Proteolytic signatures define unique thrombin-derived peptides present in human wound fluid in vivo.
The disease burden of failing skin repair and non-healing ulcers is extensive. There is an unmet need for new diagnostic approaches to better predict healing activity and wound infection. Uncontrolled and excessive protease activity, of endogenous or bacterial origin, has been described as a major contributor to wound healing impairments. Proteolytic peptide patterns could therefore correlate and "report" healing activity and infection. This work describes a proof of principle delineating a strategy by which peptides from a selected protein, human thrombin, are detected and attributed to proteolytic actions. With a particular focus on thrombin-derived C-terminal peptides (TCP), we show that distinct peptide patterns are generated in vitro by the human S1 peptidases human neutrophil elastase and cathepsin G, and the bacterial M4 peptidases Pseudomonas aeruginosa elastase and Staphylococcus aureus aureolysin, respectively. Corresponding peptide sequences were identified in wound fluids from acute and non-healing ulcers, and notably, one peptide, FYT21 (FYTHVFRLKKWIQKVIDQFGE), was only present in wound fluid from non-healing ulcers colonized by P. aeruginosa and S. aureus. Our result is a proof of principle pointing at the possibility of defining peptide biomarkers reporting distinct proteolytic activities, of potential implication for improved diagnosis of wound healing and infection.


Rectourethral fistula reconstruction in elderly patients.
This article discusses etiologic considerations, evaluation, and contemporary approaches to managing rectourethral fistula (RUF) with particular emphasis on geriatric patients. With the advent of multimodal approaches to treating prostate cancer, such as radiation and ablative therapies, the incidence of RUF is increasing, especially in the geriatric population. Surgical repair and healing of RUF in patients with prior radiation is more challenging than in those without prior radiation or ablation because of fibrotic and ischemic changes in surrounding tissues. There is, at present, a lack of consensus over a standardized approach to RUF management because of the heterogeneity in presentation and limited, primarily retrospective, experience in the literature. Nonetheless, an evolving array of surgical approaches now exists for fistula excision and tissue interposition. Immediate recognition and management of RUF is paramount to prevent related complications. Patient selection and counseling are key to selecting the best approach for repair, whereas a multidisciplinary team, including colorectal and plastic surgery colleagues, may optimize outcomes.


Sleep and morningness-eveningness in the 'middle' years of life (20-59 y).
The following four issues were assessed in a group of 110 adults between the age of 20 and 59y: (1) the effect of age (regarded as a continuous variable) on polysomnographic sleep characteristics, habitual sleep-diary patterns, and subjective sleep quality; (2) the effects of age on morningness-eveningness; (3) the effects of morningness-eveningness on sleep, after controlling for the effects of age; and (4) the role of morningness-eveningness as a mediator of the age and sleep relationship. Increasing age was related to earlier habitual waketime, earlier bedtime, less time in bed and better mood and alertness at waketime. In the laboratory, increasing age was associated with less time asleep, increased number of awakenings, decreased sleep efficiency, lower percentages of slow-wave sleep (SWS) and rapid eye movement (REM) sleep, higher percentages of Stage 1 and 2, shorter REM latency and reduced REM activity and density. Increasing age was also associated with higher morningness scores. After controlling for the effects of age, morningness was associated with earlier waketime, earlier bedtime, less time in bed, better alertness at waketime, less time spent asleep, more wake in the last 2 h of sleep, decreased REM activity, less stage REM (min and percentage), more Stage 1 (min and percentage) and fewer minutes of Stage 2. For one set of variables (night time in bed, waketime, total sleep time, wake in the last 2 h of sleep and minutes of REM and REM activity), morningness-eveningness accounted for about half of the relationship between age and sleep. For another set of variables (bedtime, alertness at waketime, percentages of REM and Stage 1), morningness-eveningness accounted for the entire relationship between age and sleep. In conclusion, age and morningness were both important predictors of the habitual sleep patterns and polysomnographic sleep characteristics of people in the middle years of life (20-59 y).


The impact of urinary stress incontinence in young and middle-age women practising recreational sports activity: an epidemiological study.
To evaluate the prevalence of urinary stress incontinence (USI) in menstruating women practising recreational sports activity, to detect specific sports with a stronger association with urinary incontinence (UI) and to evaluate risk factors possibly related to this condition. Epidemiological study. Non-competitive sports organisations in the province of Varese, Italy. 679 women of fertile age, practising recreational sports activity. Anonymous questionnaire on UI. The questionnaire included questions about patients' general characteristics, occurrence of UI in relation to sport or daily general activities, time of onset of this condition, frequency of leakage episodes, correlation of incontinence with types of movements or sports, subjective impression of being limited on such occasions and/or necessity to modify the type of sport. UI was reported by 101 women (14.9%). Of these, 32 (31.7%) complained of UI only during sports activity, 48 (47.5%) only during daily life and 21 (20.8%) in both circumstances. Body mass index and parity were significantly associated with the risk of UI. Looking at the different sports activities, a higher rate of incontinence was found in women participating in basketball (16.6%), athletics (15%), and tennis or squash (11%). 10.4% of women abandoned their favourite sport, because of USI, and a further 20% limited the way they practised their favourite sport to reduce leakage episodes. Female UI affects a significant proportion of young women practising non-competitive sports activity; it can cause abandonment of the sport or limitation of its practice.


Wharton's jelly derived mesenchymal stromal cells: Biological properties, induction of neuronal phenotype and current applications in neurodegeneration research.
Multipotent mesenchymal stromal cells, also known as mesenchymal stem cells (MSC), can be isolated from bone marrow or other tissues, including fat, muscle and umbilical cord. It has been shown that MSC behave in vitro as stem cells: they self-renew and are able to differentiate into mature cells typical of several mesenchymal tissues. Moreover, the differentiation toward non-mesenchymal cell lineages (e.g. neurons) has been reported as well. The clinical relevance of these cells is mainly related to their ability to spontaneously migrate to the site of inflammation/damage, to their safety profile thanks to their low immunogenicity and to their immunomodulation capacities. To date, MSCs isolated from the post-natal bone marrow have represented the most extensively studied population of adult MSCs, in view of their possible use in various therapeutical applications. However, the bone marrow-derived MSCs exhibit a series of limitations, mainly related to their problematic isolation, culturing and use. In recent years, umbilical cord (UC) matrix (i.e. Wharton's jelly, WJ) stromal cells have therefore emerged as a more suitable alternative source of MSCs, thanks to their primitive nature and the easy isolation without relevant ethical concerns. This review seeks to provide an overview of the main biological properties of WJ-derived MSCs. Moreover, the potential application of these cells for the treatment of some known dysfunctions in the central and peripheral nervous system will also be discussed.


Migratory capacity of large granular lymphocytes from T-gamma-lymphoproliferative disorders.
We have investigated 10 patients with T gamma-lymphoproliferative disorders (T gamma LPD) for cell migratory capacity. Large granular lymphocytes (LGLs) expanding in these subjects expressed natural killer cell markers (HNKI, B73.1, AB8.28, N901, OKM1) to a variable extent. The patients' LGLs mediated antibody-dependent cellular cytotoxicity, while appreciable natural killer activity was only measurable in 3 patients. The migratory capacity of T gamma LPD was examined by using nitrocellulose filters. The patients' LGLs migrated into filters and showed responsiveness (in 9 of 10 patients) to activated serum, used as chemoattractant, as normal LGLs do. No clearcut correlation emerged between in vitro migratory capacity and disease aggressiveness or involvement of abdominal organs. These results confirm in T gamma LPD the migratory potential of LGLs and suggest the possibility that acquisition of enhanced locomotor capacity is not a crucial determinant of disease aggressiveness in T gamma LPD.


Circulating catecholamines in control of renal electrolyte and water excretion.
Graded physiological doses of norepinephrine or epinephrine were infused either intravenously or directly into the renal artery of conscious dogs previously prepared with chronic indwelling catheters. Infusion rates ranged from 5 to 125 ng . kg-1 . min-1, and aortic plasma catecholamine concentrations were measured during intravenous infusion to determine the actual levels achieved. Even when the renal arterial plasma norepinephrine concentration was raised to 5,000 pg/ml by either intravenous or intrarenal infusion, only a modest sodium and potassium retention was observed. Only intravenous norepinephrine increased urinary flow rate. Increments of epinephrine concentration from 120 to 2,000 pg/ml decreased sodium and potassium excretion only when delivered intravenously. The concentrations of norepinephrine or epinephrine required to alter urinary sodium and potassium excretion and flow rate were in the upper physiological range or higher and the responses were small except for intravenous epinephrine, which decreased sodium excretion at very low physiological concentrations (120-400 pg/ml). We conclude that circulating epinephrine may play an important physiological role in renal sodium conservation. This effect of epinephrine is not due to a direct intrarenal mechanism.


The Effects of Accumulated Versus Continuous Exercise on Postprandial Glycemia, Insulin, and Triglycerides in Adults with or Without Diabetes: A Systematic Review and Meta-Analysis.
Postprandial dysmetabolism, an important cardiovascular disease risk factor, can be improved by exercise. Further systematic review and meta-analysis is needed to compare the effects of accumulated exercise with a single session of energy-matched continuous exercise on postprandial glucose (PPG), insulin, and triglycerides in adults with or without diabetes. Eight electronic databases were searched on August 28, 2020, and updated on April 27, 2021. Eligible studies were randomized, quasi-randomized, or non-randomized controlled or crossover trials that evaluated the acute or longitudinal effects of accumulated exercise compared with a single session of energy-matched continuous exercise on PPG, postprandial insulin, and triglycerides in diabetic and non-diabetic adults. Same-day and second-morning effects were assessed separately for acute intervention studies. Subgroup analyses were conducted based on the number of exercise bouts (2-3 bouts or frequent brief bouts (e.g., 1-6 min) throughout the day at 20-60-min intervals (known as physical activity [PA] breaks, ≥ 5 bouts)), exercise intensity, and populations. Risk of bias was assessed using the revised Cochrane risk-of-bias tool for randomized trials. Pooled effects were reported as standardized mean differences (SMD) and 95% CI using a random effects model. Twenty-seven studies (635 participants) were included. A significant difference was found for same-day PPG control, which favored accumulated exercise over one bout of energy-matched continuous exercise (SMD - 0.36 [95%CI: (- 0.56, - 0.17)], P = 0.0002, I2 = 1%), specifically in accumulated exercise with PA breaks (SMD - 0.36 [95%CI: (- 0.64, - 0.08)], P = 0.01, I2 = 30%), low-moderate intensity exercise (SMD - 0.38 [(95%CI: (- 0.59, - 0.17)], P = 0.0005, I2 = 0%), and in non-diabetic populations (SMD - 0.36 [95%CI: (- 0.62, - 0.10)], P = 0.007, I2 = 16%). No differences were found for same-day postprandial insulin and triglycerides, and second-morning effects (postprandial or fasting glucose, insulin, and triglycerides) between different exercise patterns. Compared with one session of continuous exercise, accumulated exercise-specifically in subgroups of PA breaks, low-moderate intensity exercises-produced greater acute effects on same-day PPG control for non-diabetic adults. There were no differences between continuous and accumulated patterns of exercise in terms of same-day postprandial insulin and triglycerides, and second-morning effects on all previously mentioned markers. The findings provide additional PA options for PPG control for individuals with limited time or exercise capacity to engage in PA in one session. Registration: PROSPERO (identification code: CRD42021251325).


