Effective cervical cytology screening programmes in middle-income countries: the Chilean experience.
To demonstrate that an effective cervical cancer screening programme based on the Papanicolaou (Pap) smear can be organized in a middle-income country, such as Chile. The cervical cytology screening programme in Chile is evaluated by comparing process measures and cervical cancer mortality before and after its reorganization in 1987. Two decades of opportunistic annual screening for cervical cancer from the mid-1960s to the mid-1980s did not reduce cervical cancer mortality in Chile. In 1987, a public health oriented program was launched, based on screening women aged 25-64 every 3 years, rather than the annual screening of low risk women attending family planning clinics that gathered mainly women less than 25 years of age. The reoriented program emphasized the optimization of existing resources, the timeliness of diagnosis and treatment, reliability of the Pap smear and low cost screening promotion strategies at the community level. More than 80% of women with abnormal Pap smears received prompt medical attention and 100% of the public laboratories were subject to external quality control. According to biannual national surveys, coverage by Pap smear screening in the target group rose from 40% in 1990 to 66% in 1996. The age adjusted cervical cancer mortality rate decreased from 12.8 in 1980 to 6.8 per 100,000 women in 2001. Improved organization of the national cervical cancer screening programme in Chile and more efficient use of existing resources resulted in a decrease of cervical cancer mortality.


Cutaneous phaeohyphomycosis in renal allograft recipients: report of 2 cases and review of the literature.
Dematiaceous molds are increasingly recognized as important human pathogens. We report 2 cases of cutaneous phaeohyphomycosis in renal allograft recipients, caused by Alternaria alternata and Curvularia spp., respectively, which demonstrate the diversity in clinical presentation, the different therapeutic strategies, and the clinical importance of azole antifungal-induced drug-drug interactions with immunosuppressive therapy.


Vitamin E protects against gabapentin-induced chronic hepatic and renal damage associated with the inhibition of apoptosis and tissue injury in rats.
This study aimed to investigate the potential protective effects of vitamin E against gabapentin-induced chronic liver and kidney injury associated with the inhibition of biomarkers of apoptosis and tissue injury. Four groups of adult male rats were included; control, gabapentin (100 mg/kg/day), Vitamin E (80 mg/kg/day), and a combination of gabapentin and Vitamin E for 90 days. Serum levels of AST, ALT, LDH, ALP, urea, and creatinine were measured in addition to malondialdehyde (MDA), and reduced glutathione (GSH) tissue levels. P53 gene expression, histological, and immunohistochemical examinations were performed in liver and kidney tissue samples. Gabapentin increased AST, ALT, LDH, ALP, urea, creatinine, MDA, and p53 gene expression and it reduced GSH. Moreover, gabapentin administration caused structural changes in the hepatic and renal architecture with a weak Periodic acid-Schiff (PAS) reaction that reflects glycogen deposition in the liver and kidney and a positive immunoreaction for BCL2-associated X protein (BAX) that reflects activated apoptosis. Vitamin E significantly (p<0.05) reversed the biochemical alterations associated with chronic gabapentin administration and improved the histopathological picture of hepatic and renal tissue with a partial inhibition of BAX. Chronic administration of gabapentin causes hepatic and renal impairments, which is ameliorated by Vitamin E; possibly due to the inhibition of biomarkers of apoptosis and tissue injury.


Safety Profile of Artemether-Lumefantrine: A Cohort Event Monitoring Study in Public Health Facilities in Tanzania.
Artemisinin combination therapies such as artemether-lumefantrine (AL) are effective for first-line treatment of uncomplicated acute Plasmodium falciparum malaria. However, the safety profile of AL in large populations has not been fully assessed. The objective of this study was to establish the safety of AL in public health facilities in Tanzania using the Cohort Event Monitoring (CEM) method. Patients who presented to public health facilities in four regions of Tanzania who were prescribed AL were enrolled in a CEM study, a prospective, observational cohort study to establish a profile of adverse events (AEs) for the medicine when used in routine clinical practice. Pre- and post-treatment forms were used to record baseline information and new health events before and 7 days after treatment. A total of 8040 patients were enrolled in the study, of whom 6147 were included in the analysis. Following treatment initiation, a total of 530 AEs were reported in 6% (383) of the patients. The most frequent post-treatment AEs were in alimentary system (42%), including vomiting, nausea, diarrhoea, abdominal pain and anorexia, followed by AEs in the neurological system (25%). Causality assessment of the events showed that 51.9% (275/530) were possibly related to AL. There was a significant difference in the frequency of AEs by age-group with an increase in the number of AEs as age increased (P < 0.001). There was no statistically significant difference in the frequency of the events between males and females (P = 0.504). The AE profile was consistent with the AEs reported in the product information and in other studies; no new adverse drug reactions were identified. The majority of the reported AEs were the same as the symptoms of malaria and therefore indistinguishable from the underlying disease. The safety profile of AL for treatment of malaria continues to be favourable. CEM as a pharmacovigilance tool has proven to provide reliable safety data in a short period.


Subjective well-being in heart failure patients: influence of coping and depressive symptoms.
Psychological factors play a crucial role in the well-being of chronically ill patients. This research examined coping, depressive symptoms and subjective well-being (SWB) in patients with heart failure (HF). The study also analysed whether depressive symptoms mediated the association between coping strategies and SWB. Participants (N = 60, 68.3 % men, aged between 40 and 89 years old) diagnosed with HF were recruited from the cardiology service of a general hospital. Coping strategies were assessed with 16 items of the Brief COPE Scale. The items were organised, according to theoretical and empirical data, into four types of coping: task-focused, seeking social support, maladaptive emotion-focused and acceptance coping. Depressive symptoms were assessed with the corresponding subscale of the Hospital Anxiety and Depression Scale. SWB was assessed considering the Satisfaction with Life Scale and the Positive and Negative Affect Schedule. The multiple regression analyses carried out indicated that SWB was positively associated with task-focused coping and inversely related to maladaptive strategies and depressive symptoms. Gender was also a significant predictor of SWB, with male patients reporting higher well-being than female patients. The mediational analysis showed that depressive symptoms partially mediated the relationships between task-focused coping and SWB. Results were discussed in the light of the importance of gender, depression and coping in patients with HF since these factors may affect subjective well-being and contribute to severe physical impairment.


[Migrants and caregivers: mutual recognition for effective action].
Whatever their discipline or place of practice, caregivers inevitably encounter migrants, foreign nationals who are ill and often in real physical and psychological distress. It is important that all caregivers are aware of the international and national legal rights protecting migrants, social security cover, state medical assistance and supplementary universal health insurance. The support needs to be multi-disciplinary, encouraging maximum collaboration between Government organisations, refugee charities, ONGs involved in the reception of migrants, volunteers and interpreters and, of course, caregivers.


Pre-clinical investigation of astatine-211-parthanatine for high-risk neuroblastoma.
Astatine-211-parthanatine ([211At]PTT) is an alpha-emitting radiopharmaceutical therapeutic that targets poly(adenosine-diphosphate-ribose) polymerase 1 (PARP1) in cancer cells. High-risk neuroblastomas exhibit among the highest PARP1 expression across solid tumors. In this study, we evaluated the efficacy of [211At]PTT using 11 patient-derived xenograft (PDX) mouse models of high-risk neuroblastoma, and assessed hematological and marrow toxicity in a CB57/BL6 healthy mouse model. We observed broad efficacy in PDX models treated with [211At]PTT at the maximum tolerated dose (MTD 36 MBq/kg/fraction x4) administered as a fractionated regimen. For the MTD, complete tumor response was observed in 81.8% (18 of 22) of tumors and the median event free survival was 72 days with 30% (6/20) of mice showing no measurable tumor >95 days. Reversible hematological and marrow toxicity was observed 72 hours post-treatment at the MTD, however full recovery was evident by 4 weeks post-therapy. These data support clinical development of [211At]PTT for high-risk neuroblastoma.


Blunt Trauma Massive Transfusion (B-MaT) Score: A Novel Scoring Tool.
Multiple tools predicting massive transfusion (MT) in trauma have been developed but utilize variables that are not immediately available. Additionally, they only differentiate blunt from penetrating trauma and do not account for the large range of blunt mechanisms and their difference in force. We aimed to develop a Blunt trauma Massive Transfusion (B-MaT) score that accounts for high-risk blunt mechanisms and predicts MT needs in blunt trauma patients (BTPs) prior to arrival. The adult 2017 Trauma Quality Improvement Program database was used to identify BTPs who were divided into 2 sets at random (derivation/validation). First, multiple logistic regression models were created to determine risk factors of MT (≥6 units of PRBCs within 4-hours or ≥10 units within 24-hours). Next, the weighted average and relative impact of each independent predictor was used to derive a B-MaT score. Finally, the area under the receiver-operating curve (AROC) was calculated. Of 172,423 patients in the derivation-set, 1,160 (0.7%) required MT. Heart rate ≥ 120bpm, systolic blood pressure ≤ 90mmHg, and high-risk blunt mechanisms were identified as independent predictors for MT. B-MaT scores were derived ranging from 0 -9, with scores of 6, 7, and 9 yielding a MT rate of 11.7%, 19.4%, and 32.4%, respectively. The AROC was 0.86. The validation-set had an AROC of 0.85. B-MaT is a novel scoring tool that predicts need for MT in BTPs and can be calculated prior to arrival. B-MaT warrants prospective validation to confirm its accuracy and assess its ability to improve patient outcomes and blood product allocation.


Clathrin-independent endocytosis: a cargo-centric view.
Clathrin-independent endocytosis occurs in all cells and interest in this mode of cellular entry has grown. Although this form of endocytosis was first described for entry of bacterial toxins, here we focus our attention on the endogenous cell surface "cargo" proteins that enter cells by this mechanism. The cargo proteins entering by this mechanism are varied and include nutrient transporters, ion channels, cell adhesion molecules and proteins associated with the immune system. Despite the apparent lack of selection at the cell surface, we provide some examples of specific sorting of these cargo proteins after entry, leading to distinct itineraries and cellular fates.


