-across assessment. The tools were Systematic Generation of Metabolites (SyGMa), Meteor Nexus, BioTransformer, Tissue Metabolism Simulator (TIMES), OECD Toolbox, and Chemical Transformation Simulator (CTS). Performance was characterised by sensitivity and precision determined by comparing predictions against literature reported metabolites (from 44 publications). A coverage score was derived to provide a relative quantitative comparison between the tools. Meteor, TIMES, Toolbox, and CTS predictions were run in batch mode, using default settings. SyGMa and BioTransformer were run with user-defined settings, (two passes of phase I and one pass of phase II). Hierarchical clustering revealed high similarity between TIMES and Toolbox. SyGMa had the highest coverage, matching an average of 38.63% of predictions generated by the other tools though was prone to significant overprediction. It generated 5,125 metabolites, which represented 54.67% of all predictions. Precision and sensitivity values ranged from 1.1-29% and 14.7-28.3% respectively. The Toolbox had the highest performance overall. A case study was presented for 3,4-Toluenediamine (3,4-TDA), assessed for the derivation of screening-level Provisional Peer Reviewed Toxicity Values (PPRTVs), was used to demonstrate the practical role in silico metabolism information can play in analogue evaluation as part of a read-across approach.


The Eger Macular Stressometer: pilot study.
To evaluate the sensitivity of the Eger Macular Stressometer (EMS) for early screening of age-related macular degeneration (AMD) in a clinical practice. We examined the null hypothesis that AMD eyes have EMS recovery times (RTs) that do not differ from eyes with cataract, diabetic retinopathy, or glaucoma. The design of this study was a nonrandomized clinical trial. Ninety-two eyes from 92 patients with vision 20/80 or better, age 50 and older, of either gender, and any ethnic origin, were recruited into one of four groups: AMD (30 eyes), normal or mild cataract (30 eyes), diabetic retinopathy (16 eyes), and glaucoma (16 eyes). Recovery times were obtained with the EMS, according to manufacturer's instructions. The mean (SD) [median] RT for the AMD group was 11.8 (7.6) [9] seconds, the normal/cataract group 10.0 (4.3) [9] seconds, the diabetic retinopathy group 8.4 (3.0) [8] seconds, and glaucoma group 8.6 (2.4) [8] seconds. Recovery time did not appear to be related to group (P =.58), age (P =.50), visual acuity (P =.52), or sex (P =.23). We found EMS RT distributions did not differ between AMD, cataract, diabetic retinopathy, and glaucoma groups. The EMS in its current form is not a sensitive screening tool for AMD. Further testing is needed to examine EMS sensitivity with other macular diseases such as central serous choroidopathy and diabetic macular edema.


Assembly of matched alpha/beta subunits to HLA class II peptide receptors.
Human antigen presenting cells express three human leukocyte antigen (HLA) class II isotypes (DR, DP, and DQ), which are composed of polymorphic α and β subunits. The combination of polymorphic α- and β-chains results in cis (encoded on the same chromosome) or trans (encoded on different chromosomes) combinations. Since some of the α-β combinations may yield mismatched non-functional α-β heterodimers, it is not entirely clear which type of HLA class II peptide receptors are found on the cell surface of antigen presenting cells. We have developed a combination of biochemical techniques for inspection of the assembly and intracellular transport of isotype matched and mismatched class II heterodimers.


Serum IgG antibodies against Wallemia sebi and Fusarium species in Finnish farmers.
Wallemia sebi and Fusarium species are common fungi in agricultural environments. Because Fusarium species are difficult to culture, and W. sebi has only recently been found in an agricultural environment with the use of a new culture medium, immunochemical methods may be important for evaluating exposure to these fungi. Immunoglobulin (Ig) G antibodies against W. sebi and two Fusarium species were measured in the sera of Finnish farmers to estimate exposure to fungi. Serum-specific IgG antibody levels against the fungi were determined in farmers with farmer's lung disease and asthma, as well as in asymptomatic farmers with low and high IgG antibody levels against other agricultural microorganisms, and in control persons (printing and office workers). Both enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunofiltration assay (ELIFA) techniques were used. Significantly higher IgG antibody levels against the fungi studied were observed in farmer's lung patients and asymptomatic farmers with high IgG levels against other agricultural fungi, than in the control group. On the other hand, the development of IgG antibodies to the fungi in asthmatic farmers remained unclear because of a discrepancy between the ELISA and ELIFA results. Cross-reactivity between Fusarium species was detected. The results indicate that Finnish farmers are exposed to W. sebi and Fusarium species in their work environment to a greater extent than has earlier been evaluated with air sampling and microbiologic methods.