Phenotypes and invariant alpha beta TCR expression of peripheral V alpha 14+ NK T cells.
A novel subset of peripheral T cells, peripheral NK T cells, is found to be a major population comprising 5% of splenic T and 40% of bone marrow T cells. The majority of peripheral NK T cells are characterized by the expression of an invariant TCR-alpha encoded by V alpha 14/J alpha 281 with a one nucleotide N region. Moreover, a specific reduction of V alpha 14+ NK T cells has been demonstrated to be tightly associated with various autoimmune diseases, indicating their decisive role in autoimmune disease development. In this study, we investigated the phenotypes of peripheral V alpha 14+ NK T cells and their TCR-beta repertoire. Peripheral V alpha 14+ NK T cells, comprise two populations, i.e., small and large sized cells, at an equal frequency, belonged to the CD4- CD8- fraction, and are heat stable antigen(bright), macrophage-1bright, B220bright, CD45RBdim, and Mel-14dim, but CD5-, distinct from thymic NK T cells. TCR-beta analysis clearly showed that peripheral V alpha 14+ NK T cells utilized two to three dominant invariant TCR-beta, such as V beta 8.2 D beta J beta 2.5/V beta 7 D beta J beta 2.1 in the spleen and liver, V beta 8.2 D beta J beta 2.5/V beta 8.3 D beta J beta 2.2/V beta 7 D beta J beta 2.6 in the bone marrow, and V beta 7 D beta J beta 2.1/V beta 3 D beta J beta 1.2 in intestinal intraepithelial lymphocytes. Judging from the unusual surface phenotypes, such as heat stable antigen, macrophage-1, B220, CD45RBdim, and Mel-14dim, which are known to be T cell activation markers, peripheral V alpha 14+ NK T cells may always be activated under physiologic conditions, resulting in the oligoclonal expansion of V alpha 14+ NK T cells with different invariant TCR-beta in different peripheral organs. The unique features of V alpha 14+ NK T cells are discussed.


Quality of care in family planning services in rural Mozambique with a focus on long acting reversible contraceptives: a cross-sectional survey.
In Mozambique, both the government and partners have undertaken efforts over the last decade to improve FP (family planning) services, especially through training health care providers and promoting the uptake of LARCs (Long Acting Reversible Contraceptives). Despite this, uptake of FP methods has not increased significantly. This study aims to examine women's knowledge on LARCs, including their main sources of information, and the quality of care of FP services in rural areas. We conducted a repeated cross-sectional study, interviewing 417 women leaving FP consultations in 15 health facilities in Maputo Province, Mozambique. The main quality outputs measured were: 1)discussed, preferred and received contraceptive methods, 2)information received on usage and side-effects, 3)client-provider interaction, 4)being informed about the need for a follow-up visit 5)health examinations conducted and travel time to the facility. In addition, knowledge on LARCs was measured among the clients as well as sources of information regarding FP methods. Taking into account the design effect of the study, Chi-square statistics were used to detect differences between groups and linear regression analyses to identify associations between sources of information and higher knowledge. We found that IUDs (intrauterine devices) and implants were discussed in 23 and 33% of the consultations respectively, but only administered in a very few cases(< 1%). Half of the women were counselled on side-effects of contraceptives; this did not differ between first time clients and follow-up clients. Almost all women(98%) were satisfied with the received service and 83% of the women found the waiting time acceptable. Health examinations were performed on 18% of the women. Overall, women's knowledge about LARCs was poor and misconceptions are still common. Women who had received FP information through outreach activities had better knowledge than those counselled at a facility. Our study highlights that only a minority of the women received information regarding LARCs during the consultation and that usage is almost non-existent. Counseling about all types of contraceptives during the consultation is sub-optimal, resulting in poorly informed clients. Multifaceted long-term interventions, focusing on both users and providers, are needed to improve uptake of contraceptives (including LARCs) in rural areas.


Effects of metabolic substrates and inhibitors on weak organic anion transport in rat renal proximal tubules.
Stimulatory effects of intermediates of the tricarboxylic acid cycle on renal uptake of a weak organic anion, fluorescein, were studied with the aid of the method of contact microfluorimetry of individual convoluted proximal tubules ascending to the surface of the rat renal cortex slices. The study was undertaken for verifying the hypothesis that energization of renal excretion of anionic exenobiotics is mediated through their transport across the basolateral membrane in exchange for cytoplasmic alpha-ketoglutarate serving as a counter-anion. Effects of inhibitors of the tricarboxylic acid cycle such as fluoroacetate, malonate and 5-methoxyindole-2-carboxylate on the fluorescein uptake and renal gluconeogenesis in the presence of the metabolic substrates were investigated in order to outline metabolic pathways that could be responsible for elevation of the cytoplasmic alpha-ketoglutarate. Obtained data evidence that the stimulatory effects of the tricarboxylic acid cycle intermediates on the transport process under study depend on the metabolic state of the mitochondria and involve an activation of certain reactions but not the cycle as a whole. It has been suggested that an elevation of the cytoplasmic alpha-ketoglutarate resulting from this activation can be conditioned by export of isocitrate from the mitochondria with its subsequent transformation into alpha-ketoglutarate in the cytoplasm in the isocitrate dehydrogenase reaction.


Damage of Inner Ear Sensory Hair Cells via Mitochondrial Loss in a Murine Model of Sleep Apnea With Chronic Intermittent Hypoxia.
Investigating the exact pathophysiology of obstructive sleep apnea syndrome (OSAS)-induced hearing loss is critical. We sought to verify the hypothesis that a correlation exists between mitochondrial dysfunction in inner ear hair cells and the auditory dysfunction induced by chronic intermittent hypoxia (CIH) in a murine model of sleep apnea. C57BL/6J adult male mice were randomized to 4 weeks of CIH (n = 12) or normoxia (Sham) (n = 12). Hearing threshold was determined by auditory brainstem response. The activity of mitochondria was compared between CIH and Sham mice. Histological assessment and transmission electron microscopy were performed for assessing morphologic changes in mitochondria. The number of mtDNA copies as well as the levels of PGC1-α, Tfam, and VDAC (voltage-dependent anion channel) were determined in the hair cells of CIH mice. We observed that hearing ability in CIH mice was impaired and hair-cell mitochondria in CIH mice were fewer compared to that in Sham and also displayed an aberrant morphology. The mRNA levels of PGC-1α and Tfam were higher in the CIH group than in the Sham group. Moreover, the expression of VDAC was increased in the tectorial membrane, the basilar membrane, and especially in the inner hair cells of CIH mice. This study using CIH mice as a model for OSAS provides evidence of an association between OSAS and auditory function alteration, as well as of mitochondria being part of the pathophysiology of hearing impairment. Further investigation is required to determine whether mitochondria could serve as a valid target for preventive or therapeutic purposes.


Comparison of diagnostic results obtained by fine needle aspiration cytology and tru-cut or open biopsies.
In seven cases fine needle aspiration (FNA) cytology provided a diagnosis of neoplasm when the Tru-Cut (TC) tissue biopsies (four cases) and open biopsies (three cases) were negative. The specimens consisted of two breast carcinomas, two metastatic neoplasms in the liver, one metastatic melanoma in inguinal lymph nodes, a retroperitoneal mass and a pelvic mass. In the two cases of mammary carcinoma, TC biopsies were negative and FNAs were diagnostic of carcinoma. TC biopsies in the two cases of questionable hepatic metastasis were negative, but FNAs demonstrated a malignant neoplasm. Open biopsy of a retroperitoneal mass failed to diagnose a neoplasm however, subsequent ultrasound-directed FNA demonstrated a neoplasm, possibly seminoma. FNA cytology of inguinal lymph nodes in one case was diagnostic of melanoma; open biopsy showed no neoplasm. Because of the FNA diagnosis, additional sections were made and the presence of melanoma was confirmed. This series demonstrates that FNA cytology should be considered the initial diagnostic procedure more often.


Phase II, open label, randomized comparative trial of ondansetron alone versus the combination of ondansetron and aprepitant for the prevention of nausea and vomiting in patients with hematologic malignancies receiving regimens containing high-dose cytarabine.
Background. Aprepitant is a P/neurokinin-1 receptor antagonist approved for the prevention of CINV in moderate emetic risk chemotherapy. We explored its effectiveness in patients with leukemia receiving cytarabine-based chemotherapy. Methods. Patients were randomized to ondansetron (OND) 8 mg IV 30 minutes before cytarabine followed by 24 mg IV continuous infusion daily until 6-12 hours after the last dose of chemotherapy alone or with aprepitant (APREP) oral 125 mg 6-12 hrs before chemotherapy and 80 mg daily until 1 day after the last dose of chemotherapy. Results. Forty-nine patients were enrolled in each arm; 42 in OND and 41 in OND + APREP arm were evaluable for efficacy. The ORR with OND + APREP was 80% compared to 67% with OND alone (P = 0.11). On days 6 and 7, higher proportion of patients treated with OND + APREP were free from nausea (74%, 74% versus 68%, 67%; P = 0.27 and 0.18, resp.). Requirement of rescue medications on days 2 and 3 was fewer in OND + APREP arm 7% and 5% compared to 21% and 16% in the OND arm, respectively (P = 0.06 and P = 0.07). Conclusions. There was a trend for overall improvement in emesis with ondansetron plus aprepitant. The potential benefit of this approach with specific chemotherapy combinations remains to be determined.