Field testing along a disease gradient: some geographical dimensions of tuberculosis in Puerto Rico.
The spatial pattern of reported tuberculosis incidence in Puerto Rico is characterized by numerous high-low gradients among continguous municipios. Tuberculin testing of some 1500 subjects along one such gradient reveals that there is no difference in sensitivity and suggests that the gradients are artifacts of reporting. Correlative associations with tuberculin conversion were generally weak, except for age-dependency. Collected personal histories demonstrated that the web of familial and intergenerational relationships is a major force in perpetuating the disease. Concealment of infection, denial and poor compliance in chemotherapy regimens compound the difficulties of case-discovery and case-control. Interviews in a sample of twelve health centers confirmed that, without the presence of trained and assigned tuberculosis nurses, the health care providers' 'index of suspicion' for tuberculosis is generally low. Absence of a tuberculosis clinic virtually dictates serious under-reporting of incidence in that municipio. Despite the success of Puerto Rico's control program over past decades, a reservoir of tuberculosis persists. The level of endemicity is relatively low but unsatisfactory in the context of public health aspirations.


Feline pyothorax: a retrospective study of 27 cases in Australia.
Pyothorax was diagnosed in 27 cats between 1983 and 2002. In 21 (78%) of the cases, pleural fluid culture and/or cytology was consistent with a mixed anaerobic bacterial infection of oropharyngeal origin. In six cases (22%), infection was caused by unusual pathogens or pathogens of non-oropharyngeal origin, including a Mycoplasma species, Cryptococcus gattii, Escherichia coli, Salmonella typhimurium and Staphylococcus aureus. The overall mortality rate was 22%. Treatment was successful in 18 of 19 cases (95%) where closed thoracostomy tubes were inserted. One case resolved only after thoracotomy. Actinomyces species were isolated in three cases and in contrast to dogs where thoracotomy is recommended, they were resolved with tube thoracostomy. Mechanical complications occurred in 58% of the cats with indwelling chest tubes. Probable mechanisms of pleural space infection were identified in 18 cats (67%) including haematogenous infection (n=1), direct inoculation of bacteria into the pleural space (n=1), intrathoracic oesophageal rupture (n=1) and parapneumonic extension of infection (n=15; 56%). Of the latter, perioperative aspiration was suspected in two cats, parasitic migration in two and antecedent upper respiratory tract infection was implicated in seven. Parapneumonic spread of infection after colonisation and invasion of lung tissue by oropharyngeal flora appears to be the most frequent cause of feline anaerobic polymicrobial pyothorax and contests the widespread belief that direct inoculation of pleural cavity by bite wounds is more common.


FoPA: identifying perturbed signaling pathways in clinical conditions using formal methods.
Accurate identification of perturbed signaling pathways based on differentially expressed genes between sample groups is one of the key factors in the understanding of diseases and druggable targets. Most pathway analysis methods prioritize impacted signaling pathways by incorporating pathway topology using simple graph-based models. Despite their relative success, these models are limited in describing all types of dependencies and interactions that exist in biological pathways. In this work, we propose a new approach based on the formal modeling of signaling pathways. Signaling pathways are formally modeled, and then model checking tools are applied to find the likelihood of perturbation for each pathway in a given condition. By adopting formal methods, various complex interactions among biological parts are modeled, which can contribute to reducing the false-positive rate of the proposed approach. We have developed a tool named Formal model checking based pathway analysis (FoPA) based on this approach. FoPA is compared with three well-known pathway analysis methods: PADOG, CePa, and SPIA on the benchmark of 36 GEO datasets from various diseases by applying the target pathway technique. This validation technique eliminates the need for possibly biased human assessments of results. In the cases that, there is no apriori knowledge of all relevant pathways, simulated false inputs (permuted class labels and decoy pathways) are chosen as a set of negative controls to test the false positive rate of the methods. Finally, to further evaluate the efficiency of FoPA, it is applied to a list of autism-related genes. The results obtained by the target pathway technique demonstrate that FoPA is able to prioritize target pathways as well as PADOG but better than CePa and SPIA. Also, the false-positive rate of finding significant pathways using FoPA is lower than other compared methods. Also, FoPA can detect more consistent relevant pathways than other methods. The results of FoPA on autism-related genes highlight the role of "Renin-angiotensin system" pathway. This pathway has been supposed to have a pivotal role in some neurodegenerative diseases, while little attention has been paid to its impact on autism development so far.


Ultrastructural regenerating features of nasal mucosa following microdebrider-assisted turbinoplasty are related to clinical recovery.
The nasal mucosa plays a key role in conditioning the inhaled air and in regulating the immune response. These functions led many authors to recommend mucosal sparing techniques for the surgical management of inferior turbinate hypertrophy. However, the histological modifications of chronic diseases retain the inflammatory activity and prevent the nasal physiology restoration. It has been proved that the basal cells of the nasal mucosa are able to proliferate and to repair after cold-knife incision. The aim of this study was to demonstrate that the healing process after removal of the inferior turbinate mucosa with cold techniques results in a complete structural restoration. A prospective study was performed in 18 patients who underwent Microdebrider inferior turbinoplasty (cold technique). Subjective and objective improvement of nasal patency was evaluated with visual analogue scale, rhinomanometry, videoendoscopy and mucociliary transport test. Pre- and post-operative biopsy specimens were taken from 7 patients to evaluate the healing process. Two samples were taken from two healthy patients as control. The specimens were processed for transmission electron microscopy analysis. Videoendoscopy showed reduction of lower turbinate after surgery. Nasal patency augmented and no adverse consequences were observed. After 4 months the nasal mucosa showed normal appearance, with restoration of the pseudostratified ciliated pattern, intercellular connections and normal cellular morphology. Fibrosis and submucosal edema disappeared. At longer time after operation (4 years) clinical improvement was confirmed. The total removal of the nasal mucosa with cold techniques results in a complete restoration of the normal structure and permanent resolution of the chronic inflammation typical of hypertrophic rhinopathy.


Synthesis, antimicrobial activity and toxicity to nematodes of cyclam derivatives.
The antimicrobial activity and toxicity to nematodes of the cyclam salt [H2{H2(4-CF3PhCH2)2Cyclam}](CH3COO)2⋅(CH3COOH)2 were evaluated. Estimated minimum inhibitory concentrations (MICs) of 9, 261 and 15 µg/mL were obtained for Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus, respectively. For selected Candida spp., the estimated MICs obtained ranged from 32 µg/mL to 63 µg/mL. Bactericidal activity was demonstrated but the compound was not reliably fungicidal. Concentrations of the cyclam salt up to 32 µg/mL did not significantly affect survival of the nematode Caenorhabditis elegans; however, concentrations equal or above this value significantly affected nematode survival in a dose-dependent manner.


Anatomic shoulder arthroplasty with high side reaming versus reverse shoulder arthroplasty for eccentric glenoid wear patterns with an intact rotator cuff: comparing early versus midterm outcomes with minimum 7 years of follow-up.
Eccentric glenoid bone loss patterns (B- and C-type glenoid) pose a difficult challenge when performing shoulder arthroplasty. Anatomic total shoulder arthroplasty with preferential high-side reaming (ATSA + HSR) has been an accepted method to treat this problem. Reverse shoulder arthroplasty (RSA) has become an alternative method to manage these cases with eccentric glenoid wear. The purpose of this study was to compare the early 2-year outcomes with the midterm outcomes for patients who underwent ATSA + HSR vs. RSA for eccentric glenoid wear patterns with an intact rotator cuff. From 2008 to 2014 there were 242 shoulder arthroplasties performed in the setting of eccentric glenoid wear patterns. Of that initial cohort 101 ATSA + HSR and 93 RSA had both 2-year and final follow-up with a minimum of 7 years from surgery. American Shoulder and Elbow Surgeons (ASES) scores, Simple Shoulder Test (SST), range of motion, patient satisfaction, and radiographs were evaluated for each cohort and contrasted at the 2-year follow-up point and last follow-up time point. The average follow-up in the ATSA + HSR cohort was 8.3 years compared with 7.8 years in the RSA cohort. At the 2-year follow-up point, the ATSA + HSR group had better average ASES scores (85 vs. 80 [P < .001]), SST scores (10 vs. 9.6 [P < .001]), forward elevation (162° vs. 151° [P < .001]), external rotation (47° vs. 42° [P < .001]), and internal rotation (IR) (80% full IR vs. 55% full IR [P < .001]). At the 2-year follow-up, 95% of the ATSA + HSR cohort were satisfied compared with 93% in the RSA cohort. At the final follow-up, the RSA group had better average ASES scores (80 vs. 77 [P < .001]) and SST scores (9.4 vs. 8 [P < .001]) and a similar forward elevation (152° vs. 149° [P = .025]). The ATSA + HSR had better external rotation (45° vs. 41° [P < .001]) and IR (74% full IR vs. 54% full IR [P = .005]). Patient satisfaction at the final follow-up had decreased to 82% in the ATSA + HSR group, compared with 95% satisfied in the RSA group. Of the initial ATSA + HSR cohort, 8% of patients had undergone revision compared with 2% in the RSA cohort. ATSA with HSR had better outcome scores and range of motion with a similar patient satisfaction rating to RSA at the 2-year point. Over time, the ATSA + HSR results deteriorated, and at the final midterm follow-up, the RSA group had more durable results with better outcome scores, a higher patient satisfaction rating, and a lower revision rate.


Solar Water Splitting Using Earth-Abundant Electrocatalysts Driven by High-Efficiency Perovskite Solar Cells.
Hydrogen is considered as the "holy grail" for the energy community. One of the most promising strategies to produce hydrogen is to split water using renewable energy such as solar radiation. The abundance of water and solar energy enables the potential of scaling-up of this new technology, if suitable electrocatalysts and solar cells are developed. In this work, a series of materials made of earth-abundant elements was investigated for hydrogen evolution or oxygen evolution reaction. Among the developed catalysts, MoS2 and NiFe showed the best activities for proton reduction and water oxidation, respectively. These catalysts were further integrated into an alkaline electrolyzer, which delivered a current density of 10 mA cm-2 at a cell voltage of 1.9 V for water splitting. Using two in-series-connected perovskite solar cells (PSCs) as a power source, a remarkable solar-to-hydrogen conversion efficiency of 12.67 % was achieved in an alkaline electrolyzer with a partial current density of 10.3 mA cm-2 for hydrogen production. The usage of earth-abundant catalysts in this study, together with the employment of low-cost perovskite light absorber, shows the potential of scaling up this type of photovoltaic electrolyzer for sustainable hydrogen production.