Effects of icodextrin on patient survival and technique success in patients undergoing peritoneal dialysis.
Many studies have suggested clinical benefits of icodextrin in peritoneal dialysis (PD) patients regarding fluid management, glycaemic control and metabolic improvement. However, reports on whether icodextrin can improve patient and technique survival is sparse. A total of 2163 patients from 54 centres in Korea who initiated PD from July 2003 to December 2006 were enrolled. Outcomes data were retrieved retrospectively from the Baxter Korea database. Among these patients, 641 patients who had been prescribed icodextrin for >50% of their PD duration were defined as the 'icodextrin' group and the remaining 1522 patients as the 'non-icodextrin' group. Propensity score matching yielded 640 matched pairs of patients. We compared all-cause mortality and technique failure rates between the two groups. There were no significant differences in age, gender, diabetes, cardiovascular comorbidity, socioeconomic status, biocompatible solution use in short dwells or centre experience between the two groups. Death occurred in 92 (14.4%) patients in the icodextrin group compared with 128 (20.0%) in the non-icodextrin group [hazard ratio (HR), 0.69; 95% confidence interval (CI), 0.53-0.90; P = 0.006]. In addition, icodextrin use was associated with a significantly lower risk of technique failure (HR, 0.60; 95% CI, 0.40-0.92; P = 0.018). The icodextrin group had fewer technique failures due to non-compliance compared with the non-icodextrin group whereas peritonitis- or ultrafiltration failure-related technique failure was not different between the two groups. This study further supports previous findings of long-term utilization of icodextrin solution improving patient and technique survival in PD patients. To confirm these results, a large randomized prospective study is warranted.


Changes in sEMG parameters among trunk and thigh muscles during a fatiguing bilateral isometric multi-joint task in trained and untrained subjects.
This study aimed to explore changes in the electrical activity distribution among synergist muscles involved in the maintenance of this bilateral multi-joint task. It also tested relations between changes in surface electromyographic (sEMG) parameters with endurance time. Eighteen subjects, trained and untrained in hiking, performed a submaximal (50% of maximal contraction) isometric hiking test until exhaustion. The electrical activity of main superficial muscles implicated in this posture was recorded bilaterally. Trained subjects sustained the hiking position for 315+/-82 s, versus 225+/-68 s for untrained subjects. Patterns of electrical activity and mean power frequency (MPF) were different between populations. MPF shift in abdominal muscles was higher than in other synergists for both groups. Although typical changes in sEMG parameters were observed, few relations with endurance time were found, and for untrained subjects only. Changes in the relative contribution among synergists were observed, mainly for trained subjects. It is hypothesized that the task (a complex multi-joint posture involving numerous joints and muscles) may allow some variability in the contribution of synergist muscles during fatigue especially for the trained group. This probably explains the absence of relationship between endurance time and sEMG changes for trained subjects.


The European registry of quality outcomes for cataract and refractive surgery (EUREQUO): a database study of trends in volumes, surgical techniques and outcomes of refractive surgery.
A European web-based registry for refractive surgery was established in 2008; The European Registry of Quality Outcomes for Cataract and Refractive Surgery (EUREQUO). The aim of the registry was to improve treatment and standards of care for refractive surgery. Further aims were to offer a tool for benchmarking by establishing a reference database and for surgeons to enter and analyze their own outcomes. The purpose of this study was to characterize the registry and analyze the data collected during its first decade. The characteristics of the web-based registry are described. Data collected from February 4(th) 2004 until June 30(th) 2014 are included in the analysis. The database is analyzed in terms of surgical technique, indications for surgery, complications, and refractive and visual outcomes. Data have been reported from 47 centers in 14 countries until mid-2014. About 4,000 procedures were reported annually. The most frequent procedure was laser-assisted in-situ keratomileusis (LASIK) with 11697 reported surgeries. Over time in the database, LASIK declined (p < 0.001) while photorefractive keratectomy (PRK) and refractive lens exchange (RLE) increased (p < 0.001 for both procedures). The indications for surgery, in terms of preoperative refraction and age, were stable over time, for all types of procedures. Surgical complications were reported infrequently and with a well-known relationship to the type of surgical procedure. The reported refractive outcomes were good. The visual outcomes indicate a significant increase of visual acuity after high myopia treatment by phakic intraocular lens in the anterior (phakic IOL AC) and the posterior (phakic IOL PC) chamber and a poorer visual outcome, after both myopia and hyperopia treatment, by epithelial LASIK (Epi-LASIK). We describe the establishment of a European registry for refractive surgery. The database increases at a rate of approximately 4000 refractive procedures per year. The most frequent procedure is LASIK, but both PRK and RLE are an increasing part of the reported procedures. The indications for surgery have been stable over time. Surgical complications and visual outcome vary, depending on the type of surgery.