Vitexin inhibits inflammation in murine ovalbumin-induced allergic asthma.
Vitexin is an important component of various medicinal plants frequently used to treat asthma, such as Crataegus spp., Vitex spp., Passiflora spp., and Echinodorus spp. However, there is no information about the vitexin potential as anti-asthmatic. The aim of the present work was to evaluate the anti-hypersensitive activity of vitexin in a murine ovalbumin (OVA)-induced allergic asthma model. Mice were sensitized to OVA by i.p. injection on days 1st and 10th, followed by a daily challenge with OVA using a nebulizer, from days 19th to 24th. Vitexin or dexamethasone were orally administered 1h before each OVA challenge. Vitexin attenuates migration induced by OVA-hypersensitivity of eosinophil, neutrophil, and mononuclear cells in bronchoalveolar lavage fluid (BALF). Histological analysis of the lungs shows that vitexin suppressed leukocyte infiltration, mucus production and pulmonary edema. Increases in Th2 cytokines in BALF in OVA-induced asthma is also attenuated by vitexin, as well as plasma levels of IgE. Overall, these results suggest that vitexin can suppress OVA-induced allergic inflammation in mice and provide a strong rationale for further developing vitexin as a candidate treatment for allergic hypersensitivity. These data corroborate the popular use of vitexin-rich plants for asthma treatment.


Mutational processes shape the landscape of TP53 mutations in human cancer.
Unlike most tumor suppressor genes, the most common genetic alterations in tumor protein p53 (TP53) are missense mutations1,2. Mutant p53 protein is often abundantly expressed in cancers and specific allelic variants exhibit dominant-negative or gain-of-function activities in experimental models3-8. To gain a systematic view of p53 function, we interrogated loss-of-function screens conducted in hundreds of human cancer cell lines and performed TP53 saturation mutagenesis screens in an isogenic pair of TP53 wild-type and null cell lines. We found that loss or dominant-negative inhibition of wild-type p53 function reliably enhanced cellular fitness. By integrating these data with the Catalog of Somatic Mutations in Cancer (COSMIC) mutational signatures database9,10, we developed a statistical model that describes the TP53 mutational spectrum as a function of the baseline probability of acquiring each mutation and the fitness advantage conferred by attenuation of p53 activity. Collectively, these observations show that widely-acting and tissue-specific mutational processes combine with phenotypic selection to dictate the frequencies of recurrent TP53 mutations.


Plasmodium vivax malaria.
We report 11 cases of severe Plasmodium vivax malaria in Bikaner (western India). Patients exhibited cerebral malaria, renal failure, circulatory collapse, severe anemia, hemoglobinurea, abnormal bleeding, acute respiratory distress syndrome, and jaundice. Peripheral blood microscopy, parasite antigen-based assays, and parasite 18s rRNA gene-based polymerase chain reaction showed the presence of P. vivax and absence of P. falciparum.


COVID-19 autopsies: Procedure, technical aspects and cause of fatal course. Experiences from a single-center.
Autopsies on COVID-19 have provided deep insights into a novel disease with unpredictable and potentially fatal outcome. A standardized autopsy procedure preferably with an in-situ technique and systematic tissue processing is important. Strict safety measures include personal protective equipment with a standardized protocol for dressing and undressing, usage of FFP-3 masks and minimization of aerosol production. The use of an airborne infection isolation (AIIR) room is preferred. Viral RNA analysis using swabs from throat, both lungs and other organs provides information on cross-organ viral dynamics. To correctly determine the full extent of pathological organ changes an adequate processing procedure is of the utmost importance. Systematic dissection and processing of the lungs revealed pulmonary infarction caused by thrombosis and thromboembolism and bacterial bronchopneumonia as the most frequent cause of death. Fungal pneumonia (aspergillus) was found in one case. The quality of the tissue was sufficient for histopathological and immunohistochemistry analyses in all cases. Viral RNA from throat or lung swabs was detectable post mortem in 89 % of the cases and could also be detected from paraffin-embedded tissue by real-time PCR. Complete COVID-19 autopsies including extensive histopathological studies and viral RNA analysis require approximately three times more human and technical resources and time compared to standard non-COVID autopsies. Autopsies on COVID-19 are feasible, present a manageable risk, while following a strict protocol, and provide novel insights into disease pathogenesis and the clinician with important feedback.


Pharmacokinetics of oral etoposide in patients with hepatocellular carcinoma.
Etoposide dosage in patients with liver dysfunction remains controversial. Since etoposide has a hepatic component to its clearance (CL) and shows a high degree of protein binding, hepatic impairment could affect etoposide disposition. However, the empiric recommendation that the dose of etoposide be decreased in such patients may reduce systemic exposure and be detrimental to its antitumor activity. To address these issues we studied the pharmacokinetics (PK) of etoposide in patients with hepatocellular carcinoma (HCC) and underlying cirrhosis (n = 17) treated with daily oral etoposide. Unbound etoposide was obtained by ultrafiltration. Etoposide concentrations (total and free drug) were measured by high-performance liquid chromatography (HPLC) and analyzed by noncompartmental equations. The patients had mild or moderate liver dysfunction. Albuminemia was in the normal range for all the patients. Creatininemia was normal in all but two patients. PK results (mean and range) showed that etoposide disposition was unchanged in patients with liver dysfunction. We found slightly high etoposide bioavailability [F, 61% (17-95%)] and clearance [CL, 1.1 (0.7-2.3)l h(-1) m(-2)] resulting in a normal degree of systemic exposure (AUC(oral) 27 microg h ml(-1)). Normal protein binding [PB 93.2% (84.4-98.1%)] contributed to a normal level of exposure to free drug (AUC(f, oral) 1.9 microg h ml(-1)). The distribution volume [V(SS) 8.4 (6.1-13.2) l/m2] and the effective half-life [t1/2eff, 5.1 (3.0-9.6) h] were normal. Median CL and protein binding did not differ in the seven patients with total bilirubin value of > 1.2 mg/dl as compared with the ten patients with total bilirubin levels of < or = 1.2 mg/dl (1.3 versus 1.01 h(-1) m(-2) and 92.5% versus 93.4%, respectively). In agreement with this PK finding, we observed no clinical evidence of increased toxicity in patients with hyperbilirubinemia as compared with patients with normal bilirubinemia (mean WBC decrease 38% versus 47%). The only case of severe (grade 4) hematological toxicity was observed in one patient with reduced glomerular filtration. Since the pharmacological effects of etoposide correlate with the level of systemic exposure to the free drug, our data suggest that no dose reduction is needed in patients with HCC. It is even possible to increase the dose intensity in patients with favorable PK parameters under appropriate hematological and therapeutic drug monitoring.


Rho kinase inhibition maintains intestinal and vascular barrier function by upregulation of occludin in experimental necrotizing enterocolitis.
Necrotizing enterocolitis (NEC) is a deadly disease that occurs in 5-10% of neonates. Although NEC has been extensively studied, no single therapeutic target has been identified. Rho kinase (ROCK) is a serine/threonine kinase that affects multiple cellular processes, including tight junction (TJ) function, cellular permeability, and apoptosis. We hypothesized that ROCK inhibition would decrease cellular permeability, stabilize TJ proteins (occludin), and decrease the severity of NEC. To test this hypothesis, human colon epithelial cells (Caco-2) and human endothelial cells were studied. Cells were treated with lipopolysaccharide to simulate an in vitro model of NEC. The effect of ROCK inhibition was measured by transepithelial membrane resistance (TEER) and cellular permeability to FITC-dextran. The effects of ROCK inhibition in vivo were analyzed in the rat pup model of NEC. NEC was induced by feeding formula supplemented with Cronobacter sakazakii with or without gavaged ROCK inhibitor. Rat intestines were scored based on histological degree of injury. RNA and protein assays for occludin protein were performed for all models of NEC. Treatment with ROCK inhibitor significantly decreased cellular permeability in Caco-2 cells and increased TEER. Intestinal injury scoring revealed decreased scores in ROCK inhibitor-treated pups compared with NEC only. Both cell and rat pup models demonstrated an upregulation of occludin expression in the ROCK inhibitor-treated groups. Therefore, we conclude that ROCK inhibition protects against experimental NEC by strengthening barrier function via upregulation of occludin. These data suggest that ROCK may be a potential therapeutic target for patients with NEC. NEW & NOTEWORTHY These studies are the first to demonstrate an upregulation of occludin tight junction protein in response to Rho kinase (ROCK) inhibition. Furthermore, we have demonstrated that ROCK inhibition in experimental models of necrotizing enterocolitis (NEC) is protective against NEC in both in vitro and in vivo models of disease.


Activation of multiple genes by provirus integration in the Mlvi-4 locus in T-cell lymphomas induced by Moloney murine leukemia virus.
Moloney murine leukemia virus-induced rat T-cell lymphomas harbor proviruses integrated near c-myc and near Mlvi-1/Mis-1/Pvt-1, another locus of common integration which maps 270 kilobases 3' of c-myc. In this report, we present the characterization of a new locus of common integration in Moloney murine leukemia virus-induced T-cell lymphomas (Mlvi-4) which maps 30 kilobases 3' of c-myc, between c-myc and Mlvi-1. The Mlvi-4 locus, whose chromosomal map location is conserved in rats, mice, and humans, is also the target of chromosomal rearrangements in a variety of animal and human tumors. Evidence presented elsewhere shows that provirus integration in Mlvi-4 enhances the expression of c-myc and Mlvi-1 by cis-acting mechanisms operating over long distances of genomic DNA. In this manuscript, we show that provirus integration in the Mlvi-4 locus activates, by promoter insertion, one additional gene which maps immediately 3' to the cluster of the Mlvi-4 proviruses and which is transcribed in the same orientation as c-myc, giving rise to 3- and 10-kilobase mRNA transcripts. The Mlvi-4 gene is also expressed in normal thymus and spleen at very low levels, giving rise to 3- and 5.5-kilobase messages. Although Mlvi-4 is expressed in normal thymus, it is not expressed in Moloney murine leukemia virus-induced T-cell lymphomas corresponding to several stages of T-cell differentiation, but lacking a provirus in this locus. This suggests that Mlvi-4 may be expressed only in a subpopulation of T cells. We conclude that provirus insertion in Mlvi-4 activates c-myc and two additional genes, Mlvi-1 and Mlvi-4, whose expression is restricted to, and may be developmentally regulated in, T cells. Since Mlvi-4 is the target of genetic changes in a great variety of human and animal neoplasms, these results are critical for our understanding of oncogenesis.