Inflammatory Bowel Disease in Children.
Inflammatory bowel disease is an important cause of chronic diarrhea in children, with a rising incidence, globally. The two main subtypes include Crohn's disease and ulcerative colitis. The clinical features are variable, and diagnosis requires initial first-line investigations followed by the involvement of specialist input for targeted imaging and endoscopy with biopsy, to confirm the diagnosis. Despite detailed investigation, inflammatory bowel disease may be clinically indistinguishable from chronic infections such as intestinal tuberculosis, and anti-tuberculosis treatment may be considered prior to further management considerations. The medical management of inflammatory bowel disease depends on subtype classification and severity, and may involve a step-wise approach to immunosuppressive therapies. In children, the consequences of poorly controlled disease are wide ranging, from psychosocial impacts and school non-attendance, to growth impairment and pubertal delay with subsequent impacts on bone health. In addition, an increased need for hospitalization and surgical intervention, and ultimately risk of cancer long-term. A multi-disciplinary team with expertise in inflammatory bowel disease is recommended to mitigate these risks and help to achieve the goal of sustained remission with endoscopic healing. This review focuses on updates on best clinical practice on the diagnosis and management of inflammatory bowel disease in children.


Cataracts in Dunedin Program participants: an evaluation of risk factors.
A geriatric health screening program in Dunedin, Florida, was used to evaluate risk factors leading to development of cataracts. A total of 2,787 participants completed the fourth yearly visit to the program. At the time of the fourth visit, 49.3% of women (mean age 75.1 years) and 38.2% of men (mean age 75.4 years) reported the presence of cataracts. Age was found to be the most significant risk factor in cataract development (P less than .0001). Both men and women with cataracts had significantly lower serum cholesterol concentrations than subjects without cataracts. After adjusting for age and sex, diazepam (P less than .03), furosemide (P less than .04), isosorbide (P less than .003), and ibuprofen (P less than .03) were found to be positively associated with cataracts; triamterene (P less than .05) had a negative association, indicating a protective relationship. Aspirin was not shown to have a protective effect on reported cataracts.


Prevalence and antimicrobial resistance profile of bacterial pathogens isolated from poultry in Jiangxi Province, China from 2020 to 2022.
Poultry is one of the most commonly farmed species and the most widespread meat industries. However, numerous poultry flocks have been long threatened by pathogenic bacterial infections, especially antimicrobial resistant pathogens. Here the prevalence and the antimicrobial resistance (AMR) profiles of bacterial pathogens isolated from poultry in Jiangxi Province, China were investigated. From 2020 to 2022, 283 tissue and liquid samples were collected from clinically diseased poultry, including duck, chicken, and goose, with an overall positive isolation rate of 62.90%. Among all the 219 bacterial isolates, 29 strains were gram-positive and 190 strains were gram-negative. Major bacteria species involved were avian pathogenic Escherichia coli (APEC; 57.53%; 126/219), followed by Salmonella spp. (11.87%, 26/219), Pasteurella multocida (6.39%, 14/219), and Staphylococcus spp. (1.22%, 11/219). Antimicrobial susceptibility testing showed the APEC isolates displayed considerably higher levels of AMR than the Salmonella and P. multocida isolates. The APEC isolates showed high resistance rate to amoxicillin (89.68%), ampicillin (89.68%), and florfenicol (83.33%), followed by streptomycin (75.40%), cefradine (65.87%), and enrofloxacin (64.29%). Multidrug-resistant isolates were observed in APEC (99.21%), Salmonella spp. (96.16%), and P. multocida (85.71%), and nearly 3 quarters of the APEC strains were resistant to 7 or more categories of antimicrobial drugs. Moreover, blaNDM genes associated with carbapenemase resistance and mcr-1 associated with colisitin resistance were detected in the APEC isolates. Our findings could provide evidence-based guidance for veterinarians to prevent and control bacterial diseases, and be helpful for monitoring the emerging and development of AMR in poultry bacterial pathogens.


Stepwise tracking strategy to screen ingredient from Galla Chinensis based on the "mass spectrometry guided preparative chromatography coupled with systems pharmacology".
Galla chinensis, a traditional Chinese herbal medicine, was widely used to treat ulcerative colitis (UC) in folk prescriptions, however, its active ingredients and mechanism of action in the treatment of UC remain unclear. The aim of our study was to discover the lead compounds and anti-inflammatory active ingredients of Galla chinensis and clarify their molecular mechanism for UC treatment. The ingredients of Galla chinensis were prepared by column and mass spectrometry guided preparative chromatography. Besides, the relationship among the ingredients of Galla chinensis and targets was predicted by systems pharmacology. Additionally, Lipopolysaccharide (LPS)-induced RAW264.7 macrophages were used as in vitro model. The cell viability, the level of the pro-inflammatory factors, the generation of reactive oxygen species (ROS), and trans epithelial electric resistance (TEER) values were detected to screen out the active ingredients of Galla chinensis. Moreover, 4% dextran sodium sulfate (DSS)-induced ulcerative colitis mice were used as the UC animal model. The disease activity index (DAI), pathological degree of colon tissue, activities of antioxidant-related enzymes and expression level of pro-inflammatory cytokines were performed to assess the anti-UC effects of the active ingredients. Meanwhile, the mRNA expression level of inflammatory factors and antioxidant related genes were analyzed by real-time quantitative polymerase chain reaction (Q-PCR). And the expression of nuclear factor erythroid-2 related factor 2 (Nrf2) pathway related proteins, intestinal mucosal proteins and nuclear factor kappa-B (NF-κB) pathway related proteins in colon tissues were analyzed by Western Blotting. Herein, a stepwise tracking strategy was adopted to screen out the anti-inflammatory active ingredients of Galla Chinensis based on "preparative chromatography pharmacology combined with mass spectrometry guidance and system". 11 categories of ingredients of Galla chinensis were prepared and ethyl gallate (EG) was screened out the lead compound and anti-inflammatory active ingredient of Galla Chinensis through in silico, in vitro and in vivo studies. In addition, EG had a significant therapeutic effect on ameliorating DSS-induced UC mice and protected intestinal mucosal integrity through Nrf2 and NF-κB signaling pathway. Ethyl gallate was the lead compound and anti-inflammatory active ingredient in Galla chinensis. And it was discovered for the first time that EG could treat mice with ulcerative colitis. This research not only found the lead compound of Galla Chinensis for UC treatment and determined the possible mechanism, but also provided valuable references for finding lead compounds from natural products by systems pharmacology coupled with equivalent components group technology.


Storing apheresis platelets without agitation with simulated shipping conditions during two separate periods: immediately after collection and subsequently between Day 2 and Day 3.
Apheresis platelet (PLT) units are not routinely agitated during transit. Our study compared the in vitro properties of apheresis PLT units that were stored with continuous agitation (CA) and without continuous agitation (WCA) during two separate periods, immediately after collection and between Day 2 and Day 3 of storage. Two identical apheresis PLTs units were prepared from collections with Amicus (n = 11, Fenwal, Inc.) and Trima (n = 10, CaridianBCT) cell separators. One apheresis PLT unit was continuously agitated, starting routinely within 30 minutes of collection, and an identical apheresis PLT unit was held without agitation initially for 7 to 8 hours and subsequently for 24 hours between Day 2 and Day 3 of storage. The apheresis PLT units were maintained WCA at 20 to 24 °C in a shipping box. In vitro PLT properties were evaluated on Day 1 (day after collection), after 5 and 7 days of storage. With both Amicus and Trima apheresis PLT units, the mean PLT content and concentration of CA and WCA were comparable and essentially constant throughout storage. Mean pH levels (± 1 SD) after 5 days for Amicus apheresis PLT units were 6.97 ± 0.20 (WCA) and 7.13 ± 0.16 (p < 0.001, CA) and for Trima apheresis PLT units 6.97 ± 0.21 (WCA) and 7.22 ± 0.17 (p < 0.001, CA). In vitro variables, including percentage of disc PLTs, extent of shape change, and hypotonic stress levels, after 5 days of storage, showed mean differences between WCA and CA that were less than 15%. The in vitro results show that apheresis PLT units can be stored without agitation for 7 to 8 hours immediately after collection and also subsequently during storage for 24 hours with minimal influence on in vitro PLT properties compared to continuously agitated PLTs.


Determining the pharmacologic window of bisphosphonates that mitigates severe injury-induced osteoporosis and muscle calcification, while preserving fracture repair.
Following severe injury, biomineralization is disrupted and limited therapeutic options exist to correct these pathologic changes. This study utilized a clinically relevant murine model of polytrauma including a severe injury with concomitant musculoskeletal injuries to identify when bisphosphonate administration can prevent the paradoxical decrease of biomineralization in bone and increased biomineralization in soft tissues, yet not interfere with musculoskeletal repair. Systemic and intrinsic mechanisms in bone and soft tissues help promote biomineralization to the skeleton, while preventing it in soft tissues. However, severe injury can disrupt this homeostatic biomineralization tropism, leading to adverse patient outcomes due to a paradoxical decrease of biomineralization in bone and increased biomineralization in soft tissues. There remains a need for therapeutics that restore the natural tropism of biomineralization in severely injured patients. Bisphosphonates can elicit potent effects on biomineralization, though with variable impact on musculoskeletal repair. Thus, a critical clinical question remains as to the optimal time to initiate bisphosphonate therapy in patients following a polytrauma, in which bone and muscle are injured in combination with a severe injury, such as a burn. To test the hypothesis that the dichotomous effects of bisphosphonates are dependent upon the time of administration relative to the ongoing biomineralization in reparative bone and soft tissues, this study utilized murine models of isolated injury or polytrauma with a severe injury, in conjunction with sensitive, longitudinal measure of musculoskeletal repair. This study demonstrated that if administered at the time of injury, bisphosphonates prevented severe injury-induced bone loss and soft tissue calcification, but did not interfere with bone repair or remodeling. However, if administered between 7 and 21 days post-injury, bisphosphonates temporally and spatially localized to sites of active biomineralization, leading to impaired fracture callus remodeling and permanence of soft tissue calcification. There is a specific pharmacologic window following polytrauma that bisphosphonates can prevent the consequences of dysregulated biomineralization, yet not impair musculoskeletal regeneration.


The Multifactorial Contribution of Publications in Plastic Surgery Journals in Microsurgery Education.
Microsurgery is one of the most complex operative skills. Recent restrictions on residents' working hours challenge residency program directors to ensure skill acquisition with scant time dedicated to microsurgery practice. We aimed to summarize the contribution of plastic surgery journals in microsurgical education. A comprehensive literature search was performed. We observed an increasing number of publications on microsurgery education over the years. This could be due to the adoption of new technologies developed in the last 2 decades, the concerns about quality of resident training in the context of reduced work hours, the well-described benefit of medical simulations in other specialties, and the pressure on trainees to be proficient before operating on patients. The variety of aspects addressed in plastic surgery publications is broad: simulators, courses, skills assessment, national surveys, and technology trends. There is an upward trend in the number of publications and plastic surgery journals, demonstrating a remarkable contribution to microsurgery training.