Stimulating equity of services to nonwhites in community mental health centers.
This paper describes a special date-based approach by the National Institute of Mental Health (NIMH) and the Health, Education and Welfare (HEW) regional offices to improve mental health service utilization nationwide for nonwhites and equalize these services with those available to whites.


The optimization of serum-free medium for the production of the scu-PA by the addition of algal extracts.
The addition of 2.8 μg/ml algal extracts enhanced both scu-PA production and cell growth in a serum-free medium, compared to a conventional serum-free medium for the cultivation of recombinant CHO cells. The growth rate and scu-PA production were relatively lower in the serum-free medium than 5% serum containing medium: however, specific scu-PA production rate was higher in the serum-free medium due to the long-term period of cultivation (3.66×10(-4) vs. 2.48×10(-4) IU/cell/day). Overall scu-PA production rate was also greater in an enforced serum-free medium as 25,000 IU/day over 50 d of perfusion cultivation. The conversion ratio of scu-PA to tcu-PA was greatly reduced in the serum-free medium during perfusion cultivation (10% compared to 20% conversion in a serum containing medium).


Screening of bacterial DNA in bile sampled from healthy dogs and dogs suffering from liver- or gallbladder-associated disease.
Although the biliary system is generally aseptic, gallbladder microbiota has been reported in humans and some animals apart from dogs. We screened and analyzed the bacterial deoxyribonucleic acid in canine gallbladders using bile sampled from 7 healthy dogs and 52 dogs with liver- or gallbladder-associated disease. PCR screening detected bacteria in 17.3% of diseased dogs (9/52) and none in healthy dogs. Microbiota analysis of PCR-positive samples showed that the microbial diversity differed between liver- and gallbladder-associated disease groups. Thus, a specific bacterial community appears to occur at a certain frequency in the bile of diseased dogs.


Proportional assist versus pressure support ventilation in patients with acute respiratory failure: cardiorespiratory responses to artificially increased ventilatory demand.
To test the hypothesis that in response to increased ventilatory demand, dynamic inspiratory pressure assistance better compensates for increased workload compared with static pressure support ventilation (PSV). Randomized clinical crossover study. General intensive care u nits of a university hospital. Twelve patients with acute respiratory failure. Patients received PSV, proportional assist ventilation (PAV), and PAV+ automatic tube compensation (ATC) in random order while maintaining mean inspiratory airway pressure constant. During each setting, ventilatory demand was increased by adding deadspace without ventilator readjustment. Cardiorespiratory, ventilatory, and work of breathing variables were assessed by routine monitoring plus pneumotachography; airway, esophageal, and abdominal pressure measurements; and nitrogen washout. After deadspace addition, tidal volume and end-expiratory lung volume increased similarly in all ventilatory modalities. Ventilator work, peak inspiratory flow, and maximum airway pressure increased significantly during PAV+ATC when compared with PSV after deadspace addition. However, increase in ventilator work did not result in a smaller increase in patients' work of breathing with elevated ventilatory demand during PAV+ATC (PSV 807 +/- 204 mJ/L, PAV 802 +/- 193 mJ/L, and PAV+ATC 715 +/- 202 mJ/L, p = .11). Increase in patients' work of breathing was mainly caused by a significantly higher resistive workload during PAV and PAV+ATC. In patients with acute respiratory failure, dynamic inspiratory pressure assistance modalities are not superior to PSV with respect to cardiorespiratory function and inspiratory muscles unloading after increasing ventilatory demand. The latter might be explained by higher peak flows resulting in nonlinearly increased resistive workload that was incompletely compensated by PAV+ATC.


Firewalking.
Firewalking is known throughout recorded history and around the world. Ordinarily it is associated with religious beliefs or mystical states of mind in which the gods or unusual mental powers provide extraordinary protection for true believers or those with proper training. However, firewalking commonly involves hot materials of low heat capacity and poor thermal conductivity and sometimes the use of insulation. The excited or trance-like states of firewalkers contribute to the firewalkers' subjective experience but are not required for a successful walk. We conclude that elementary knowledge of physics and psychology is sufficient to explain the known observations of firewalking.