On the active agents of Valerian.
(13)C-NMR shifts of valepotriathydrines show a characteristic dependence on type and position of the acyloxy substituents. The structures of well known and of new valepotriathydrines have been clarified.


Design of a phased array for the generation of adaptive radiation force along a path surrounding a breast lesion for dynamic ultrasound elastography imaging.
This work demonstrates, with numerical simulations, the potential of an octagonal probe for the generation of radiation forces in a set of points following a path surrounding a breast lesion in the context of dynamic ultrasound elastography imaging. Because of the in-going wave adaptive focusing strategy, the proposed method is adapted to induce shear wave fronts to interact optimally with complex lesions. Transducer elements were based on 1-3 piezocomposite material. Three-dimensional simulations combining the finite element method and boundary element method with periodic boundary conditions in the elevation direction were used to predict acoustic wave radiation in a targeted region of interest. The coupling factor of the piezocomposite material and the radiated power of the transducer were optimized. The transducer's electrical impedance was targeted to 50 Ω. The probe was simulated by assembling the designed transducer elements to build an octagonal phased-array with 256 elements on each edge (for a total of 2048 elements). The central frequency is 4.54 MHz; simulated transducer elements are able to deliver enough power and can generate the radiation force with a relatively low level of voltage excitation. Using dynamic transmitter beamforming techniques, the radiation force along a path and resulting acoustic pattern in the breast were simulated assuming a linear isotropic medium. Magnitude and orientation of the acoustic intensity (radiation force) at any point of a generation path could be controlled for the case of an example representing a heterogeneous medium with an embedded soft mechanical inclusion.


Effect of pegbovigrastim on fertility and culling in grazing dairy cows and its association with prepartum nonesterified fatty acids.
This randomized controlled trial on 4 commercial grazing dairy farms investigated whether treatment with pegbovigrastim (PEG) affected fertility and culling as measured during the full lactation. We also explored the effect of potential interactions of PEG treatment with parity, prepartum body condition score, prepartum nonesterified fatty acid concentration (pre-NEFA), and early-lactation clinical disease on these outcomes. Holstein cows were randomly assigned to 1 of 2 trial arms: a first PEG dose approximately 7 d before the expected calving date and a second dose within 24 h after calving (PEG: primiparous = 342; multiparous = 697) compared with untreated controls (control: primiparous = 391; multiparous = 723). Cox's proportional hazards regression models were used to analyze rate of first insemination, rate of pregnancy [within 150 and 305 d in milk (DIM)], and hazard of culling. Additional analyses were performed on data that were stratified by parity group and pre-NEFA class (low ≤0.3; high >0.3 mM). In high pre-NEFA cows, PEG treatment increased the rate of first insemination [hazard ratio (HR) = 1.15]. Early-lactation clinical mastitis (CM) and uterine disease (UD: retained placenta, metritis, or both) were associated with a reduced rate of pregnancy within 150 DIM (HR = 0.49 and 0.78, respectively). Pegbovigrastim treatment in high pre-NEFA cows with CM and UD increased the rate of pregnancy within 150 DIM (HR = 1.75 and 1.46, respectively). In high pre-NEFA cows, PEG treatment resulted in a lower hazard of culling (HR = 0.79). No treatment effect was detected in low pre-NEFA cows. This study shows that the effect of PEG treatment on fertility and culling interacts with pre-NEFA. In high pre-NEFA cows, PEG treatment increased the rate of first insemination, counteracted the negative association of early-lactation CM and UD with the rate of pregnancy, and decreased the hazard of culling.


Methylenetetrahydrofolate reductase activity is involved in the plasma membrane redox system required for pigment biosynthesis in filamentous fungi.
Methylenetetrahydrofolate reductases (MTHFRs) play a key role in biosynthesis of methionine and S-adenosyl-l-methionine (SAM) via the recharging methionine biosynthetic pathway. Analysis of 32 complete fungal genomes showed that fungi were unique among eukaryotes by having two MTHFRs, MET12 and MET13. The MET12 type contained an additional conserved sequence motif compared to the sequences of MET13 and MTHFRs from other eukaryotes and bacteria. Targeted gene replacement of either of the two MTHFR encoding genes in Fusarium graminearum showed that they were essential for survival but could be rescued by exogenous methionine. The F. graminearum strain with a mutation of MET12 (FgDeltaMET12) displayed a delay in the production of the mycelium pigment aurofusarin and instead accumulated nor-rubrofusarin and rubrofusarin. High methionine concentrations or prolonged incubation eventually led to production of aurofusarin in the MET12 mutant. This suggested that the chemotype was caused by a lack of SAM units for the methylation of nor-rubrofusarin to yield rubrofusarin, thereby imposing a rate-limiting step in aurofusarin biosynthesis. The FgDeltaMET13 mutant, however, remained aurofusarin deficient at all tested methionine concentrations and instead accumulated nor-rubrofusarin and rubrofusarin. Analysis of MET13 mutants in F. graminearum and Aspergillus nidulans showed that both lacked extracellular reduction potential and were unable to complete mycelium pigment biosynthesis. These results are the first to show that MET13, in addition to its function in methionine biosynthesis, is required for the generation of the extracellular reduction potential necessary for pigment production in filamentous fungi.


Initial experience with real-time hybrid single-photon emission computed tomography/computed tomography-guided percutaneous transthoracic needle biopsy.
The aim of this study was to explore a technique that uses real-time fusion image of single-photon emission computed tomography/computed tomography (SPECT/CT) to guide percutaneous transthoracic needle biopsy (PTNB) and test its feasibility and safety in patients. Twelve patients with intrathoracic lesions suspicious for malignancy underwent real-time 99m-technetium sestamibi SPECT/CT-guided PTNB. Chest SPECT/CT fusion images were used for biopsy planning and intraprocedure fusion of SPECT with guiding CT was used to adjust the puncture angle and direction. Tissues were sampled when the tip of needle was placed on the margin of the hyperactive area within the mass. Postoperation CT scan was performed to exclude acute complications. The technical success rate, complications, and histological results were recorded. Room time and operation time were calculated. All biopsy procedures fulfilled the primary endpoint of yielding diagnostic results: lung adenocarcinoma (n=5), lung squamous cell carcinoma (n=4), lung small cell carcinoma (n=1), mediastinum lymphoma (n=1), and pleura inflammation (n=1). There were no major complications. The mean room time was 74.3±10.4 (range: 57-91) min, and the mean operation time was 33.5±9.1 (range: 15-45) min. The average number of CT guiding scans was 3.2 (range: 1-4). The pilot study explored a new technique of real-time guidance of PTNB using SPECT/CT and verified its feasibility and safety.


Mechanism of the phenylpyruvate tautomerase activity of macrophage migration inhibitory factor: properties of the P1G, P1A, Y95F, and N97A mutants.
Phenylpyruvate tautomerase (PPT) has been studied periodically since its activity was first described over forty years ago. In the last two years, the mechanism of PPT has been investigated more extensively because of the discovery that PPT is the same protein as the immunoregulatory cytokine known as macrophage migration inhibitory factor (MIF). The mechanism of PPT is likely to involve general base-general acid catalysis. While several lines of evidence implicate Pro-1 as the general base, the identity of the general acid remains unknown. Crystal structures of MIF with the competitive inhibitor (E)-2-fluoro-p-hydroxycinnamate bound in the active site and that of the protein complexed with the enol form of a substrate, (p-hydroxyphenyl)pyruvate, suggest that Tyr-95 is the only candidate in the vicinity that can function as a general acid catalyst. Although Tyr-95 is nearby the bound inhibitor and substrate, it is not within hydrogen bonding distance of either ligand. In this study, Tyr-95 was mutated to phenylalanine, and the kinetic and structural properties of the Y95F mutant were determined. This alteration produces a fully active enzyme, which shows no significant structural changes in the active site. The results indicate that Tyr-95 does not function as the general acid catalyst in the reaction catalyzed by wild-type PPT. The mechanism of PPT was studied further by constructing and characterizing the kinetic properties of two mutants of Pro-1 (P1G and P1A) and one mutant of Asn-97 (N97A). The mutation of Asn-97, a residue implicated in the binding of the phenolic hydroxy group of the keto and enol isomers of (p-hydroxyphenyl)pyruvate and of (E)-2-fluoro-p-hydroxycinnamate affects only the binding affinity of the inhibitor. However, the mutations of Pro-1 have a profound effect on the values of k(cat) and k(cat)/K(m) and clearly show that Pro-1 is a critical residue in the reaction. The results are discussed in terms of a mechanism in which Pro-1 functions as both the general acid and the general base catalyst.


c-Jun N-terminal Kinase Mediates Ligand-independent p75NTR Signaling in Mesencephalic Cells Subjected to Oxidative Stress.
The p75 neurotrophin receptor (p75NTR) is a multifunctional protein that regulates cellular responses to pathological conditions in specific regions of the nervous system. Activation of p75NTR in certain neuronal populations induces proteolytic processing of the receptor, thereby generating p75NTR fragments that facilitate downstream signaling. Expression of p75NTR has been reported in neurons of the ventral midbrain, but p75NTR signaling mechanisms in such cells are poorly understood. Here, we used Lund Human Mesencephalic cells, a population of neuronal cells derived from the ventral mesencephalon, to evaluate the effects of oxidative stress on p75NTR signaling. Subjection of the cells to oxidative stress resulted in decreased cell-surface localization of p75NTR and intracellular accumulation of p75NTR fragments. Oxidative stress-induced p75NTR processing was reduced by pharmacological inhibition of metalloproteases or γ-secretase, but was unaltered by blockade of the ligand-binding domain of p75NTR. Furthermore, inhibition of c-Jun N-terminal Kinase (JNK) decreased p75NTR cleavage induced by oxidative damage. Altogether, these results support a mechanism of p75NTR activation in which oxidative stress stimulates JNK signaling, thereby facilitating p75NTR processing via a ligand-independent mechanism involving induction of metalloprotease and γ-secretase activity. These findings reveal a novel role for JNK in ligand-independent p75NTR signaling, and, considering the susceptibility of mesencephalic neurons to oxidative damage associated with Parkinson's disease (PD), merit further investigation into the effects of p75NTR on PD-related neurodegeneration.