Acoustic Analysis of Indian Teachers' Voice: Pre and Post Teaching Circumstances.
Compared to people employed in other occupations, teachers are more likely to report having voice problems. They are more likely to perceive that their voice problems limit their current job performance and also adversely affect their future career options. The current study examines the acoustic parameters that are sensitive to vocal loading in pre and post teaching circumstances and adds to the existing literature. Voice samples were recorded from 30 primary school teachers, 15 females and 15 males in the age range of 28-35 years (mean age 29.3 years), with teaching experience of 10-12 years. Mean pitch, minimum pitch, maximum pitch, number of voice breaks, jitter local, shimmer local and mean harmonic to noise ratio were estimated using PRAAT software before and after a typical teaching day. Significant difference was seen when number of voice breaks was compared in pre and post teaching conditions in both males (p = 0.02) and females (p = 0.02) in the conversation task. Moreover, significant differences in mean pitch was observed in the task of slogan repetition (p = 0.03), but only in males. These parameter can be used as indicators of vocal fatigue among teachers and can be used in objective determination of at risk population.


Megakaryocyte colony-stimulating factor and thrombopoiesis.
Although megakaryocyte differentiation and proliferation is understood to be regulated by "humoral" factors, the molecular identities of such factors have, until recently, been obscure. The "two factor" model of megakaryocytopoiesis/thrombopoiesis is critically reviewed. In this model, "Megakaryocyte Colony-Stimulating Factor" (Meg-CSF) determines the early differentiational events of megakaryocytopoiesis, and "Thrombopoietin" (Tpo) is held responsible for the maturation of the megakaryocyte and the biochemical/cytological events in platelet formation and release. To date, neither of these growth factors have been molecularly cloned. When this occurs, the clarification of the roles Meg-CSF, Tpo and other secondary modulators (such as IL-3 and GM-CSF) play in platelet formation in health and disease will be made manifest.


A causal model of contraceptive intention and its gender comparison among Taiwanese sexually inexperienced adolescents.
To test latent constructs of social influences, contraceptive attitude and self-efficacy for contraception as a causal model of contraceptive intention among adolescents and to search for possible gender differences in the causal model of contraceptive intention. A greater understanding of the causal model of contraceptive intention among sexually inexperienced adolescents will help nurses design contraceptive programmes to improve adolescent contraceptive use when they have sex. Design. This was a cross-sectional study; 770 boys and 685 girls that self-reported not being sexually experienced were selected for this study. An anonymous questionnaire was used to collect data. By structural equation modelling using the eqs 6.1 software, a hypothesized structural model of contraceptive intention was tested. For both genders, social influences affected contraceptive intention indirectly through the contraceptive attitude and self-efficacy for contraception. Contraceptive attitude and self-efficacy for contraception affected contraceptive intention directly. Contraceptive attitude also affected contraceptive intention indirectly through the mediation of self-efficacy for contraception. There were gender differences in the variances of contraceptive intention explained by contraceptive attitude, self-efficacy for contraception and social influences. Nevertheless, the data explain only a low proportion of the variability in contraceptive intention. More causal constructs influencing contraceptive intention should be explored in future. Personal factors and social influences operate interdependently to influence contraceptive intention among sexually inexperienced adolescents. Gender is a moderator that can modify the influential level of social influences, contraceptive attitude and self-efficacy for contraception on contraceptive intention. Nurses should operate personal factors and social influences interdependently when they are designing intervention programmes for sexually inexperienced adolescents. To make intervention more effective, nurses also need to provide gender-specific intervention programmes for sexually inexperienced adolescents.


Disruptions to the patient-provider relationship and patient utilization and outcomes: Evidence from medicaid managed care.
The patient-provider relationship is considered a cornerstone to delivering high-value healthcare. However, in Medicaid managed care settings, disruptions to this relationship are disproportionately common. In this paper, I evaluate the impact of a primary provider's exit from a Medicaid managed care plan on adult beneficiary healthcare utilization and outcomes. Using an event study approach, I estimate a 5% decrease in the number of beneficiaries with primary care visits in the year following the exit, with slightly larger effects in terms of percentage points for patients with chronic conditions. Additionally, I observe a nearly 50% increase in the number of beneficiaries with a chronic condition who are hospitalized following a disruption.


Resumption of anti-programmed cell death 1 monotherapy for severe immune-related adverse events experienced patient with renal cell carcinoma.
Combined anti-cytotoxic-T-lymphocyte antigen 4 and programmed cell death 1 blockade induced high rates of immune-related adverse events in patients with renal cell carcinoma. However, the safety of reinitiating anti-programmed cell death 1 monotherapy for patients who discontinued combination therapy due to immune-related adverse events is largely unknown. We report the case of 74-year-old man who received combination therapy with anti-cytotoxic-T-lymphocyte antigen 4 and programmed cell death 1 inhibitors for advanced renal cell carcinoma. After three cycles of combination therapy, he complained severe immune-related adverse events including grade 3 nausea and anorexia, and grade 3 diarrhea, leading to discontinuation of the therapy. He started readministration of anti-programmed cell death 1 monotherapy at 41 weeks after discontinuation due to the new lung metastatic lesion. Importantly, he experienced only grade 1 diarrhea, which can be controlled with prednisolone. The readministration of anti-programmed cell death 1 monotherapy with close monitoring can be an acceptable treatment even after discontinuation of combination therapy.


Relationship between urinary fibrinogen degradation products and various types of chronic nephritis.
The concentration of urinary fibrin(ogen) degradation products (FDP) was determined by using enzyme immunoassay and radio immunoassay, and their urinary levels were compared with histologically classified types of glomerulonephritis. Urinary FDP levels were higher in the severe type of proliferative glomerulonephritis and at the active phase of systemic lupus erythematosus (SLE). They were also high in the membranous glomerulonephritis. Molecular weight of urinary FDP of a patient with severe proliferative glomerulonephritis was determined to be 150,000 and 68,000, respectively after gel filtration. Urinary FDP levels were higher in patients with glomerular fibrin deposit than in patients without fibrin deposit or normal volunteers. The amounts of excreted protein in urine was not related to the amounts of FDP. Decrease in the reciprocal of serum creatinine levels resulted in high urinary FDP levels, indicating that high urinary FDP levels may represent deterioration of renal function.


Can Bottom Sediments Be a Prospective Fertilizing Material? A Chemical Composition Analysis for Potential Reuse in Agriculture.
Every year, huge amounts of bottom sediments are extracted worldwide, which need to be disposed. The recycling of bottom sediments for soil fertilization is in line with the long-promoted circular economy policy and enables the use of micro and macronutrients accumulated in sediments for soil fertilization. When considering potential agricultural reuse of the dredge sediments, the first necessary step should be to analyze whether the heavy metal content meets the obligatory criteria. Then, the contents of valuable elements required for plant growth and their ratios should be assessed. In this study, the content of nitrogen, organic carbon, phosphorus, and potassium was tested and iron, sulfur, calcium, and magnesium were also analyzed along vertical profiles of sediments extracted from four urban retention tanks in Gdańsk (Poland). The sediments were indicated to have a low content of nutrients (Ntot 0.01-0.52%, Corg 0.1-8.4%, P2O5 0.00-0.65%, K 0.0-1.0%), while being quite rich in Fe and S (0.2-3.3%, 0.0-2.5%, respectively). The C/N ratio changed in the range of 17.4-28.4, which proved good nitrogen availability for plants. The mean values of the Fe/P ratio were above 2.0, which confirms that phosphorus in the sediments would be available to the plants in the form of iron phosphate. To summarize, the bottom sediments from municipal retention reservoirs are not a perfect material for soil fertilization, but they are a free waste material which, when enriched with little cost, can be a good fertilizer. Future research should focus on cultivation experiments with the use of sediments enriched with N, P, Corg.


Active unfolding of the glucocorticoid receptor by the Hsp70/Hsp40 chaperone system in single-molecule mechanical experiments.
The glucocorticoid receptor (GR) is an important transcription factor and drug target linked to a variety of biological functions and diseases. It is one of the most stringent physiological clients of the Hsp90/Hsp70/Hsp40 chaperone system. In this study, we used single-molecule force spectroscopy by optical tweezers to observe the interaction of the GR's ligand-binding domain (GR-LBD) with the Hsp70/Hsp40 chaperone system (Hsp70/40). We show in real time that Hsp70/40 can unfold the complete GR-LBD in a stepwise manner. Each unfolding step involves binding of an Hsp70 to the GR-LBD and subsequent adenosine triphosphate (ATP) hydrolysis, stimulated by Hsp40. The kinetics of chaperone-mediated unfolding depend on chaperone concentrations as well as the presence of the nucleotide exchange factor BAG1. We find that Hsp70/40 can stabilize new unfolding intermediates, showing that Hsp70/40 can directly interact with the folded core of the protein when working as an unfoldase. Our results support an unfolding mechanism where Hsp70 can directly bind to folded protein structures and unfold them upon ATP hydrolysis. These results provide important insights into the regulation of GR by Hsp70/40.


A mitophagy-related gene signature associated with prognosis and immune microenvironment in colorectal cancer.
Colorectal cancer (CRC) is a heterogeneous disease and one of the most prevalent malignancies worldwide. Previous research has demonstrated that mitophagy is crucial to developing colorectal cancer. This study aims to examine the association between mitophagy-related genes and the prognosis of CRC patients. Gene expression profiles and clinical information of CRC patients were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Univariate Cox regression and the least absolute shrinkage and selection operator (LASSO) regression analysis were applied to establish a prognostic signature using mitophagy related genes. Kaplan-Meier and receiver operating characteristic (ROC) curves were used to analyze patient survival and predictive accuracy. Meanwhile, we also used the Genomics of Drug Sensitivity in Cancer (GDSC) database and Tumor Immune Dysfunction and Exclusion (TIDE) algorithm to estimate the sensitivity of chemotherapy, targeted therapy and immunotherapy. ATG14 overexpression plasmid was used to regulate the ATG14 expression level in HCT116 and SW480 cell lines, and cell counting kit-8, colony formation and transwell migration assay were performed to validate the function of ATG14 in CRC cells. A total of 22 mitophagy-driven genes connected with CRC survival were identified, and then a novel prognostic signature was established based on 10 of them (AMBRA1, ATG14, MAP1LC3A, MAP1LC3B, OPTN, VDAC1, ATG5, CSNK2A2, MFN1, TOMM22). Patients were divided into high-risk and low-risk groups based on the median risk score, and the survival of patients in the high-risk group was significantly shorter in both the training cohort and two independent cohorts. ROC curve showed that the area under the curves (AUC) of 1-, 3- and 5-year survival were 0.66, 0.66 and 0.64, respectively. Multivariate Cox regression analysis confirmed the independent prognostic value of the signature. Then we constructed a Nomogram combining the risk score, age and M stage, which had a concordance index of survival prediction of 0.77 (95% CI 0.71-0.83) and more robust predictive accuracy. Results showed that CD8+ T cells, regulatory T cells and activated NK cells were significantly more enriched in the high-risk group. Furthermore, patients in the high-risk group are more sensitive to targeted therapy or chemotherapy, including bosutinib, elesclomol, lenalidomide, midostaurin, pazopanib and sunitinib, while the low-risk group is more likely to benefit from immunotherapy. Finally, in vitro study confirmed the oncogenic significance of ATG14 in both HCT116 and SW480 cells, whose overexpression increased CRC cell proliferation, colony formation, and migration. In conclusion, we developed a novel mitophagy-related gene signature that can be utilized not only as an independent predictive biomarker but also as a tool for tailoring personalizing treatment for CRC patients, and we confirmed ATG14 as a novel oncogene in CRC.