Knee dislocations: a magnetic resonance imaging study correlated with clinical and operative findings.
Our objectives were to determine retrospectively the prevalence, patients' demographics, mechanism of injury, combination of torn ligaments, associated intra-articular and extra-articular injuries, fractures, bone bruises, femoral-tibial alignment and neurovascular complications of knee dislocations as evaluated by magnetic resonance (MR) imaging. From 17,698 consecutive knee examinations by magnetic resonance imaging (MRI) over a 6-year period, 20 patients with knee dislocations were identified. The medical records of these patients were subsequently reviewed for relevant clinical history, management and operative findings. The prevalence of knee dislocations was 0.11% [95% confidence interval (95% CI) 0.06-0.16)]. There were 16 male patients and four female patients, with ages ranging from 15 years to 76 years (mean 31 years). Fifteen patients had low-velocity injuries (75%), of which 11 were amateur sports related and four were from falls. Four patients (20%) had suffered high-velocity trauma (motor vehicle accidents). One patient had no history available. Anatomic alignment was present at imaging in 16 patients (80%). Eighteen patients had three-ligament tears, two had four-ligament tears. The four-ligament tears occurred with low-velocity injuries. The anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) were torn in every patient; the lateral collateral ligament (LCL) was torn in 50%, and the medial collateral ligament (MCL) in 60%. Intra-articular injuries included meniscal tears (five in four patients), fractures (eight in seven patients), bone bruises (15 patients), and patellar retinaculum tears (eight partial, two complete). The most common extra-articular injury was a complete biceps femoris tendon tear (five, 25%). There were two popliteal tendon tears and one iliotibial band tear. One patient had received a vascular injury following a motor vehicle accident (MVA) and had been treated prior to undergoing MRI. Bone bruises (unrelated to fractures), four-ligament tears, biceps femoris tears, and popliteus tendon tears were encountered only in the low-velocity knee dislocations. Twelve were treated surgically, five conservatively, and three had been lost to follow-up. The biceps femoris tendon was repaired in every patient who was treated surgically. Knee dislocations occurred more commonly in low-velocity injuries than in high-velocity injuries, predominantly affecting amateur athletes. Biceps femoris tendon tears were the most common extra-articular injury requiring surgery. Neurovascular injury (5%) was uncommon. At imaging, femoral-tibial alignment was anatomic in the majority of patients.


Violence, alcohol problems and other problems in disintegrating families.
Violence is more than twice as likely to occur in families with rather than without alcohol problems.


Complement killing of clinical Klebsiella pneumoniae isolates is serum concentration dependent.
Klebsiella pneumoniae is an opportunistic gram-negative pathogen causing serious infections, including sepsis. In plasma, activation of the complement cascades is important for killing bacteria. Thirty clinical Klebsiella spp. blood isolates were analyzed for serum susceptibility in 75% normal human serum (NHS). Twenty-two were serum resistant and eight were serum sensitive, and subsequently tested in 5-75% NHS. Two isolates were killed in 5% and the remaining six in 50%-75% NHS. The two 5% sensitive isolates showed binding of complement (C)4 and C3 in 5% NHS with formation of membrane attack complex (MAC). Inhibition of the classical/lectin mediated pathways (CP/LP) using a C4 specific nanobody, hC4Nb8, led to survival of both isolates in 5% NHS. Using nanobody hC3Nb1, inhibiting the alternative pathway (AP), the isolates were killed in 5% NHS, and amplification of the CP/LP by AP was not necessary for killing. Sole AP killing of these isolates when inhibiting CP/LP with hC4Nb8 was observed in 50% NHS, stressing the concentration dependent functionality of AP. For the less sensitive isolates, killing required activation of CP/LP and AP demonstrated by inhibition with nanobodies. AP inhibition resulted in no C3 deposition on the serum resistant isolate, supporting that AP was the sole activation pathway.


Therapy adapted to molecular response in patients with chronic myelogenous leukaemia in first chronic phase: results of the Duesseldorf study.
This study evaluates response-adapted treatment of chronic myelogenous leukaemia (CML) in chronic phase using molecular response criteria. bcr-abl/G6PDH ratios were assessed by Light-Cycler quantitative real-time polymerase chain reaction (PCR( in 277 peripheral blood samples from 33 patients, before and every 3 months during therapy. Sixty-six per cent (22/33) of the patients fulfiled our molecular response criterion of > or = 1 log decrease in bcr-abl transcript after 6 or > or = 2 log decrease after 9 and every following 3 months. Dose escalation was necessary for 33% (11/33) of the patients. Of these, 54% (6/11) achieved a reduction of bcr-abl mRNA by > or = 2 log (n = 3) or > or = 3 log (n = 3) with 800 mg Imatinib. Forty-five per cent (5/11) showed insufficient molecular response with 800 mg Imatinib and received Nilotinib. In conclusion, the assessment of molecular response permits an individual patient-tailored treatment of CML in first chronic phase, resulting in the majority of patients achieving a major molecular response after 2 years of therapy.