Neural and neurocognitive markers of vulnerability to gambling disorder: a study of unaffected siblings.
Psychological and neurobiological markers in individuals with gambling disorder (GD) could reflect transdiagnostic vulnerability to addiction or neuroadaptive consequences of long-term gambling. Using an endophenotypic approach to identify vulnerability markers, we tested the biological relatives of cases with GD. Male participants seeking treatment for GD (n = 20) were compared with a male control group (n = 18). Biological siblings of cases with GD (n = 17, unrelated to the current GD group) were compared with a separate control group (n = 19) that overlapped partially with the GD control group. Participants completed a comprehensive assessment of clinical scales, neurocognitive functioning, and fMRI of unexpected financial reward. The GD group displayed elevated levels of self-report impulsivity and delay discounting, and increased risk-taking on the Cambridge Gamble Task. We did not observe impaired motor impulsivity on the stop-signal task. Siblings of GD showed some overlapping effects; namely, elevated impulsivity (negative urgency) and increased risk-taking on the Cambridge Gamble Task. We did not observe any differences in the neural response to win outcomes, either in the GD or sibling analysis compared with their control group. Within the GD group, activity in the thalamus and caudate correlated negatively with gambling severity. Increased impulsivity and risk-taking in GD are present in biological relatives of cases with GD, suggesting these markers may represent pre-existing vulnerability to GD.


The assessment of occupational functioning: a screening tool for use in long-term care.
This paper describes the development of the Assessment of Occupational Functioning (AOF), a screening tool designed to assess the functional capacity of residents in long-term treatment settings who have physical and/or psychiatric problems. The assessment is based on six variables of the Model of Human Occupation. A study of 83 community and institutionalized elderly subjects was conducted to examine the AOF's dimensionality, test-retest reliability, interrater reliability, concurrent validity, and ability to discriminate between healthy and institutionalized adults. Item analysis suggests that ratings tend to correspond with components of the theoretical model. Both test-retest reliability and interrater reliability correlations for total test scores were above accepted minimum levels. Correlations of the screening tool with scores on the Life Satisfaction Index-Z, a concurrent validity measure, yielded positive correlations. Correlations of the screening tool score with another concurrent validity measure, the Geriatric Rating Scale score, yielded mixed results. Discrimination results indicated that the instrument can distinguish between the adaptive performance of normal and institutionalized populations.


Effect of an environmental health educational programme for paediatricians in an Egyptian University Hospital: before and after study.
To study the effect of an educational intervention on paediatricians' knowledge, attitudes and practices regarding children's environmental health and to identify the sources of information and common environmental history taking constrains. Before and after study. Zagazig University Paediatric Hospital. Practising paediatricians from all specialty units. The outcome of a specifically designed educational programme about paediatric environmental health was assessed using structured pre- and post-test questionnaires. Nearly half the participants were aware about most of the paediatric environmental health-related topics. Textbooks/guidelines (85.7%) and the Internet (64.3%) were the main sources of information. The participants demonstrated relatively strong positive attitudes towards the importance of children's environmental health. However, less than half of them (44.6%) reported environmental history taking as a routine practice; where lack of time (94.6%), wide range of hazardous exposures (91.1%) and lack of expertise and training (91.1%) were the main constrains. Significant improvement in participants' knowledge, attitudes and practices was revealed after the educational programme. There is a demand for continuous medical education about environmental health in paediatric practice, particularly environmental and occupational history taking.


Fibroblast tissue priming-not so nice to C you!
The molecular mechanisms explaining why relapses of inflammatory arthritis occur at previously affected sites are unknown. In this issue of Immunity, Friščić et al. propose that local fibroblasts perpetuate inflammation after priming through cell-intrinsic complement C3, which reprograms their bioenergetics and activates the inflammasome.


Intracellular localization of actin in cultured fibroblasts by electron microscopic immunocytochemistry.
Antibodies to skeletal muscle actin were produced in rabbits and purified by affinity chromatography. Direct labeling of SDS-PAGE gels of whole cell homogenates from mouse fibroblast cells showed that actin was the only protein detected by these antibodies. Using this immunospecific reagent, we localized actin in cultured fibroblasts using the EGS fixation-permeabilization procedure with the ferritin bridge labeling technique. Swiss 3T3-4 mouse fibroblasts were chosen as an example of highly adherent untransformed cells with prominent microfilament bundles, and L929 mouse fibroblasts were chosen as an example of poorly adherent, rounded, transformed cells with prominent microvilli. Using these two cell types, we have characterized the intracellular distribution of action. Actin was only detected in locations in which morphologically recognizable 60 A microfilaments were found. By both fluorescence and electron microscopy, actin was found in surface ruffles, microvilli, microfilament bundles, the microfilament mat, and the leading lamellae of Swiss 3T3 and L929 cells. In addition, actin was found surrounding micropinosomes and macropinosomes. On the other hand, there was no actin detected around the base of coated pits. Morphometric quantitation showed that almost all the actin was localized in microfilamentous structures. Our results suggest that actin has an important role in cell motility and adhesion, and in the endocytosis of pinosomes, but that actin may not be involved in intracellular processes such as saltatory motion of intracellular organelles.


Neisseria lactamica meningitis.
Neisseria lactamica was recovered from the blood and cerebrospinal fluid of a 7-month-old girl with acute purulent meningitis. The isolate was identified initially as N meningitidis. However, additional biochemical testing at the Center for Disease Control showed that the organism fermented lactose and produced beta-D-galactosidase, thereby confirming its identity as N lactamica.


Diagnostic assessment of recurrent unexplained syncope with a new subcutaneously implantable loop recorder. Reveal-Investigators.
Patients with recurrent syncope undiagnosed after extensive non-invasive and invasive testing pose a diagnostic and therapeutic dilemma. Holter monitoring is nondiagnostic in 90% of cases. Recent developments in loop recorder technology permit long-term ECG monitoring in patients with recurrent unexplained syncope. The aim of this study was to report the worldwide experience with a new subcutaneously implantable loop recorder, implanted in 133 patients with unexplained syncope and negative laboratory investigations. The implantable loop recorder monitors continuously a single lead electrogram using two sensing electrodes on the device shell. The device was implanted in 133 patients, 67 male and 66 female with recurrent syncope. During a mean follow-up of 10.8 +/- 4.3 months after device implantation, 83 patients (62%) experienced syncope or pre-syncope. In the remaining 50 patients no diagnosis could be made because either no events occurred, the patients were lost to follow-up, had adverse events, or died prior to diagnosis. In 72 of the 83 patients with syncope during follow-up (87%), loop recording definitively determined whether an arrhythmia was the cause of symptoms or not. Diagnosis included bradycardia in 21 patients, pacemaker dysfunction in one patient, and tachycardia in 10 patients. One patient experienced multiple rhythm disturbances. Syncope was non-arrhythmic in 40 patients. The remaining 11 patients failed to press the activator. Therapy was instituted in all patients, in whom an arrhythmic cause was found. Severe anticipated device related complications occurred in three patients. An implantable loop recorder is useful for establishing a diagnosis when symptoms are recurrent but too infrequent for conventional monitoring techniques.


[Morphometric study of atherosclerosis of the extra- and intracranial cerebral arteries].
Visual-planimetric studies of atherosclerosis of the major arteries of the brain in 507 dead persons aged 30 years and older who had died of casual causes and diseases, were carried out. Collection and investigation of materials were conducted in accordance with the WHO programme (Uemura et al, 1964). Considerable differences in the degree of manifestation of atherosclerosis in the arteries under study and in the rate of their development in the course of life were established. The development of atherosclerosis in the extracranial arteries in men was more pronounced than in women. As to the degree of manifestation of the atherosclerotic process, incidence of stenosis of the investigated arteries inflicted more than 50 per cent of the lumen was not observed, there were no considerable differences between those who had died of complications of atherosclerosis with and without combination with hypertension. Marked pathologically convoluted and folded carotid and vertebral arteries were rare.


Proton-electron-coupled functionalities of conductivity, magnetism, and optical properties in molecular crystals.
Proton-electron-coupled reactions, specifically proton-coupled electron transfer (PCET), in biological and chemical processes have been extensively investigated for use in a wide variety of applications, including energy conversion and storage. However, the exploration of the functionalities of the conductivity, magnetism, and dielectrics by proton-electron coupling in molecular materials is challenging. Dynamic and static proton-electron-coupled functionalities are to be expected. This feature article highlights the recent progress in the development of functionalities of dynamic proton-electron coupling in molecular materials. Herein, single-unit conductivity by self-doping, quantum spin liquid state coupled with quantum fluctuation of protons, switching of conductivity and magnetism triggered by the disorder-order transition of deuterons, and their external responses under pressure and in the presence of an electric field are introduced. In addition, as for the functionalities of proton-d/π-electron coupling in metal dithiolene complexes, magnetic switching with multiple PCET and vapochromism induced by electron transfer through hydrogen-bond (H-bond) formation is introduced experimentally and theoretically. We also outlined the basic and applied issues and potential challenges for development of proton-electron-coupled molecular materials, functionalities, and devices.


Who participates? Accounting for longitudinal retention in the MIDUS national study of health and well-being.
This article uses data from MIDUS (Midlife in the United States), a national study of Americans (N = 7,108), to investigate factors that predict longitudinal retention. With its extensive age range (25-75 at Time 1) and long-term design (9- to 10-year survey interval), MIDUS is useful for investigating common sociodemographic and health predictors of continuing participation. The authors conducted logistic regression analyses of baseline sociodemographic and health variables predicting retention. Select interaction terms examined the interplay between targeted variables. Consistent with prior research, higher retention rates were found among Whites, females, and married individuals as well as those with better health and more education. Interaction analyses further clarified that (a) health status better predicted retention among older compared to younger respondents and among women compared to men, (b) marital status better predicted retention among Whites compared to non-Whites and among women compared to men, and (c) economic status better predicted retention among those with poorer functional health status. The authors' analyses clarify that longitudinal retention varied depending on respondents' sociodemographic characteristics and their health status. The unique contribution of this article is that factors predicting nonparticipation can be offset by, or compensated for, other factors.