Complementation with HLA-A and HLA-D locus alleles in ankylosing spondylitis with peripheral arthritis.
Fifty-nine patients with HLA-B27 positive ankylosing spondylitis were HLA genotyped to look for immunogenetic differences between patients with associated peripheral arthritis and those with disease limited to the axial skeleton. An association was found between the peripheral arthropathy and 2 antigens, HLA-A11 and HLA-DR7 at the p less than 0.05 level. Complementation between these 2 alleles and HLA-B27 occurred in both the cis and trans positions. Four patients with peripheral arthritis had a rare HLA-B27 haplotype (HLA-B27, HLA-DR7) which was not found in the group with axial disease alone.


Health-related quality of life burden associated with treatment-resistant depression in UK patients: Quantitative results from a mixed-methods non-interventional study.
Major depressive disorder (MDD) and its more intractable variant, treatment-resistant depression (TRD), are common conditions that adversely affect patient well-being and health-related quality of life (HRQoL). This study aimed to quantify the impact of MDD and particularly TRD on the HRQoL, functioning and productivity of UK patients to support clinical and reimbursement decisions and policymaking. 148 patients with clinician-verified symptomatic (non-treatment-resistant) MDD (Patients-MDD; n = 61) or TRD (Patients-TRD; n = 87) were recruited from ten clinical sites. Participants completed validated patient-reported outcome measures assessing depressive symptom severity (Patient Health Questionnaire-9 [PHQ-9]), HRQoL (EQ-5D-5 L/abbreviated World Health Organization Quality of Life Questionnaire [WHOQOL-BREF]) and work productivity/activity impairment (WPAI:D). Patients-TRD and Patients-MDD reported similar levels of depressive symptom severity (mean PHQ-9 16.2/16.6, respectively). However, HRQoL was significantly poorer for Patients-TRD compared with Patients-MDD, both in the overall cohort (median EQ-5D-5 L utility 0.606/0.721, respectively [p = 0.021]; WHOQOL-BREF overall score 55.2/58.8 [p = 0.024]) and in patients with a PHQ-9 score ≥15 (median EQ-5D-5 L utility 0.415/0.705, respectively [p<0.001]). Although a numerically lower proportion of Patients-TRD were employed (45% vs 57% of Patients-MDD; p = 0.204), employed Patients-MDD reported significantly higher absenteeism and work productivity loss. A minority of patients screened as having symptomatic MDD or TRD self-reported low PHQ-9 symptom severity. This was addressed with a subgroup analysis of patients with more severe depression. TRD is associated with an added patient HRQoL burden, above that observed for non-treatment-resistant MDD. This highlights the unmet need for greater access to improved treatment, including new treatment options for Patients-TRD.


Brave new world: integrating electronics into a hospital security plan.
Although approximately 90% of cameras that are currently installed in hospitals are analog-based, the trend is to switch to IP network-based digital cameras. How IT, security, and other departments can work together to successfully implement the new systems is explained in this article.


Cesarean myomectomy in the last ten years; A true shift from contraindication to indication: A systematic review and meta-analysis.
A lot of debate is present about Cesarean myomectomy (CM) in women with uterine myoma whether to consider it a feasible and safe procedure or an absolute contraindication. To assess the safety and feasibility of myomectomy during cesarean section in women with uterine myoma. Electronic search was made on MEDLINE, EMBASE, Cochrane Library, ISI web of knowledge and Scopus from January 1, 2008 to December 31, 2019 using terms "Caesarean section", "Myomectomy", "Fibroid", "Caesarean myomectomy". All full length studies either prospective or retrospective that address caesarean myomectomy were included. The outcomes studied were haemorrhage, mean change in haemoglobin, operative time, need for blood transfusion, febrile morbidity and duration of hospital stay. Total 249 studies were assessed for eligibility and 17 studies included in analysis with 6545 women. There were 4702 (71.85 %) women in caesarean myomectomy (CM) group and 1843 (28.15 %) women in cesarean section (CS) group. There was statistically significant but clinically insignificant decrease in hemoglobin [MD = 0.27, 95 %CI = 0.08-0.45, p = 0.005; very low quality], significant higher need for blood transfusion [RR = 1.45, 95 %CI = 1.05-1.99, p = 0.02; high quality] in CM group versus CS alone. The mean operative time (minutes) [MD = 14.77, 95 %CI = 6.91-22.64, p = 0.0002; moderate quality] and mean hospital stay (days) [MD = 0.36, 95 %CI = 0.19-0.53, p < 0.00001; high quality] was significantly less in CM group, though of not any clinical significance. No difference in incidence of haemorrhage [RR = 1.16, 95 %CI = 0.86-1.56, p = 0.32; moderate quality evidence] and fever [RR = 1.17, 95 %CI = 0.83-1.65), p = 0.36; moderate quality] in two groups. The meta-analysis suggests CM is associated with clinical insignificant increase in operative time, blood loss and hospital stay, especially with multiple and large size myomas. CM should be preferred over CS alone especially by experienced surgeons with appropriate haemostatic techniques and tertiary care centres.


High frequency of X chromosome abnormalities in women with short stature and elevated liver enzymes.
Paucisymptomatic forms of Turner's syndrome (TS), in which short stature is the predominant clinical abnormality, remain underdiagnosed. Abnormal liver tests are extremely frequent in adult TS patients reflecting various types of hepatic lesions. The objective of the study was to investigate whether unexplained elevated liver enzymes in women with short stature could reveal X chromosome abnormalities of undiagnosed TS. Thirty-one consecutive short stature women displaying elevated liver enzymes and no previous diagnosis of TS were compared with 31 age-matched controls in a prospective study. Liver biopsy was performed in 26 patients. Systematic karyotype analysis and fluorescence in situ hybridization. X chromosome abnormalities were found in 27 patients and one control (87.0% vs 3.2%, P < .0001), including a 45,X/46,XX mosaicism in 24 patients and isochromosome of the long arm in three. Liver histological analysis showed architectural changes in 17 patients with nodular regenerative hyperplasia in 12. Biliary lesions were present in 13 patients and liver steatosis in 20. X chromosome abnormalities indicative of cryptic TS are extremely frequent in short-stature women with unexplained elevated liver enzymes. In short-stature women, abnormal liver tests should lead to systematic karyotype analysis.


Effects of high intensity interval training on cardiorespiratory fitness and salivary levels of IL-8, IL-1ra, and IP-10 in adults with asthma and non-asthma controls.
The purpose of this study was to determine whether high intensity interval training (HIIT) would lead to improvements in 1) maximal VO2, VE, VE/VCO2, and VE/MVV, and/or 2) resting salivary concentrations of pro-inflammatory markers Interleukin (IL-8), interferon-gamma-inducible-protein (CXCL10/IP-10)) and anti-inflammatory marker IL-1 receptor antagonist (IL-1ra) in adults with well-controlled asthma compared to non-asthma controls. Participants completed a maximal exercise test at the beginning (T1) and end (T2) of a 6-week HIIT intervention; saliva samples were obtained at the beginning and 30 min following the first (T1) and last (T2) exercise session. Adults with asthma (n = 20; age: 21.4 ± 2.4 years) and non-asthma controls (n = 12; age: 22.5 ± 3.4 years) completed the intervention. VO2max increased from T1 to T2 in both groups (asthma T1 32.9 ± 8, T2 38.6 ± 8.2 ml/kg/min; controls T1 34.5 ± 11.8, T2 38.9 ± 12.3 ml/kg/min). VEmax also increased in both groups (asthma T1 97.7, T2 110.8 units, p < 0.001, hp2 = <0.04; control T1 106.3, T2 118.1, p < 0.001, hp2 0.02). An increase in VE/VCO2 (F(1, 10)=22.11, p = 0.001) and VE/MVV (F(1, 10) = 111.30, p < 0.001) was observed in the control group; no differences were observed in the asthma group. No differences in IL-8 or IL-1ra were observed between groups. In the asthma group, resting salivary IP-10 concentrations significantly decreased from T1 (0.025 pg/ug protein) to T2 (0.015 pg/ug protein, p = 0.039, hp2 = 0.3 (moderate effect)). A 6-week HIIT intervention led to a similar increase in VO2max and VEmax in those with and without asthma, and a decrease in resting salivary IP-10 levels among adults with asthma.


Application of Machine Learning Methods to Improve the Performance of Ultrasound in Head and Neck Oncology: A Literature Review.
Radiomics is a rapidly growing area of research within radiology that involves the extraction and modeling of high-dimensional quantitative imaging features using machine learning/artificial intelligence (ML/AI) methods. In this review, we describe the published clinical evidence on the application of ML methods to improve the performance of ultrasound (US) in head and neck oncology. A systematic search of electronic databases (MEDLINE, PubMed, clinicaltrials.gov) was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Of 15,080 initial articles identified, 34 studies were selected for in-depth analysis. Twenty-five out of 34 studies (74%) focused on the diagnostic application of US radiomics while 6 (18%) studies focused on response assessment and 3 (8%) studies utilized US radiomics for modeling normal tissue toxicity. Support vector machine (SVM) was the most commonly employed ML method (47%) followed by multivariate logistic regression (24%) and k-nearest neighbor analysis (21%). Only 11/34 (~32%) of the studies included an independent validation set. A majority of studies were retrospective in nature (76%) and based on single-center evaluation (85%) with variable numbers of patients (12-1609) and imaging datasets (32-1624). Despite these limitations, the application of ML methods resulted in improved diagnostic and prognostic performance of US highlighting the potential clinical utility of this approach.