Association of MMP-8 promoter gene polymorphisms with carotid atherosclerosis: preliminary study.
Matrix metalloproteinases (MMPs) are involved in the remodeling of the extracellular matrix in the arterial wall. Collagen I is associated with vascular smooth muscle cell (VSMC) migration and monocyte differentiation. MMP-8 is expressed in atherosclerotic plaque and preferentially cleaves collagen type I. The aim of this study was to investigate the associations of two MMP-8 promoter polymorphisms, rs11225395 (-799C/T) and rs1320632 (-381 A/G), with carotid plaque occurrence, and the influence of these polymorphisms on MMP-8 mRNA expression in plaque tissue. The study included a total of 766 participants: 277 controls and 489 patients with carotid atherosclerosis undergoing endarterectomy. The two investigated polymorphisms were genotyped by PCR-RFLP. The gene expression analysis was performed by real-time PCR. In females only, a significantly higher frequency of the -381G allele was found in patients with carotid atherosclerosis compared to controls (OR, 1.7; 95% CI 1.1-2.9; p = 0.001). Significant up-regulation of MMP-8 gene expression was observed in patients carrying the -381G allele compared to those with the AA genotype (mean factor, 3.54; S.E. range, 0.643-19.551; p = 0.007). Carotid plaque tissue of the haplotype G(-381)T(-799) showed a significantly higher mRNA level compared with the reference A(-381)C(-799) haplotype (p = 0.003). Our preliminary results indicate that MMP-8 -381A/G and -799C/T gene polymorphisms could be risk factors for carotid atherosclerosis. Further validation and functional studies are needed to establish the potential regulatory role of these polymorphisms and their impact on susceptibility to carotid atherosclerosis.


The Epidemiology of Infundibular Caries in Donkeys in Inner Mongolia Autonomous Region of China and Associated Risk Factors.
Infundibular caries (IC) affects donkeys of all ages and causes pain, difficulty in mastication and weight loss. The study aimed to determine the epidemiology of IC in donkeys and examine the potential risk factors associated with the disease development. A total of 2118 donkeys in Inner Mongolia were sampled. The first section of the survey was performed by veterinarians and included the oral health of the donkeys. A survey on the donkey's signalment, diet, and husbandry was also conducted. The risk factors associated with IC were assessed using multivariable logistic regression analysis. Univariate analysis of 11 variables assessed revealed that only four factors, including age, type of forage, pasture time and water source, increased the risk of IC. The findings of this study enhance our knowledge of the management and prevention of IC in donkeys.


The better effects of microbubble ultrasound transfection of miR-940 on cell proliferation inhibition and apoptosis promotion in human cervical cancer cells.
Cervical cancer is the second leading cause of women's cancer-related death. MiR-940 has been reported as a critical factor in various cancers. Based on the high transfection efficiency and low side effect, the clinical application of microbubble ultrasound contrast agent in gene treatment has attracted a widespread attention. In this study, we determined the mechanism of miR-940 inhibiting cell proliferation and cycle procession, and promoting cell apoptosis in cervical cancer Hela cells. In addition, we compared the effects of different transfection methods, including liposome, microbubble, ultrasound, and microbubble coupled with ultrasound. MTT assay, PI staining, and Annexin-Ⅴ/PI staining assays were, respectively, performed to evaluate cell proliferation status, cell cycle progression, and apoptosis status. RT-PCR and Western blot were conducted to measure the levels of cell cycle- and apoptosis-related factors, and the phosphorylation levels of PI3K and Akt. Results showed that the overexpression of miR-940 inhibited cell proliferation, blocked cell cycle, and promoted apoptosis by regulating cell cycle-related factors (such as inhibited Cyclin D1 and CDK4) and apoptosis-related factors (such as promoted Puma and Bax, inhibited Bcl-2 and Cleaved caspase9), and inhibiting the phosphorylation and activation of PI3K/AKT pathway. Among all of them, miR-940 transfected with microbubble and ultrasound showed the greatest changes. It provides evidence that miR-940 could be a wonderful biomarker and treatment agent for cervical cancer, and microbubble ultrasound would have more wide application in the clinical treatment of cancers.