Risk of Malignant Neoplasm in Patients with Incident Rheumatoid Arthritis 1980-2007 in relation to a Comparator Cohort: A Population-Based Study.
Objective. To determine whether the incidence of malignancy is increased in patients with rheumatoid arthritis (RA) compared to a matched comparison cohort and to identify risk for any individual malignancy in RA. Methods. A cohort of 813 Olmsted County, Minnesota, residents who first fulfilled 1987 ACR criteria for RA in 1980-2007 was previously identified by medical record review. Medical records of 813 RA cases and a comparison cohort of age and sex matched Olmsted County residents without RA were evaluated retrospectively for cancer occurrence. Patients in both cohorts were followed until death, migration from Olmsted County, or 12/31/2014. Results. The RA and non-RA cohorts (mean age at incidence/index date: 55.9 [SD: 15.7] years; 68.4% females in both cohorts) were followed on average of 14.1 (SD: 7.7) and 14.9 (SD: 8.1) years, respectively. Prior to RA incidence/index date, 52 RA patients and 66 non-RA subjects had malignancies excluding NMSC (p = 0.21). During follow-up, significantly more malignancies occurred in patients with RA (n = 143) than in comparator subjects (n = 118; hazard ratio: 1.32; p = 0.027). Inclusion of NMSC obviated this difference. Conclusion. After excluding NMSC, there was a small to moderately increased risk of malignancies in patients with RA. Cancer surveillance is imperative in all patients with RA.


Detection of residual head and neck squamous cell carcinoma after (chemo)radiotherapy: a pilot study assessing the value of diffusion-weighted magnetic resonance imaging as an adjunct to PET-CT using 18F-FDG.
Diagnosing residual malignancy after (chemo)radiotherapy presents a diagnostic challenge because of overlapping symptoms and imaging characteristics. We assessed the added diagnostic value of diffusion-weighted imaging (DWI) to positron emission tomography combined with computed tomography (PET-CT) in patients with head and neck squamous cell carcinoma (HNSCC) with residual fluorodeoxyglucose (18F-FDG) uptake at the primary tumor site 3 months after (chemo)radiotherapy. For this retrospective study from January 2010 to June 2012, 22 cases (median patient age of 61 years; range 41-77 years) were included for analysis. Both PET-CT and magnetic resonance imaging (MRI), including DWI, were performed as part of the institutional protocol and were qualitatively assessed for the presence of residual malignancy at the primary tumor site. The sensitivity and specificity of PET-CT were 100% and 47%, respectively. For DWI, sensitivity and specificity were 80% and 82%, respectively. When DWI was added to PET-CT with residual 18F-FDG uptake, and only a positive read on both PET-CT and DWI was considered to be overall positive, sensitivity remained 80% (95% confidence interval [CI] 28%-99%), and specificity was 88% (95% CI 64%-99%). In this pilot study of the selected patients with residual 18F-FDG uptake at the primary tumor site 3 months after (chemo)radiotherapy, we demonstrated that the addition of DWI to PET-CT has the potential to increase the specificity of the response evaluation with limited decrease in sensitivity.


TRPML2 and mucolipin evolution.
The TRPML2 protein, encoded by the Mcoln2 gene, is one of the three mucolipins (TRPML1-3), a subset of the TRP superfamily of ion channels. Although there are no thorough studies on the cellular distribution of TRPML2, its mRNA appears to be largely restricted to lymphocytes and other immune cells. This contrasts with the ubiquitous expression of TRPML1 and the limited but diverse expression of TRPML3 and clearly suggests a specialized role for TRPML2 in immunity. Localization studies indicate that TRPML2 is present in lysosomes (including the specialized lysosome-related organelle that B-lymphocytes use for processing of the antigen-bound B-cell receptor), late endosomes, recycling endosomes, and, at a much lower level, the plasma membrane. Heterologously expressed TRPML2, like TRPML1 and/or TRPML3, forms ion channels that can be activated by a gain-of-function mutation (alanine to proline in the fifth transmembrane domain, close to the pore) that favors the open state, by a transient reduction of extracellular sodium followed by sodium replenishment, by small chemicals related to sulfonamides, and by PI(3,5)P2, a rare phosphoinositide that naturally accumulates in the membranes of endosomes and lysosomes and thus could act as a physiologically relevant agonist. TRPML2 channels are inwardly rectifying and permeable to Ca(2+), Na(+), and Fe(2+). When heterologously co-expressed, TRPML2 can form heteromultimers with TRPML1 and TRPML3. In B-lymphocytes, TRPML2 and TRPML1 may play redundant roles in the function of their specialized lysosome. Although the specific subcellular function of TRPML2 is unknown, distribution and channel properties suggest roles in calcium release from endolysosomes, perhaps to regulate vesicle fusion and/or subsequent scission or to release calcium from intracellular acidic stores for signaling in the cytosol. Alternatively, TRPML2 could function in the plasma membrane, and its abundance in vesicles of the endocytic pathway could simply be due to regulation by endocytosis and exocytosis. The Mcoln2 gene is closely downstream from and in the same orientation as Mcoln3 in the genomes of most jawed vertebrates (from humans to sharks) with the exception of pigs, Xenopus tropicalis, and ray-finned fishes. The close homology of TRPML2 and 3 (closer to each other than to TRPML1) suggests that Mcoln2 and Mcoln3 arose from unequal crossing over that duplicated a common ancestor and placed both gene copies in tandem. These genes would have come apart subsequently in pigs, Xenopus, and the ancestor to ray-finned fishes. All jawed vertebrates for which we have thorough genomic knowledge have distinct Mcoln1, 2, and 3 genes (except ray-finned fishes which, probably due to the whole-genome duplication in their common ancestor, have two Mcoln1-like genes and two Mcoln3-like genes, although only one Mcoln2 gene). However, the available genomes of invertebrate deuterostomes (a sea urchin, lancelet, and two tunicates) contain a single mucolipin gene that is equally distant from the three vertebrate mucolipins. Hence, vertebrate mucolipins arose through two rounds of gene duplication (the first one likely producing Mcoln1 and the ancestor to Mcoln2 and 3) at some time between the onset of craniates and that of jawed vertebrates. This is also the evolutionary period during which adaptive immunity appeared. Given the restricted expression of TRPML2 in immune cells, this evolutionary history suggests a functional role in the adaptive immunity characteristic of vertebrates.


Independent community pharmacist interest in participating in community pharmacy research networks.
To assess the interest of American Pharmacy Services Corporation (APSC) independent community pharmacists in participating in a community pharmacy research network (CPRN) and to identify perceived barriers to participation in a CPRN. Descriptive, exploratory, nonexperimental study. University of Kentucky and APSC during 2009-10. 65 APSC independent community pharmacists in Kentucky. Single-mode survey. Independent community pharmacists' willingness to participate in community-based research and perceived barriers to participation. A total of 65 independent community pharmacists from 191 pharmacies returned the survey. The majority of independent community pharmacists were "interested" or "very interested" (83.8%) in participating in a CPRN. Respondents were willing to participate for a mean (±SD) of 6.5 ± 5.8 hours per week. However, they reported only being able participate in a CPRN for 5.2 ± 4.1 hours per week, with time being the greatest limitation to participation. An overwhelming percentage of respondents (92.1%) were interested in learning more about opportunities to participate in a CPRN in the future. CPRNs are an emerging interest in community pharmacy practice. A CPRN is an opportunity for independent community pharmacies to collaborate and use resources as a group to conduct research to solve issues in the community pharmacy setting.


Forming Physicians: Evaluating the Opportunities and Benefits of Structured Integration of Humanities and Ethics into Medical Education.
This paper offers a novel, qualitative approach to evaluating the outcomes of integrating humanities and ethics into a newly revised pre-clerkship medical education curriculum. The authors set out to evaluate medical students' perceptions, learning outcomes, and growth in identity development. Led by a team of interdisciplinary scholars, this qualitative project examines multiple sources of student experience and perception data, including student essays, end-of-year surveys, and semi-structured interviews with students. Data were analyzed using deductive and inductive processes to identify key categories and recurring themes. Results suggest that students not only engaged with the curricular content and met the stated learning objectives but also acknowledged their experience in the humanities and ethics curriculum as an opportunity to reflect, expand their perceptions of medicine (and what it means to be "in" medicine), connect with their classmates, and further cultivate their personal and professional identities. Results of this qualitative study show how and in what ways the ethics and humanities curriculum motivates students past surface-level memorization of factual knowledge and encourages thoughtful analysis and evaluation about how the course material relates to and influences their thinking and how they see themselves as future doctors. The comprehensive qualitative approach reflects a holistic model for evaluating the integration of humanities and ethics into the pre-clerkship medical education curriculum. Future research should examine if this approach provides a protective factor against the demonstrated ethical erosion and empathy decrease during clinical training.


Linking depressive symptoms and functional disability in late life.
We hypothesized that the relationship of depressive symptoms to functional disability might be mediated by cognitive processes such as memory and problem-solving. The study sample consisted of 147 community-dwelling older adults (mean age = 74.0 years, SD = 5.9). In regression models that included terms for age, gender, and years of education, depressive symptoms were significantly inversely associated with two performance-based measures of functioning: everyday problems test (beta = -0.15, p = 0.04) and observed tasks of daily living (beta = -0.14, p = 0.02). When memory and problem-solving ability were added to the model, the relationship of depressive symptoms with function was attenuated. A structural equation model based on our conceptual framework revealed that both memory and problem-solving abilities were important mediators in the relationship of depressive symptoms and functional disability. The results suggest that intervention studies intended to limit functional disability secondary to depression among older adults may need to consider the effect of depression on cognition.


The computation of hyperbolic dependences in enzyme kinetics.
A computer program aimed at analysing results following Michaelis-Menten kinetics can be used unmodified in the treatment of other kinetic results provided that the kinetic equations in these cases can be written in the form of the Michaelis-Menten equation. A list is presented of the parameters to be set instead of substrate concentration and reaction rate, and of constants replacing Km and V, if such a program is applied in analysing enzyme inhibitions, activations and pH-dependences.


Fluid and electrolyte disturbances in critically ill patients.
Disturbances in fluid and electrolytes are among the most common clinical problems encountered in the intensive care unit (ICU). Recent studies have reported that fluid and electrolyte imbalances are associated with increased morbidity and mortality among critically ill patients. To provide optimal care, health care providers should be familiar with the principles and practice of fluid and electrolyte physiology and pathophysiology. Fluid resuscitation should be aimed at restoration of normal hemodynamics and tissue perfusion. Early goal-directed therapy has been shown to be effective in patients with severe sepsis or septic shock. On the other hand, liberal fluid administration is associated with adverse outcomes such as prolonged stay in the ICU, higher cost of care, and increased mortality. Development of hyponatremia in critically ill patients is associated with disturbances in the renal mechanism of urinary dilution. Removal of nonosmotic stimuli for vasopressin secretion, judicious use of hypertonic saline, and close monitoring of plasma and urine electrolytes are essential components of therapy. Hypernatremia is associated with cellular dehydration and central nervous system damage. Water deficit should be corrected with hypotonic fluid, and ongoing water loss should be taken into account. Cardiac manifestations should be identified and treated before initiating stepwise diagnostic evaluation of dyskalemias. Divalent ion deficiencies such as hypocalcemia, hypomagnesemia and hypophosphatemia should be identified and corrected, since they are associated with increased adverse events among critically ill patients.