HDAC6: a key regulator of cytoskeleton, cell migration and cell-cell interactions.
Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that regulates many important biological processes, including cell migration, immune synapse formation, viral infection, and the degradation of misfolded proteins. HDAC6 deacetylates tubulin, Hsp90 and cortactin, and forms complexes with other partner proteins. Although HDAC6 enzymatic activity seems to be required for the regulation of cell morphology, the role of HDAC6 in lymphocyte chemotaxis is independent of its tubulin deacetylase activity. The diverse functions of HDAC6 suggest that it is a potential therapeutic target for the treatment of a range of diseases. This review examines the biological actions of HDAC6, focusing on its deacetylase activity and its potential scaffold functions in the regulation of cell migration and other key biological processes in which the cytoskeleton plays an important role.


Cardiac Involvement in Non-Hodgkin Lymphoma, an Incidental Large Atrial Mass: A Case Report.
Cardiac involvement as an initial presentation of malignant lymphoma has been a rare occurrence. We have reported a 78 year old man with complaint of abdominal pain and vomiting. In patients preoperative evaluation for surgical management of an intra-abdominal mass, a large intracardiac mass has found incidentally during the echocardiography. Pathologic biopsy of right atrial mass that has removed by open heart surgery shown: non Hodgkin-B cell lymphoma. Bone marrow biopsy was taken and was positive for lymphomatous involvement. The patient has treated by CHOP chemotherapy regiment successfully and after completion of treatment, there was complete response.


Head and neck cancer patient and family member interest in and use of E-mail to communicate with clinicians.
E-mail is actively discussed as a promising method for clinical communication, but little study of patient and family preferences regarding its use has been done. This study aimed to describe patients' and family members' interest in and use of E-mail with their surgeons and nurses after head and neck cancer surgery. Surveys were distributed to patients and family members attending postoperative clinic visits. Seventy-four patients and 35 caregivers completed the surveys. Although one in three patients expressed interest in E-mailing their clinicians, only 9.5% reported actually doing so. Symptom management and prescription refills were the most common issues addressed by E-mail. Few family members expressed any interest in using E-mail. The findings suggest that E-mail communication between patients with head and neck cancer or their family members with surgeons and nurses is not common. Interest in using E-mail tends to be stronger among patients than family members.


Conventional superficial X-ray versus Grenz ray therapy in the treatment of constitutional eczema of the hands.
Twenty-five patients with symmetrical constitutional eczema of the hands, resistant to topical treatment, took part in a double-blind trial which showed that 300 rad (3 Gy) of conventional superficial X-ray therapy was superior to 900 rad (9 Gy) of Grenz ray therapy (both given in three divided doses at 21 day intervals).


Association of time intervals in cancer screenings and older participants' characteristics, in a nationally representative sample.
Health agencies and guidelines have proposed various recommendations regarding breast and prostate cancer screening intervals for older adults. However, there is limited data about factors that could impact older individuals' adherence to these guideline-based intervals. This study emphasized the differences in screening rates between men and women undergoing screening for breast (mammogram) and prostate (prostate-specific antigen [PSA] test) cancer. It also investigated the socio-demographic and emotional factors associated with screening time intervals. This cross-sectional design study used data from the National Social Life Health and Aging Project Wave 3 (NSHAP-W3, 2015). The outcome measures were screening time intervals (PSA test or mammogram). Individuals were asked, "About how long has it been since you last had a screening?" Response categories ranged from 1 = within the past year to 5 = never. Differences in screening time intervals were evaluated and displayed by age group (PSA vs. mammogram). The association between the outcome measures and participants' characteristics was evaluated via ordinal logistic regression. There were 2320 participants included: 52% women and 48% men. They had a mean age of 66.9 years old, were mostly White (74%) and college graduates (68%). The average time interval between screenings was greater for PSA testing than mammography (mean [M] = 2.28 vs. M = 1.89, p < 0.001). The middle age groups (PSA: 60-79 and mammogram: 65-74), had significantly more frequent screenings compared to the youngest group (50-54). In contrast, older (80+) individuals did not display shorter screening time intervals compared to the youngest group. Furthermore, shorter time intervals between screenings were associated with higher household income (mammogram: odds ratio [OR] = 0.804; PSA: OR = 0.785, p < 0.05), African American descent (mammogram: OR = 0.458, p < 0.001), and higher frequency of physical activity (PSA: OR = 0.921, p = 0.030). Lastly, women who responded "yes" to skipping care due to lack of insurance reported longer periods between mammograms (OR = 1.784, p = 0.002). Findings from this real-world US population representative database highlight the role of age, income, and insurance in the timing between screenings; participants aged between 60 and 79 years old, African American women, and physically active men are more likely to pursue earlier screening. These results emphasize the importance of socioeconomic and lifestyle factors when seeking to impact screening timing.


Retinal astrocytoma.
A 41-year-old man had a 6 x 6 x 5-disk diameter amelanotic tumor in the posterior fundus. The clinical and fluorescein angiographic appearance suggested a benign retinal vascular tumor, although amelanotic choroidal melanoma and retinoblastoma were diagnostic possibilities. An incisional 48-hour radioactive phosphorus (32P) uptake test was performed and the result showed an increased uptake over the tumor mass of 100% as compared to the control quadrants. The globe was enucleated and the pathologic diagnosis was isolated astrocytic glioma of the retina with minimal, if any, malignant potential. The highly developed vascular system of the tumor probably contributed to the false-positive test result.


TSG6 Plays a Role in Improving Orbital Inflammatory Infiltration and Extracellular Matrix Accumulation in TAO Model Mice.
TSG-6 plays a wide anti-inflammatory and therapeutic role in a variety of autoimmune diseases as the key mediator of mesenchymal stem cells (MSCs). We aimed to test whether TSG-6 could exert similar effects as MSCS in TAO via establishing TAO animal model immunized by hTSHR-A subunit plasmid. We tested the expression level of TSG-6 on intraconal orbital fat from controls and patients with TAO. We established a stable thyroid-associated ophthalmopathy animal model by immunizing 6-week-old female Balb/c mice with recombination hTSHR-A subunit plasmid. After four immunizations, TSG-6 or dexamethasone was injected through the tail vein. The effects of the drugs on body weight, thyroid function, orbital inflammation, fibrosis and lipogenesis were observed. The expression of TSG-6 in the orbital tissues of TAO patient is lower than that of normal people. In our animal model, mice showed weight loss, higher TT4 and TSHR antibody levels, and ocular symptoms such as inflammation and proptosis. TSG-6 can reduce ocular fibrosis and lipogenesis by inhibiting the infiltration of CD3+ T lymphocytes and macrophages in the mouse model of thyroid associated ophthalmopathy. Compared with dexamethasone, TSG-6 showed comparable anti-inflammatory effect, moreover, it has given a better performance in inhibiting adipogenesis. It was demonstrated that TSG-6 has a considerable positive impact on improving eye symptoms of TAO mice, which could be a novel candidate for the early treatment of TAO.


Subzero water transport characteristics of boar spermatozoa confirm observed optimal cooling rates.
Incomplete understanding of the water transport parameters (reference membrane permeability, L(pg), and activation energy, E(Lp)) during freezing in the presence of extracellular ice and cryoprotective agents (CPAs) is one of the main limiting factors in reconciling the difference between the numerically predicted value and the experimentally determined optimal rates of freezing in boar (and in general mammalian) gametes. In the present study, a shape-independent differential scanning calorimeter (DSC) technique was used to measure the water transport during freezing of boar spermatozoa. Water transport data during freezing of boar sperm cell suspensions were obtained at cooling rates of 5 and 20 degrees C/min in the presence of extracellular ice and 6% (v/v) glycerol. Using previously published values, the boar sperm cell was modeled as a cylinder of length 80.1 microm and a radius of 0.31 microm with an osmotically inactive cell volume, V(b), of 0.6 V(o), where V(o) is the isotonic cell volume. By fitting a model of water transport to the experimentally obtained data, the best-fit water transport parameters (L(pg) and E(Lp)) were determined. The "combined-best-fit" parameters at 5 and 20 degrees C/min for boar spermatozoa in the presence of extracellular ice are: L(pg) = 3.6 x 10(-15) m(3)/N. s (0.02 microm/min-atm) and E(Lp) = 122.5 kJ/mole (29.3 kcal/mole) (R(2) = 0.99); and the corresponding parameters in the presence of extracellular ice and glycerol are: L(pg)[cpa] = 0.90 x 10(-15) m(3)/N. s (0.005 microm/min-atm) and E(Lp)[cpa] = 75.7 kJ/mole (18.1 kcal/mole) (R(2) = 0.99). The water transport parameters obtained in the present study are significantly different from previously published parameters for boar and other mammalian spermatozoa obtained at suprazero temperatures and at subzero temperatures in the absence of extracellular ice. The theoretically predicted optimal rates of freezing using the new parameters ( approximately 30 degrees C/min) are in close agreement with previously published but experimentally determined optimal cooling rates. This analysis reconciles a long-standing difference between theoretically predicted and experimentally determined optimal cooling rates for boar spermatozoa.


Lack of association between plasma myeloperoxidase levels and angiographic severity of coronary artery disease in patients with acute coronary syndrome.
To evaluate the association between plasma myeloperoxidase (MPO) levels and angiographic severity of coronary atherosclerotic lesions in patients with non-ST elevation acute coronary syndrome (ACS). This cross-sectional study examined high-risk ACS patients who underwent coronary angiography within 72 h of the onset of symptoms by measuring their plasma MPO levels after sheath insertion. Gensini score was used to evaluate angiographic severity of coronary artery disease. A total of 48 patients were included in the study. Median MPO levels and Gensini scores were 6.9 ng/mL (4.4-73.5 ng/mL) and 10 (0-87.5), respectively. Spearman's correlation coefficient did not show a significant association between MPO levels and Gensini scores (r (s) = 0.2; p = 0.177). There was no correlation between MPO and age, hypertension, diabetes, leukocyte count, troponin I, CK-MB ≥ 2 × ULN (upper limit of normal), TIMI risk score ≥ 4 and Gensini score in the multivariate analysis. Our findings indicate that MPO expression is not associated with anatomical severity of coronary lesions in ACS.