Interim Results of the PROMISE I Trial to Investigate the LimFlow System of Percutaneous Deep Vein Arterialization for the Treatment of Critical Limb Ischemia.
To investigate the feasibility, safety, and effectiveness of the LimFlow stent-graft system in performing percutaneous deep vein arterialization (pDVA) for treatment of critical limb ischemia (CLI) patients ineligible for conventional endovascular or surgical revascularization procedures. Ten no-option CLI patients (mean age, 67 ± 11 years; 30% women) were enrolled. All patients were classified as Rutherford class 5 or 6 and were deemed by a committee of experts to be ineligible for endovascular or surgical procedures to restore blood flow. Eighty percent were categorized as stage 4 (high risk of amputation) based on Society for Vascular Surgery wound, ischemia, and foot infection (SVS WIfI) scoring index. The primary safety endpoint was amputation-free survival (AFS) at 30 days. A secondary safety endpoint evaluated AFS at 6 months. Other secondary endpoints included primary patency, wound healing, and technical success. Amputation-free survival was achieved in 100% of patients, with no deaths or index limb above-ankle amputations observed at 30 days and 6 months. Technical success rate was 100%. No procedural complications were reported. Primary patency rates at 1 month and 6 months were 90% and 40%, respectively, with reintervention performed in 30% of patients. By 6 months, 30% of patients experienced complete (100%) wound healing, half of patients had 84%-93% wound healing, and 20% of patients experienced 60% healing. pDVA using the LimFlow system is a novel approach for treating patients with no-option CLI and may reduce amputation in this population for whom it would otherwise be considered inevitable. Initial findings from this early feasibility trial are promising and additional study is warranted.


In vivo and in vitro analyses of the immunogenicity of B16 melanoma cells.
In vitro grown B16, an H-2b melanoma cell line, was found to kill B10 (H-2b), B10.BR (H-2k), CBA (H-2k), and BALB/c (H-2d) but not B10.D2 (H-2d) mice. BALB/c mice could be protected against a lethal dose of B16 by co-administration of H-2b spleen or peritoneal exudate cells, suggesting B16 was susceptible to an immune response but unable to induce it. However, evidence for the immunogenicity of B16 tumour in vivo was shown in two ways--(i) by immunization with irradiated B16 before lethal tumour challenge, and (ii) by demonstration of specific immunity in BALB/c mice which survived a low dose of viable B16 tumour. The resistance of most B10.D2 mice to doses of B16 tumour which were lethal to four other strains of mice was also compatible with the immunogenicity of B16 in vivo. By contrast, B16 was unable to induce a primary Tc-cell response in vitro but was able to induce a secondary response. The significance of these results for theories of T cell immunity to foreign tissue and for improving immunogenicity of tumours is discussed.


Effects of plasma concentrations of 5-fluorouracil on long-term survival after treatment with a definitive 5-fluorouracil/cisplatin-based chemoradiotherapy in Japanese patients with esophageal squamous cell carcinoma.
A substantial body of literature has accumulated during the past 20 years showing the plasma concentrations of 5-fluorouracil (5-FU) to correlate with clinical response and/or toxicity in colorectal cancer, and head and neck cancer, but little information is available concerning effects on long-term survival. Here, Japanese patients with esophageal squamous cell carcinoma (ESCC) were followed up for 5 years after treatment with a definitive 5-FU/cisplatin (CDDP)-based chemoradiotherapy (CRT), and the association between prognosis and the plasma concentration of 5-FU was evaluated. Forty-nine patients with ESCC, who were treated with a definitive 5-FU/CDDP-based CRT, were enrolled. A course consisted of the continuous infusion of 5-FU at 400 mg/m2/day for days 1-5 and 8-12, the infusion of CDDP at 40 mg/m2/day on days 1 and 8, and the radiation at 2 Gy/day on days 1 to 5, 8 to 12, and 15 to 19, with a second course repeated after a 2-week interval. Plasma concentrations of 5-FU were determined by high performance liquid chromatography at 5:00 PM on days 3, 10, 38 and 45, and at 5:00 AM on days 4, 11, 39 and 46. The overall 5-year survival rate was 42.9%. Age (P = 0.020), body weight (P = 0.019), and disease stage (P = 0.048) affected the survival, and the survival depended on the clinical response assessed at 1 month after the treatment (P = 0.001). Higher plasma concentrations of 5-FU resulted in a better clinical response (P = 0.043), and trended to prolong survival (P = 0.321). The long-term survival after treatment with a definitive 5-FU/CDDP-based CRT possibly depends on the plasma concentrations of 5-FU, and further clinical studies with a larger number of cases are needed to clarify the relationship between them.