The zebrafish nodal-related gene southpaw is required for visceral and diencephalic left-right asymmetry.
We have identified and characterized a new zebrafish gene, southpaw, that is required for visceral and diencephalic left-right asymmetry. southpaw encodes a new member of the nodal-related class of proteins, a subfamily within the transforming growth factor beta superfamily of secreted factors. southpaw is expressed bilaterally in paraxial mesoderm precursors and then within the left lateral plate mesoderm. At late somite stages, left-sided southpaw expression transiently overlaps the left-sided expression domains of other genes that mark the developing heart, such as lefty2. We have injected morpholinos to block the translation of the southpaw mRNA or to block splicing of the southpaw pre-mRNA. These morpholinos cause a severe disruption of early (cardiac jogging) and late (cardiac looping) aspects of cardiac left-right asymmetry. As the left-right asymmetry of the pancreas is also affected, southpaw appears to regulate left-right asymmetry throughout a large part of the embryo. Consistent with the morphological changes, the left-sided expression domains of downstream genes (cyclops, pitx2, lefty1 and lefty2) are severely downregulated or abolished within the lateral plate mesoderm of Southpaw-deficient embryos. Surprisingly, despite the absence of southpaw expression in the brain, we find that early diencephalic left-right asymmetry also requires Southpaw activity. These observations lead to a model of how visceral organ and brain left-right asymmetry are coordinated during embryogenesis.


Tracing the ancestry of modern bread wheats.
For more than 10,000 years, the selection of plant and animal traits that are better tailored for human use has shaped the development of civilizations. During this period, bread wheat (Triticum aestivum) emerged as one of the world's most important crops. We use exome sequencing of a worldwide panel of almost 500 genotypes selected from across the geographical range of the wheat species complex to explore how 10,000 years of hybridization, selection, adaptation and plant breeding has shaped the genetic makeup of modern bread wheats. We observe considerable genetic variation at the genic, chromosomal and subgenomic levels, and use this information to decipher the likely origins of modern day wheats, the consequences of range expansion and the allelic variants selected since its domestication. Our data support a reconciled model of wheat evolution and provide novel avenues for future breeding improvement.


Efficient image projection by Fourier electroholography.
An improved efficient projection of color images is presented. It uses a phase spatial light modulator with three iteratively optimized Fourier holograms displayed simultaneously--each for one primary color. This spatial division instead of time division provides stable images. A pixelated structure of the modulator and fluctuations of liquid crystal molecules cause a zeroth-order peak, eliminated by additional wavelength-dependent phase factors shifting it before the image plane, where it is blocked with a matched filter. Speckles are suppressed by time integration of variable speckle patterns generated by additional randomizations of an initial phase and minor changes of the signal.


First evidence of Panulirus argus Virus 1 (PaV1) in spiny lobster from Cuba and clinical estimation of its prevalence.
The present study documents the first finding of Panulirus argus Virus 1 (PaV1) in spiny lobster Panulirus argus from Cuba. Samples originated from 2 nursery sites, Matias Keys and Bocas de Alonso Keys, and 2 fishing sites, La Grifa and El Ramajo. Lobsters from the nursery sites (artificial reefs) were collected by SCUBA diving, while those from the fishing sites were collected from artificial shelters known as 'casitas cubanas'. In these shelters it was observed that healthy lobsters tended to avoid infected lobsters. Prevalence of PaV1 in the sampling sites was assessed by using clinical signs such as lethargy, an opaque reddish shell coloration, and milky white hemolymph with loss of clotting activity. The presence of PaV1 was subsequently confirmed by histology and PCR of tissues and hemolymph samples from suspected individuals. Histological sections of the hepatopancreas, gills, gonads, and gut showed infected hemocytes with hypertrophied nuclei and eosinophilic intranuclear Cowdry type A inclusions. A 499 bp band was observed by PCR. The sequence of the amplified fragments was 96% similar to the PaV1 sequence in GenBank. The overall mean prevalence of PaV1 was 4.48% (range: 0 to 9.3%) after pooling the results of the 4 sampling sites.


Personalized medicine: the impact on chemistry.
An effective strategy for personalized medicine requires a major conceptual change in the development and application of therapeutics. In this article, we argue that further advances in this field should be made with reference to another conceptual shift, that of network pharmacology. We examine the intersection of personalized medicine and network pharmacology to identify strategies for the development of personalized therapies that are fully informed by network pharmacology concepts. This provides a framework for discussion of the impact personalized medicine will have on chemistry in terms of drug discovery, formulation and delivery, the adaptations and changes in ideology required and the contribution chemistry is already making. New ways of conceptualizing chemistry's relationship with medicine will lead to new approaches to drug discovery and hold promise of delivering safer and more effective therapies.


Sketch2Stress: Sketching With Structural Stress Awareness.
In the process of product design and digital fabrication, the structural analysis of a designed prototype is a fundamental and essential step. However, such a step is usually invisible or inaccessible to designers at the early sketching phase. This limits the user's ability to consider a shape's physical properties and structural soundness. To bridge this gap, we introduce a novel approach Sketch2Stress that allows users to perform structural analysis of desired objects at the sketching stage. This method takes as input a 2D freehand sketch and one or multiple locations of user-assigned external forces. With the specially-designed two-branch generative-adversarial framework, it automatically predicts a normal map and a corresponding structural stress map distributed over the user-sketched underlying object. In this way, our method empowers designers to easily examine the stress sustained everywhere and identify potential problematic regions of their sketched object. Furthermore, combined with the predicted normal map, users are able to conduct a region- wise structural analysis efficiently by aggregating the stress effects of multiple forces in the same direction. Finally, we demonstrate the effectiveness and practicality of our system with extensive experiments and user studies.


Purification and characterization of a protein associated with peripheral-type benzodiazepine binding sites.
The photoaffinity ligand [3H]PK 14105 was utilized to modify covalently peripheral-type benzodiazepine binding sites in rat adrenal mitochondrial preparations. The photolabeled membrane preparations were then solubilized in 1% digitonin and the detergent-soluble extracts subjected to fractionation by ion-exchange chromatography and reversed-phase high performance liquid chromatography. This scheme resulted in the purification of the putative binding site protein for PK 14105 which we have entitled PKBS. Purified preparations of PKBS exhibited a single band with a Mr of approximately 17,000 when analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by silver-staining or autoradiographic detection. Additional criteria examining the purity of PKBS preparations were provided by radioiodination with Bolton-Hunter reagent, amino acid analysis, gas-phase sequencing, and reversed-phase chromatography suggesting that this protein was purified to apparent homogeneity. These results demonstrate that a protein associated with peripheral-type benzodiazepine recognition sites has been isolated thus facilitating more direct studies on the structure of this receptor and on the role of these binding sites in mediating responses elicited by benzodiazepines acting at these sites.


The disease-free interval in breast cancer trials: scientific or spurious?
Reports that stem from the National Surgical Adjuvant Breast and Bowel Project clinical trials have had a major influence on the trend toward adjuvant chemotherapy. These reports use life-table analysis to report survival or disease-free survival (DFS). DFS is reported more frequently than survival, and most studies report an increase in DFS with adjuvant therapy but no difference in survival. This means a shorter time between recurrence (end of DFS) and death. A conceptual model is presented herein with five possible explanations for this observation: (1) Bias exists in randomizing (entrance); (2) bias is introduced by the examining physician (exit end point); (3) the spectrum of micrometastases is selectively affected; (4) the sites of systemic recurrence (macrometastases) are affected; (5) treatment after recurrence (salvage) is less effective in the previously treated group; probably because of the induction of resistance to antineoplastic therapy. Hypothesis 5 seems most probable, and if so, the benefit of chemotherapy should be reserved for those women who need it rather than rendering everyone less treatable. The disease-free interval, with its doctor-determined end point, is insufficiently reliable to be used for major decisions regarding adjuvant therapy.


Autocatalytic formation of fluorinated ferrocenophanes from 1,1'-bis(trifluorovinyl)ferrocene.
1,1'-Bis(trifluorovinyl)ferrocene is obtained in excellent yields from a Negishi type coupling reaction. Under certain redox conditions and in the presence of a suitable nucleophile, the highly reactive compound undergoes a transformation to fluorinated ferrocenophanes. Intra and intermolecular [2+2]-cycloaddition products are formed upon heating.


Is There a Force Target That Predicts Early Patient-reported Outcomes After Kinematically Aligned TKA?
Four mechanical alignment force targets are used to predict early patient-reported outcomes and/or to indicate a balanced TKA. For surgeons who use kinematic alignment, there are no reported force targets. To date the usefulness of these mechanical alignment force targets with kinematic alignment has not been reported nor has a specific force target for kinematic alignment been identified. (1) Does hitting one of four mechanical alignment force targets proposed by Gustke, Jacobs, Meere, and Menghini determine whether a patient with a kinematically aligned TKA had better patient-reported Oxford Knee and WOMAC scores at 6 months? (2) Can a new force target be identified for kinematic alignment that determines whether the patient had a good/excellent Oxford Knee Score of ≥ 34 points (48 best, 0 worst)? Between July 2017 and November 2017, we performed 148 consecutive primary TKAs of which all were treated with kinematic alignment using 10 caliper measurements and verification checks. A total of 68 of the 148 (46%) TKAs performed during the study period had intraoperative measurements of medial and lateral tibial compartment forces during passive motion with an instrumented tibial insert and were evaluated in this retrospective study. Because the surgeon and surgical team were blinded from the display showing the compartment forces, there was no attempt to hit a mechanical alignment force target when balancing the knee. The Oxford Knee Score and WOMAC score measured patient-reported outcomes at 6 months postoperatively. For each mechanical alignment force target, a Wilcoxon rank-sum test determined whether patients who hit the target had better outcome scores than those who missed. An area under the curve (AUC) analysis tried to identify a new force target for kinematic alignment at full extension and 10°, 30°, 45°, 60°, 75°, and 90° of flexion that predicted whether patients had a good/excellent Oxford Knee Score, defined as a score of ≥ 34 points. Patients who hit or missed each of the four mechanical alignment force targets did not have higher or lower Oxford Knee Scores and WOMAC scores at 6 months. Using the Gustke force target as a representative example, the Oxford Knee Score of 41 ± 6 and WOMAC score of 13 ± 11 for the 31 patients who hit the target were not different from the Oxford Knee Score of 39 ± 8 (p = 0.436) and WOMAC score of 17 ± 17 (p = 0.463) for the 37 patients who missed the target. The low observed AUCs (from 0.56 to 0.58) at each of these flexion angles failed to identify a new kinematic alignment force target associated with a good/excellent (≥ 34) Oxford Knee Score. Tibial compartment forces comparable to those reported for the native knee and insufficient sensitivity of the Oxford Knee and WOMAC scores might explain why mechanical alignment force targets were not useful and a force target was not identified for kinematic alignment. Intraoperative sensors may allow surgeons to measure forces very precisely in the operating room, but that level of precision is not called for to achieve a good/excellent result after calipered kinematically aligned TKA, and so its use may simply add expense and time but does not improve the results from the patient's viewpoint. Level III, therapeutic study.