What is an exposure-response curve?
Exposure-response curves are among the most widely used tools of quantitative health risk assessment. However, we propose that exactly what they mean is usually left ambiguous, making it impossible to answer such fundamental questions as whether and by how much reducing exposure by a stated amount would change average population risks and distributions of individual risks. Recent concepts and computational methods from causal artificial intelligence (CAI) and machine learning (ML) can be applied to clarify what an exposure-response curve means; what other variables are held fixed (and at what levels) in estimating it; and how much inter-individual variability there is around population average exposure-response curves. These advances in conceptual clarity and practical computational methods not only enable epidemiologists and risk analysis practitioners to better quantify population and individual exposure-response curves but also challenge them to specify exactly what exposure-response relationships they seek to quantify and communicate to risk managers and how to use the resulting information to improve risk management decisions.


MRI lesions masked by brain development: a case of infant-onset focal epilepsy.
A 3-month-old male presented with right-side-dominant focal seizures. Focal spikes were observed on the left side of an electroencephalogram obtained at the time of onset. The immature development in the left middle temporal lobe was observed by initial magnetic resonance imaging (MRI). The hypoperfusion in the left temporal lobe observed with single-photon computed tomography was consistent with MRI findings. These MRI findings were not observed in a second MRI at 11 months of age. This observation may explain one of the causes of infant-onset focal epilepsy.


Consequences of regional inotropic stimulation of ischemic myocardium on regional myocardial blood flow and function in anesthetized swine.
Determination of the effect of inotropic stimulation on regionally ischemic and hypokinetic myocardium is complicated when intravenous administration of the inotropic agent also causes stimulation of nonischemic adjacent and distant regions, thereby altering global ventricular hemodynamics. To obviate such events, 16 anesthetized swine were studied during regional inotropic stimulation by infusion of dobutamine hydrochloride (2.5 +/- 1 microgram/min) into the cannulated left anterior descending coronary artery. Coronary inflow was controlled by a pump in an extracorporeal circuit. Two groups of swine with different degrees of ischemia were studied. In the first group of animals (n = 8), reduction in coronary inflow to produce a fall in coronary artery pressure (CAP) from 114 +/- 7 mm Hg to 62 +/- 2 mm Hg caused a decrease in percent systolic wall thickening (%WTh) from 34.6 +/- 8.1% to 25.4 +/- 5.8% (p less than 0.005). In the second group of animals (n = 8), CAP was decreased to 46 +/- 5 mm Hg (control: 115 +/- 8 mm Hg) and % WTh decreased from 34.1 +/- 16.4% to 10.4 +/- 6.9% (p less than 0.001). Subendocardial blood flow was reduced from 1.41 +/- 0.38 ml/min/g to 0.65 +/- 0.13 ml/min/g (group 1, p less than 0.001) and from 1.08 +/- 0.22 ml/min/g to 0.24 +/- 0.08 ml/min/g (group 2, p less than 0.001). Regional infusion of dobutamine caused asynchronous ventricular contraction with early systolic augmentation in wall thickening followed by late systolic thinning. Therefore, during hypoperfusion regional myocardial function assessed by %WTh remained unchanged (26.2 +/- 5.8%, p = NS) in group 1 and decreased significantly to 1.6 +/- 5.1% (p less than 0.041) in group 2. Subendocardial blood flow decreased to 0.44 +/- 0.15 ml/min/g in group 1 (p less than 0.005) and to 0.15 +/- 0.07 ml/min/g in group 2 (p less than 0.012). To account for the augmented early systolic thickening that occurred during asynchronous contraction, a myocardial work index was developed in which the sum of the instantaneous left ventricular pressure-wall thickness product was calculated for estimation of regional myocardial work. Increases in this work index were apparent with the addition of dobutamine at both levels of hypoperfusion. This significant enhancement in regional myocardial function in group 2 caused a significant increase of 16% (p less than 0.009) in overall left ventricular power during ejection. Thus, regional inotropic stimulation with dobutamine caused enhancement of maximum work of the ischemic myocardium in the steady state despite a further decrease in subendocardial blood flow.


[Assessment of patient satisfaction in geriatric hospitals: a methodological pilot study].
The assessment of patient satisfaction using mailed questionnaires is an established method of quality management in acute care hospitals in our health care system. The needs of aged patients and the inter-professional approach of geriatric medicine are, however, not taken into account by such surveys. To date, validated German instruments to assess patient opinions in geriatric in-hospital care are rare. We report the results of a multi-center feasibility study of a questionnaire developed especially for such needs. We examined 1918 patients with a median age of 82 years and a mean Mini- Mental Score (MMS) of 25 points in 3 Swiss geriatric hospitals. We examined the results of all completed written questionnaires for their psychometric properties. In parallel, we assessed the satisfaction of the patient's spouses or family members applying the same instrument. The return rate was 32% when the instrument was applied as a questionnaire and 60% when applied as an interview. In questionnaires, the return rate was dependent on cognition with lower return in patients with low MMS scores. The return rate of questionnaires mailed to family members was 35%. The theoretical construct patient satisfaction was reliable and valid. The Cronbach-Alpha values in different item areas ranked between 0.67 (hotel services, room quality) and 0.92 (physicians). We were not able to assess the quality of medical therapies and of pain treatment due to low answer frequencies. Overall, patients were satisfied with all medical services in the participating hospitals. In contrast, satisfaction was low in family members regarding the quality of information flow between family members and physicians or nurses. An instrument to assess patient opinions can easily be introduced into a geriatric hospital. Such an instrument can provide important information for the improvement of quality in different areas of geriatric care such as medical, nursing care or guest services.


Cloning of a chromosomal locus (exp) which regulates the expression of several exoprotein genes in Staphylococcus aureus.
Insertion of the erythromycin resistance transposon Tn551 into a single site of the Staphylococcus aureus chromosome resulted in decreased production of alpha-toxin, serine and metallo-proteinases and several other extracellular proteins and a simultaneous increase in the production of protein A. The site of insertion, designated exp, was separate from the structural gene for alpha-toxin and protein A. Hybridization analysis showed that the effect of the insertional mutation on the expression of the alpha-toxin and protein A was at the level of transcription. The chromosomal DNA flanking the transposon and the corresponding DNA of the wild-type strain was cloned in Escherichia coli. Northern blot hybridization experiments revealed that the exp locus codes for a major RNA of approximately 3.5 kb. This RNA was not found in the insertional mutant nor in a spontaneous exp mutant. A map of the exp locus constructed by Northern blot and restriction enzyme analysis showed that the insertional mutation was located in the middle of the coding sequence of the 3.5 kb RNA. The insertional mutant was reverted to wild type by inserting a recombinant plasmid containing most of the coding sequence of the 3.5 kb RNA.


[Polyfunctional role of the alveolar brush cells in the rat lung].
By means of scanning and transmission electron microscopy it was demonstrated that the number of vacuoles located in the apical part of cytoplasm in alveolar brush cells of the regenerating rat lung increases, hyperplasia of Golgi-complex takes place and the activation of the protein-synthetising apparatus is evident. The immature surfactant material (osmiophilic lamellar bodies) and secretory dense core vesicles were found in the cytoplasm of alveolar brush cells. Intramuscular injections of colchicin to rats (0.1 mg/100 g body weight) 6 times during 24 hours before decapitation does not influence the number, topography and structure of microfibrilla bundles contained in a sufficient amount by alveolar brush cells. At the same time a part of microvilli of alveolar brush cells undergoes destruction and resorption under the action of colchicin. The data on ultrastructural organization of alveolar brush cells show that they are able to fulfill several functions: absorptive, contractile and secretory.


Phylogenetic analysis of two genotype 3 Hepatitis E viruses from wild boar, Italy.
The complete and near-complete genome sequences (7206 nt and 7229 nt) of two wild boar HEV strains detected in Southern Italy were obtained by the next generation sequencing. Phylogenetic analysis and p distance comparisons of one of the strains with HEV-3 reference subtype strains confirmed the detection of a subtype 3i (p distance = 0.110) strain in wild boar, never detected in Italy either in wild boar or pigs. The sequence of the second strain was not classifiable in any of the subtypes defined to date, showing a p distance > 0.138 and a low nucleotide identity with all HEV reference strains. The virus may represent a novel subtype, with a low relationship to other strains of genotype 3 detected in wild boar, pigs, or humans in Europe. This result suggests the circulation in Italy of an emerging or uncommon HEV strain. Sequencing followed by phylogenetic analyses of the complete HEV coding regions are important tools for understanding the evolutionary and epidemiological dynamics underlying the wide genetic diversity of HEV strains.


Application of standard addition for the determination of carboxypeptidase activity in Actinomucor elegans bran koji.
Leucine carboxypeptidase (EC 3.4.16) activity in Actinomucor elegans bran koji was investigated via absorbance at 507 nm after stained by Cd-nihydrin solution, with calibration curve A, which was made by a set of known concentration standard leucine, calibration B, which was made by three sets of known concentration standard leucine solutions with the addition of three concentrations inactive crude enzyme extract, and calibration C, which was made by three sets of known concentration standard leucine solutions with the addition of three concentrations crude enzyme extract. The results indicated that application of pure amino acid standard curve was not a suitable way to determine carboxypeptidase in complicate mixture, and it probably led to overestimated carboxypeptidase activity. It was found that addition of crude exact into pure amino acid standard curve had a significant difference from pure amino acid standard curve method (p < 0.05). There was no significant enzyme activity difference (p > 0.05) between addition of active crude exact and addition of inactive crude kind, when the proper dilute multiple was used. It was concluded that the addition of crude enzyme extract to the calibration was needed to eliminate the interference of free amino acids and related compounds presented in crude enzyme extract.


Proteolysis: anytime, any place, anywhere?
Proteolysis via the ubiquitin-proteasome system (UPS) is a rapid and effective method of degrading a specific protein at a specific time, and in many cases a protein is degraded only in response to a particular cellular signal or event. However, an added dimension to the control of protein degradation is possible because the ubiquitin system can be spatially regulated. Controlling where a protein is degraded can enhance the specificity and timing of proteolysis, generate asymmetry and maintain sub-compartments even in the mitotic cell. Here, we discuss this aspect of the UPS.


Draft genome sequence of Fusicladium effusum, cause of pecan scab.
Pecan scab, caused by the plant pathogenic fungus Fusicladium effusum, is the most destructive disease of pecan, an important specialty crop cultivated in several regions of the world. Only a few members of the family Venturiaceae (in which the pathogen resides) have been reported sequenced. We report the first draft genome sequence (40.6 Mb) of an isolate F. effusum collected from a pecan tree (cv. Desirable) in central Georgia, in the US. The genome sequence described will be a useful resource for research of the biology and ecology of the pathogen, coevolution with the pecan host, characterization of genes of interest, and development of markers for studies of genetic diversity, genotyping and phylogenetic analysis. The annotation of the genome is described and a phylogenetic analysis is presented.