The role of oxygen-derived free radicals in the pathogenesis of acute pancreatitis.
Acute pancreatitis may be initiated in the ex vivo, perfused canine pancreas preparation by a variety of stimuli. These include oleic acid infusion (FFA), partial duct obstruction with secretin stimulation (POSS), and a 2-hour period of ischemia (ISCH). In each model, pancreatitis is characterized by weight gain, edema, and hyperamylasemia. Oxygen-derived free radicals such as superoxide, hydrogen peroxide, and the hydroxyl radical are highly reactive toxic substances that are normally produced in small amounts during oxidative metabolism. Ordinarily, these substances are detoxified by endogenous intracellular enzymes called free radical scavengers (FRS), such as superoxide dismutase (SOD) and catalase (CAT). These studies were undertaken to evaluate the possible role of oxygen-derived free radicals in the initiation of acute pancreatitis in the isolated canine model. All preparations were perfused for 4 hours with autologous blood. Controls (N = 6): these glands remained normal in appearance, gained minimal weight (6 +/- 1 g), and serum amylase remained normal (less than 1000 u/dl). FFA pancreatitis, FFA alone (N = 6): these glands became edematous, gained weight (113.5 +/- 27.0 g), and developed hyperamylasemia (2087 +/- 387 u/dl). FFA + FRS (N = 6), SOD (50 mg) and CAT (50 mg) were added to the perfusate at time zero: these glands became only minimally edematous, gained less weight (31.8 +/- 10.1 g, p less than 0.05), and amylase remained normal (p less than 0.05). POSS pancreatitis, POSS alone (N = 8): these glands became edematous, gained weight (38.6 +/- 4.6 g), and developed marked hyperamylasemia (9522 +/- 3226 u/dl). POSS + FRS (N = 6): these glands did not develop edema, gained less weight (15.1 +/- 2.6 g, p less than 0.05), and serum amylase only increased to 1815 +/- 343 u/dl, (p less than 0.05). ISCH pancreatitis, ISCH alone (N = 6): these glands became edematous, gained weight (75.8 +/- 25 g), and developed hyperamylasemia (1679 +/- 439 u/dl). ISCH + FRS (N = 6): these glands did not develop edema, gained only 18.3 +/- 9.0 g (p less than 0.005), and serum amylase remained normal (p less than 0.05). These studies demonstrate that, in this canine preparation, acute pancreatitis is significantly ameliorated by oxygen-free radical scavengers. Since this was true whether the pancreatitis was produced by FFA infusion, POSS, or ischemia, it suggests that oxygen-derived free radicals may mediate a common essential step in the pathogenesis of all forms of pancreatitis.


Adaptation of American College of Rheumatology Rheumatoid Arthritis Disease Activity and Functional Status Measures for Telehealth Visits.
To provide guidance on the implementation of recommended American College of Rheumatology (ACR) rheumatoid arthritis (RA) disease activity and functional status assessment measures in telehealth settings. An expert panel was assembled from the recently convened ACR RA disease activity and functional status measures working groups to summarize strategies for implementation of ACR-recommended RA disease activity (the Clinical Disease Activity Index [CDAI], Disease Activity Score in 28 joints using the erythrocyte sedimentation rate or the C-reactive protein level [DAS28-ESR/CRP], Patient Activity Scale II [PAS-II], Simplified Disease Activity Index [SDAI], and Routine Assessment of Patient Index Data 3 [RAPID3]) and functional status (the Health Assessment Questionnaire II [HAQ-II], Multidimensional Health Assessment Questionnaire [MDHAQ], and PROMIS physical function 10-item short form [PROMIS PF-10]) measures in telehealth settings. Measures composed of patient-reported items (disease activity: PAS-II, RAPID3; functional status: HAQ-II, MDHAQ, PROMIS PF-10) require minimal modification for use in telehealth settings. Measures requiring formal joint counts (the CDAI, DAS28-ESR/CRP, and SDAI) can be calculated using patient-reported swollen and tender joint counts. When the feasibility of laboratory testing is limited, the CDAI can be used in place of the SDAI, and scoring modifications of the DAS28-ESR/CRP without the acute-phase reactant are available. Assessment of the validity of these modifications is limited. Implementation of these measures can be facilitated by electronic health record collection, mobile applications, and provider/staff administration during telehealth visits. The ACR-recommended RA disease activity and functional status measures can be adapted for use in telehealth settings to support high-quality clinical care. Research is needed to better understand how telehealth settings may impact the validity of these measures.


Evolution: Escaping the Inevitability of Ageing.
William Hamilton argued that even species inhabiting the farthest flung corners of the universe should age. However, a recent study shows that to find a species that escapes ageing, you only need to look as far as your local pond.


Captopril before and after spironolactone therapy in primary aldosteronism. Pathogenetic and therapeutical aspects.
In three patients with primary aldosteronism, the acute effect of a single dose of captopril on the elevated mean arterial blood pressure (MAP) was studied before and after 4 weeks of treatment with spironolactone. Before spironolactone therapy, captopril did not cause any drop in MAP. Four weeks later, after an oral daily dose of 400 mg spironolactone, MAP was still elevated in all three patients, though electrolyte abnormalities were fully corrected. Since plasma renin activity (PRA) was increased to values above the normal range, the acute effect of captopril on MAP was tested again. A single dose of 25 mg captopril then caused a fall in MAP to normal. These data reveal the conversion from a renin-independent to a renin-dependent kind of hypertension after spironolactone therapy in three patients with primary aldosteronism syndrome. This might be of pathogenetic and therapeutic interest.