Deep Learning Approach for High-accuracy Electron Counting of Monolithic Active Pixel Sensor-type Direct Electron Detectors at Increased Electron Dose.
Electron counting can be performed algorithmically for monolithic active pixel sensor direct electron detectors to eliminate readout noise and Landau noise arising from the variability in the amount of deposited energy for each electron. Errors in existing counting algorithms include mistakenly counting a multielectron strike as a single electron event, and inaccurately locating the incident position of the electron due to lateral spread of deposited energy and dark noise. Here, we report a supervised deep learning (DL) approach based on Faster region-based convolutional neural network (R-CNN) to recognize single electron events at varying electron doses and voltages. The DL approach shows high accuracy according to the near-ideal modulation transfer function (MTF) and detector quantum efficiency for sparse images. It predicts, on average, 0.47 pixel deviation from the incident positions for 200 kV electrons versus 0.59 pixel using the conventional counting method. The DL approach also shows better robustness against coincidence loss as the electron dose increases, maintaining the MTF at half Nyquist frequency above 0.83 as the electron density increases to 0.06 e-/pixel. Thus, the DL model extends the advantages of counting analysis to higher dose rates than conventional methods.


Agents of empathy: How medical interpreters bridge sociocultural gaps in genomic sequencing disclosures with Spanish-speaking families.
To describe how linguistic tools used by interpreters during return of genomic sequencing results may have impacted communication with Spanish-speaking families, and to discuss the implications for the role of medical interpreters. Using discourse analysis, we identified and categorized the various ways hospital-based interpreters adapted clinicians' language in 37 audio-recorded sessions in which Spanish-speaking parents participating in a clinical trial received their child's genomic sequencing results from English-speaking clinicians. We found that interpreters adapted clinicians' statements using five empathic linguistic tools: contextualization, encouragement, checking comprehension, endearment, and softening. Interpreters used an average of four linguistic tools per session, with contextualization and encouragement being the most frequently used. Interpreters used empathic linguistic tools to alter clinicians' statements when communicating genomic information to Spanish-speaking families. Our findings demonstrate the critical role of interpreters as cultural mediators and facilitators of understanding for Spanish-speaking families. This study expands upon the definition of clinical empathy in interpreter-mediated sessions. Our findings suggest that revisions of standards of medical interpretation practice may be warranted regarding interpreters' ability to adapt clinicians' language in a culturally sensitive manner during interpretation.


The Relationship between Clinical Outcome in Subarachnoidal Hemorrhage Patients with Emergency Medical Service Usage and Interhospital Transfer.
Prompt diagnosis and appropriate transport of patients with subarachnoid hemorrhage (SAH) is critical. We aimed to study differences in clinical outcomes by emergency medical services (EMS) usage and interhospital transfer in patients with SAH. We analyzed the CAVAS (CArdioVAscular disease Surveillance) database which is an emergency department-based, national cohort of cardiovascular disease in Korea. Eligible patients were adults with non-traumatic SAH diagnosed between January 2007 and December 2012. We excluded those whose EMS use and intershopital transfer data was unknown. The primary and secondary outcomes were mortality and neurologic status at discharge respectively. We compared the outcomes between each group using multivariable logistic regressions, adjusting for sex, age, underlying disease, visit time and social history. Of 5,461 patients with SAH, a total of 2,645 were enrolled. Among those, 258 used EMS and were transferred from another hospital, 686 used EMS only, 1,244 were transferred only, and 457 did not use EMS nor were transferred. In the regression analysis, mortality was higher in patients who used EMS and were transferred (OR 1.40, 95% CI 1.02-1.92), but neurologic disability was not meaningfully different by EMS usage and interhospital transfer. In Korea, SAH patients' mortality is higher in the case of EMS use or receiving interhospital transfer.


Targeting Ion Channel TRPM4.
The transient receptor potential melastatin 4 (TRPM4) ion channel is ubiquitously expressed. Dysregulation and/or functional mutations of TRPM4 lead to several diseases. Within our studies, we screened for TRPM4 inhibitors and identified small molecules that block TRPM4 in the low µM range. Furthermore, we investigated the pathophysiology of TRPM4 in cardiac conditions, immune diseases and cancer using these novel inhibitors, molecular biology techniques and functional assays.


Opening Wedge Osteotomy for the Correction of Adolescent Tibia Vara.
Tibia vara, or Blount's disease, is a pathologic angular deformity of upper tibial physis causing a bow leg deformity. Adolescent Blount's disease may be unilateral or bilateral and is diagnosed during or just before the adolescent growth spurt. In addition to predisposing genetic factors, biomechanical overload of the proximal tibial physis causes asymmetric growth leading to a varus deformity.Surgical intervention is usually required for adolescent Blount's disease. Hemiepiphysiodesis has had some success in arresting or correcting the deformity. Tibial osteotomy can achieve correction acutely with internal or external fixation or gradually with external fixation.This article reports the outcomes of correcting adolescent tibia vara with a proximal opening wedge osteotomy (POWO) and internal fixation in nine patients with a primary diagnosis of Adolescent Blount's Disease. We conducted a retrospective review of patients treated with POWO between April 2007 and July 2015. Fifty charts were selected using ICD9 codes for tibia vara and CPT codes for osteotomy. Nine patients (11 tibia) meeting eligibility criteria were identified. In addition to pre-operative data; operative factors, such as blood loss; and post-operative outcomes such as radiographic accuracy of correction, time to healing, time to full weight-bearing, number of office visits and complication rates were collected. Pre-operative radiographic measurements showed the varus deformity was primarily tibial. Post-operative correction demonstrated a mean correction of 17.64° (range, 7°-26°). Patients returned to full weight bearing status around 67 days after surgery and required very few follow-up visits during the course of treatment. Three of nine patients experienced complications including seroma requiring drainage, metallosis mistaken for infection leading to hardware removal, and a wound abscess treated with antibiotics (one patient each). No patients lost correction, experienced nerve palsy, compartment syndrome nor complained of leg length discrepancy. Proximal opening wedge osteotomy (POWO) is a reproducible, safe and effective technique for correction of adolescent tibia vara, with potential advantages of fewer return visits and sooner return to weight bearing than external fixation. In select patients, it is a useful alternative to external fixation or closing wedge osteotomy.Level of Evidence: IV.


Pleural abnormalities: thoracic ultrasound to the rescue!
Diaphragmatic hernias that are diagnosed in adulthood may be traumatic or congenital in nature. Therefore, respiratory specialists need to be aware of the presentation of patients with these conditions. In this report, we describe a case series of patients with congenital and traumatic diaphragmatic hernias and highlight a varied range of their presentations. Abnormalities were noted in the thorax on the chest radiographs, but it was unclear as to the nature of the anomaly. The findings on thoracic ultrasound conducted by a pulmonologist helped to direct appropriate investigations avoiding unnecessary interventions. Instead of pleural effusions, consolidation or collapse, thoracic computed tomography demonstrated diaphragmatic hernias which were managed either conservatively or by surgery. There is increasing evidence that pulmonary specialists should be trained in thoracic ultrasonography to identify pleural pathology as well as safely conducting pleural-based interventions.


Low-Pass Filter Effects on Metrics of Countermovement Vertical Jump Performance.
Harry, JR, Blinch, J, Barker, LA, Krzyszkowski, J, and Chowning, L. Low-pass filter effects on metrics of countermovement vertical jump performance. J Strength Cond Res 36(5): 1459-1467, 2022-Countermovement vertical jump (CMVJ) studies using ground reaction force (GRF) data analyze either unfiltered (i.e., raw) or filtered data while providing little-to-no justification for the selected filtering process. Inappropriate filter choices can lead to inaccurate study results and erroneous interpretations. We examined the effects of not filtering GRF data in comparison with filtering data with various objectively and subjectively selected cutoff frequencies. Twenty-one collegiate male basketball players completed 3 maximal-effort CMVJ trials while GRF data were obtained from 2 force platforms. Countermovement vertical jump performance, explosiveness, power output, and neuromuscular function variables were compared among the following methods using one-way repeated-measures analyses of variance (α = 0.05): no filtering (raw data), a standard 50-Hz cutoff (50 Hz), a visually determined cutoff frequency describing the frequency band containing the majority of the summed (visual inspection 1) or not-summed (visual inspection 2) GRF signal's frequency content, filtering the summed (99% signal power 1) or not-summed (99% signal power 2) GRF using a cutoff frequency retaining 99% of the signal power. The raw data method produced significantly shorter concentric phase times and significantly greater center of mass flight heights (∼3%), modified reactive strength indices (RSIMOD; ∼4%), power outputs (∼6%), and push-off distances (∼4%) than 99% signal power 1 and 2 (p < 0.05). Discrete GRF and phase-specific yank magnitudes were not different among methods (p ≥ 0.05). Importantly, no differences were detected between the raw data and 50 Hz methods for any variable (p > 0.05). Low-pass filtering is not necessary when analyzing GRF data from the CMVJ. However, a low-pass filter with a 50-Hz cutoff can remove noise without altering results when compared with raw data. Explicit methodological descriptions of filtering processes should always be provided to improve the integrity of future CMVJ analyses, comparisons among various studies' results, or both.