Total plasma heme concentration increases after red blood cell transfusion and predicts mortality in critically ill medical patients.
Relationships between red blood cell (RBC) transfusion, circulating cell-free heme, and clinical outcomes in critically ill transfusion recipients are incompletely understood. The goal of this study was to determine whether total plasma heme increases after RBC transfusion and predicts mortality in critically ill patients. This was a prospective cohort study of 111 consecutive medical intensive care patients requiring RBC transfusion. Cell-free heme was measured in RBC units before transfusion and in the patients' plasma before and after transfusion. Total plasma heme levels increased in response to transfusion, from a median (interquartile range [IQR]) of 35 (26-76) μmol/L to 47 (35-73) μmol/L (p < 0.001). Posttransfusion total plasma heme was higher in nonsurvivors (54 [35-136] μmol/L) versus survivors (44 [31-65] μmol/L, p = 0.03). Posttransfusion total plasma heme predicted hospital mortality (odds ratio [95% confidence interval] per quartile increase in posttransfusion plasma heme, 1.76 [1.17-2.66]; p = 0.007). Posttransfusion total plasma heme was not correlated with RBC unit storage duration and weakly correlated with RBC unit cell-free heme concentration. Total plasma heme concentration increases in critically ill patients after RBC transfusion and is independently associated with mortality. This transfusion-associated increase in total plasma heme is not fully explained by RBC unit storage age or cell-free heme content. Additional studies are warranted to define mechanisms of transfusion-related plasma heme accumulation and test prevention strategies.


High-throughput quantitation of serological dimethylarginines by LC/MS/MS: Potential cardiovascular biomarkers for rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by systemic inflammation of the joints and extra-articular tissues. The incidence of cardiovascular disease (CVD) remains the main cause of morbidity and mortality in patients with RA. Despite the development of new therapeutics targeting the articular manifestations, the relief of the cardiovascular burden is still an unmet medical need during the management of RA. So, the early prognosis of RA-associated CVD plays a crucial role in improving the clinical outcomes of RA patients. Recently, circulating dimethylarginines have gained attention as potential biomarkers for CVDs. Here, we present the development and validation of a high-throughput liquid chromatography-tandem mass spectrometric (LC/MS/MS) method for simultaneous quantification of creatinine, arginine, and dimethylarginines in human serum within 2 mins by isotope dilution mass spectrometry. This method employed a protein precipitation method for rapid sample preparation, trichloroacetic acid (TCA)-based ion pairing chromatography for fast analyte separation, and multiple reaction monitoring (MRM) with stable isotope-labeled internal standards (ISs) for simultaneous quantitation. To assure the quality, our method was validated against the FDA guidelines for lower limit of quantitation (0.2 µM), linearity (square of coefficient correlation>0.99), precision (intra-&inter-assay imprecision < 10 %), accuracy (intra-&inter-assay inaccuracy < 10 %), sample preparation recovery (recovery ≥ 90 %), stability (instability < 10 %), matrix effect (signal suppression < 55 %), and carryover ( < 0.01 %). Afterward, we applied the validated method to a retrospective cross-sectional study. We aimed to evaluate the utility of serological dimethylarginines as potential cardiovascular biomarkers in the development of RA-associated CVD. Our results revealed that the serological ratio of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), an indicator of physiological arginine methylation status, was significantly elevated in patients with RA. This finding might provide value in detecting CVD to improve clinical outcomes in RA management.


Do infants of depressed mothers cry more than other infants?
This study compared the crying behaviour of infants of depressed and non-depressed mothers at 3 and 6 months of age. Twenty-nine depressed and 44 non-depressed mothers, their infants and partners participated in this study. Mothers were asked to complete 24-hour diaries of the amount their infants cried for 1 week. The diurnal variations in crying patterns of infants of depressed and non-depressed mothers were not significantly different. However, infants of depressed mothers were found to cry significantly more in total per day than infants of non-depressed mothers at 3 months of age, but not at 6 months. The results could not be explained by differences in infant temperament. Maternal depression may be a contributory factor to infant crying at 3 months of age.


Effect of pulse duration on selective ablation of atherosclerotic plaque by 480- to 490-nanometer laser radiation.
The effect of varying pulse duration on selective ablation of human arterial plaque was evaluated by measuring ablation thresholds and ablation efficiencies on fresh human fibrofatty plaque, calcified plaque, normal intima, deep media, and adventitia using 480- to 490-nm laser radiation at 1, 8, and 50-microseconds pulse durations. For all tissues examined, the ablation threshold energy increased with increasing pulse duration, but the threshold for normal tissue ablation was approximately twice that of plaque at all pulse durations. Ablation efficiency was studied at a fluence that was twice the ablation threshold for plaque. For those fluences, normal intima had detectable ablation only at 50 microseconds. The ablation efficiency of fibrofatty plaque was minimally reduced with prolongation of pulse duration; however, there was a substantial decrease in the ablation efficiency of calcified plaque when the pulse duration was lengthened from 8 to 50 microseconds. These data show significant selective ablation of fibrofatty and calcified plaque at 1, 8, and 50 microseconds and suggest that the optimal pulse width for selective ablation of all plaque in the 480- to 490-waveband is less than 50 microseconds.


Transient global amnesia as a manifestation of Epstein-Barr virus encephalitis.
A 43-year-old man developed severe global amnesia with uncinate fits and a single generalised convulsion 10 days after a febrile infection. CSF pleocytosis and serological findings indicated an acute Epstein-Barr virus encephalitis. All of the symptoms cleared within 2 weeks except for occasional generalised seizures. This seems to be the first observation of Epstein-Barr virus encephalitis presenting predominantly as transient global amnesia.


Protein control of membrane and organelle dynamics: Insights from the divergent eukaryote Toxoplasma gondii.
Integral membrane protein complexes control key cellular functions in eukaryotes by defining membrane-bound spaces within organelles and mediating inter-organelles contacts. Despite the critical role of membrane complexes in cell biology, most of our knowledge is from a handful of model systems, primarily yeast and mammals, while a full functional and evolutionary understanding remains incomplete without the perspective from a broad range of divergent organisms. Apicomplexan parasites are single-cell eukaryotes whose survival depends on organelle compartmentalisation and communication. Studies of a model apicomplexan, Toxoplasma gondii, reveal unexpected divergence in the composition and function of complexes previously considered broadly conserved, such as the mitochondrial ATP synthase and the tethers mediating ER-mitochondria membrane contact sites. Thus, Toxoplasma joins the repertoire of divergent model eukaryotes whose research completes our understanding of fundamental cell biology.


Substitution of isoleucine for methionine at position 1153 in the beta-subunit of the human insulin receptor. A mutation that impairs receptor tyrosine kinase activity, receptor endocytosis, and insulin action.
The intracellular domain of the insulin receptor possesses activity as a tyrosine-specific protein kinase. The receptor tyrosine kinase is stimulated by insulin binding to the extracellular domain of the receptor. Previously, we have identified a patient with a genetic form of insulin resistance who is heterozygous for a mutation substituting Ile for Met1153 in the tyrosine kinase domain of the receptor near the cluster of the three major autophosphorylation sites (Tyr1158, Tyr1162, and Tyr1163). In this investigation, the Ile1153 mutant receptor was expressed by transfection of mutant cDNA into NIH-3T3 cells. The mutation impairs receptor tyrosine kinase activity and also inhibits the ability of insulin to stimulate 2-deoxyglucose uptake and thymidine incorporation. These data support the hypothesis that the receptor tyrosine activity plays a necessary role in the ability of the receptor to mediate insulin action in vivo. Furthermore, expression of the Ile1153 mutant receptor exerted a dominant negative effect to inhibit the ability of endogenous murine receptors for insulin and insulin-like growth factor I to mediate their actions upon the cell. This observation is consistent with previous suggestions that mutant receptors dimerize with wild type receptors, thereby creating hybrid molecules which lack biological activity. The dominant negative effect of the mutant receptor may explain the dominant mode of inheritance of insulin resistance caused by the Ile1153 mutation. Finally, the mutation inhibits the ability of insulin to stimulate receptor endocytosis. This may explain the normal number of insulin receptors on the surface of the patient's cells in vivo. Despite the presence of markedly elevated levels of insulin in the patient's plasma, the receptors were resistant to down-regulation.


Hyperglycemia with occipital seizures: images and visual evoked potentials.
Hyperglycemia may rarely be seen with visual seizures. Observation of both visual evoked potentials (VEPs) and magnetic resonance imaging (MRI) in visual status epilepticus (SE) has not been reported. We describe acute and follow-up VEP and MRI findings of a patient with hyperglycemia-related visual SE of occipital origin. In a 59-year-old diabetic woman, complex visual hallucinations and illusions developed with < or =10 seizures per hour as an initial manifestation of nonketotic hyperglycemia. Neurologic examination revealed ictal nystagmus to the right and continuous right hemianopsia. Ictal electroencephalography (EEG) and Tc-99m hexamethylpropylene amine oxime (HMPAO) single-photon emission computed tomography (SPECT) revealed an epileptogenic focus in the left occipital lobe. MRI with fluid-attenuated inversion recovery showed focal subcortical hypointensity and gyral hyperintensity. Follow-up MRI showed only minimal gyral hyperintensity at 6 months. The P100 amplitude of VEP was significantly higher at the right occipital area during SE, but slightly higher on the left after the patient had been seizure free for 6 months. Occipital seizures and hemianopsia can be caused by hyperglycemia and may be accompanied by special MRI and VEP findings.


Professional Relevance of the Learning Curve: Developing an "A" Team.
The term "learning curve" is common professional vernacular for describing a period of profound and intensive learning. Learning can actually be impeded when the curve is consistently on a steep vertical incline. Viewing the learning curve as an "S" instead of a steep bar offers a professional development perspective, as well as a team development perspective, that supports progression and helps to balance team strength. [J Contin Educ Nurs. 2020;51(7):300-301].


Disseminated enteropathy-type T-cell lymphoma: cauda equina syndrome complicating coeliac disease.
A patient with coeliac disease developed a progressive cauda equina syndrome in the 2 months prior to his death, for which no cause could be identified. At post-mortem examination this proved to be due to disseminated enteropathy-type T-cell lymphoma. Although rare, disseminated enteropathy-type T-cell lymphoma should enter the differential diagnosis in any patient with coeliac disease developing new neurological signs.