Molecular cloning and binding properties of the human type II activin receptor.
A full-length cDNA for the type II human activin receptor was cloned by hybridization from a human testis cDNA library. The sequence encodes a 513 amino acid protein that is 99% identical, at the amino acid level, with the mouse type II activin receptor. The type II human activin receptor consists of an extracellular domain that specifically binds activin A with a Kd of 360 pM, a single-membrane spanning domain, and an intracellular kinase domain with predicted serine/threonine specificity.


Quantification of plagiocephaly and brachycephaly in infants using a digital photographic technique.
The aims of the study were: (1) to develop a technique to quantify plagiocephaly that is safe, accurate, objective, easy to use, well tolerated, and inexpensive; and (2) to compare this method with tracings from a flexicurve ruler. A case-control study of 31 case infants recruited from outpatient plagiocephaly clinics and 29 control infants recruited from other pediatric outpatient clinics. Infants in the study had been diagnosed with nonsynostotic plagiocephaly or brachycephaly and were between 2 and 12 months old. Infants' head shapes were measured using (a) digital photographs of a head circumference band and (b) a flexicurve ruler. Flexicurve tracings were scanned, and both the digital photos and the scanned flexicurve tracings were analyzed using a custom-written computer program. The oblique cranial length ratio was used to quantify cranial asymmetry, and the cephalic index was used to quantify the degree of brachycephaly. The infants tolerated the photo technique better than the flexicurve. Also, mothers preferred the photo technique. There was less within-subject variance for the photos than for the flexicurve measurements. The results suggested that an oblique cranial length ratio of >or= 106% can define plagiocephaly and that a cephalic index of >or= 93% can define brachycephaly. The photographic technique was better accepted and more repeatable than the flexicurve measuring system. We propose that "normal" head shape is indicated in infants with both an oblique cranial length ratio of less than 106% and a cephalic index of less than 93%.


Outer Membrane Vesicle-Based Nanohybrids Target Tumor-Associated Macrophages to Enhance Trained Immunity-Related Vaccine-Generated Antitumor Activity.
Trained immunity refers to the innate immune system building memory-like features in response to subsequent infections and vaccinations. Compared with classical tumor vaccines, trained immunity-related vaccines (TIrV) are independent of tumor-specific antigens. Bacterial outer membrane vesicles (OMVs) contain an abundance of PAMPs and have the potential to act as TIrV-inducer, but face challenges in endotoxin tolerance, systemic delivery, long-term training, and trained tumor-associated macrophage (TAM)-mediated antitumor phagocytosis. Here, an OMV-based TIrV is developed, OMV nanohybrids (OMV-SIRPα@CaP/GM-CSF) for exerting vaccine-enhanced antitumor activity. In the bone marrow, GM-CSF-assisted OMVs train bone marrow progenitor cells and monocytes, which are inherited by TAMs. In tumor tissues, SIRPα-Fc-assisted OMVs trigger TAM-mediated phagocytosis. This TIrV can be identified by metabolic and epigenetic rewiring using transposase-accessible chromatin (ATAC) and transcriptome sequencing. Furthermore, it is found that the TIrV-mediated antitumor mechanism in the MC38 tumor model (TAM-hot and T cell-cold) is trained immunity and activated T cell response, whereas in the B16-F10 tumor model (T cell-hot and TAM-cold) is primarily mediated by trained immunity. This study not only develops and identifies OMV-based TIrV, but also investigates the trained immunity signatures and therapeutic mechanisms, providing a basis for further vaccination strategies.


The role of ubiquitination in the regulation of primary cilia assembly and disassembly.
The primary cilium is a cellular antenna found on the surface of many eukaryotic cells, whose main role is to sense and transduce signals that regulate growth, development, and differentiation. Although once believed to be a vestigial organelle without important function, it has become clear that defects in primary cilium are responsible for a wide variety of genetic diseases affecting many organs and tissues, including the brain, eyes, heart, kidneys, liver, and pancreas. The primary cilium is mainly present in quiescent and differentiated cells, and controls must exist to ensure that this organelle is assembled or disassembled at the right time. Although many protein components required for building the cilium have been identified, mechanistic details of how these proteins are spatially and temporally regulated and how these regulations are connected to external cues are beginning to emerge. This review article highlights the role of ubiquitination and in particular, E3 ubiquitin ligases and deubiquitinases, in the control of primary cilia assembly and disassembly.