Short to mid-term outcome of total hip arthroplasty with cementless implants in patients younger than 25 years old.
Total hip arthroplasty (THA) was once reserved for old patients with hip arthritis but has become more common in very young patients (≤25 years old) diagnosed with various joint disease that were not relieved with conservative treatment. The purpose of this study was to evaluate short to mid-term outcome of THA in patients younger than 25 years old. This retrospective study included 45 patients younger than 25 years (mean age 21.8 ± 2.14 years) who underwent THA. The surgical indications, implant selection, leg length discrepancy, medication history, radiographic outcome, survival and clinical results including the modified Harris hip score (mHHS) and SF-36 score were assessed. The mean follow-up period recorded for patients was 7.82 years (range 5-12 years). The most common diagnosis was avascular necrosis (37.7%) followed by ankylosing spondylitis (24.4%), developmental dysplasia of the hip (17.7%) and rheumatoid arthritis (8.8%). The preoperative leg length discrepancy (LLD), which ranged from 0.5-7 cm significantly improved after surgery ranging from 0-1 cm. The mean preoperative mHHS was 32.44 ± 18.90 compared with the postoperative score of 94.54 ± 5.81 (p < 0.001). The preoperative p-value of SF-36 was lower compared to the postoperative value in all subgroups of SF-36 (p < 0.001). At the latest follow-up there were no radiological signs of loosening and all the implants were classified as well-integrated. At present total hip arthroplasty is considered to be safe and a good solution for young patients below 25 years suffering from end-stage joint disease; however, longer follow-up is required to evaluate the long-term function and outcome of the prosthesis in order to restore the normal lifestyle of the patients.


The pharmacokinetics of subcutaneous dihydroergotamine with and without a dextran 70 infusion.
The pharmacokinetics of subcutaneous dihydroergotamine (DHE) with or without dextran 70 infusion was evaluated in a single- and multiple-dose study in 30 patients. Radioimmunoassay was used to measure plasma DHE and the anthrone method to determine the dextran concentration. In the single-dose study no significant interaction between DHE and dextran was noted with respect to their plasma levels. The absorption of s.c. DHE was rapid and the disappearance curve followed a biphasic pattern, t0.5 alpha being 1.4 and 2.0 h, t0.5 beta 22 and 21 h for DHE and DHE/dextran 70, respectively. In the multi-dose study the trough level of DHE initially had a tendency to rise, in accordance with simulated plasma concentration curves. DHE trough levels were about 0.5 ng/ml and were well above the assumed minimum effective value to induce venoconstriction (0.06 ng/ml). Dextran concentrations were significantly higher when DHE was co-administered, possibly, due to changes in plasma volume. It is concluded that DHE 0.5 mg s.c. twice daily will give an adequate plasma concentration and that there was no important interaction between it and infused dextran 70.


Radiation Modality (Proton/Photon), Timing, and Complication Rates in Patients With Breast Cancer Receiving 2-Stages Expander/Implant Reconstruction.
Our purpose is to explore the effect of postmastectomy radiation therapy (PMRT) modality and timing on complication rates in breast cancer patients receiving immediate 2-stages expander/implant. We reviewed the charts of 661 patients who underwent immediate 2-stages expander/implant with/without PMRT at our institution from 2000 to 2019. Patients were divided into 3 cohorts: no radiation, PMRT to expanders (RTE), and PMRT to implants after expander exchange (RTI). PMRT was delivered either with 3-dimensional conformal photon with or without chest wall boost (CWB) or proton therapy. Reconstruction complications were defined as infection/necrosis requiring debridement, capsular-contracture requiring capsulotomy, and reconstruction failure requiring prothesis removal. Logistic regression and Cox models were used to assess the effect of different radiation therapy modalities on complication rates and local control. Among 661 patients, 309 (46.7%) received PMRT, 220 of the 309 (71.2%) received RTE before exchange, and 89 (28.8%) received RTI after exchange. Seventeen out of 309 (5.5%) patients received proton therapy. The complications among RTE versus RTI cohorts were 22.7% versus 15.7% for infection/necrosis, 13.6% versus 19.1% for capsular-contracture, and 39.5% versus 31.5% for overall reconstruction failure, respectively. Among proton patients, 8/17 (47%) developed capsular contracture compared with 16.4% (24/146) and 10.3% (15/146) in CWB and non-CWB groups, respectively. Adjusted multivariable analysis showed no significant difference between RTI and RTE in terms of infection/necrosis and capsular contracture. Yet, RTE significantly increased overall reconstruction failure compared with RTI (39.5% vs 31.5%; odds ratio [OR], 2.11; P = .02). Protons significantly increased capsular contracture compared with both CWB and non-CWB groups (OR, 5.4; P = .01 and OR, 10.9; P < .001, respectively). Moreover, proton significantly increased overall reconstruction failure. The 5-year local control rates were 95.3% and 97.7% for RTE and RTI, respectively (hazard ratio, 1.2; P = .7). Early radiation to the expander before the exchange to implant significantly increased overall reconstruction failure without improving local control. Protons significantly increased capsular contracture rates and overall reconstruction failure leading to more revision surgeries.


Sulfate-binding protein, CysP, is a candidate vaccine antigen of Moraxella catarrhalis.
Moraxella catarrhalis causes otitis media in children and respiratory tract infections in adults with chronic obstructive pulmonary disease (COPD). A vaccine to prevent M. catarrhalis infections would have an enormous impact globally in preventing morbidity caused by M. catarrhalis in these populations. Using a genome mining approach we have identified a sulfate binding protein, CysP, of an ATP binding cassette (ABC) transporter system as a novel candidate vaccine antigen. CysP expresses epitopes on the bacterial surface and is highly conserved among strains. Immunization with CysP induces potentially protective immune responses in a murine pulmonary clearance model. In view of these features that indicate CysP is a promising vaccine antigen, we conducted further studies to elucidate its function. These studies demonstrated that CysP binds sulfate and thiosulfate ions, plays a nutritional role for the organism and functions in intracellular survival of M. catarrhalis in human respiratory epithelial cells. The observations that CysP has features of a vaccine antigen and also plays an important role in growth and survival of the organism indicate that CysP is an excellent candidate vaccine antigen to prevent M. catarrhalis otitis media and infections in adults with COPD.


Oral beclomethasone dipropionate in patients with mild to moderate ulcerative colitis: a dose-finding study.
Systemic glucocorticosteroids have demonstrated efficacy in ulcerative colitis (UC) but cause undesired systemic side effects. Beclomethasone dipropionate (BDP) has potent topical activity and is extensively metabolized. This randomized double-blind study investigated an oral gastroresistant controlled-release preparation of BDP in 57 patients with mild to moderately severe extensive or left-sided UC. Patients were assigned to receive BDP 5 or 10 mg/d; a third group took a clinically inactive dose (1.6 g/d) of 5-aminosalicylic acid (5-ASA). Both BDP doses displayed excellent efficacy confirmed by results of endoscopy, biopsy, and clinical evaluation. Significant improvement from baseline occurred in most signs and symptoms of UC, particularly stool frequency, rectal bleeding, and mucus in the stool (P<.01). Tolerability was good in both BDP groups. Morning plasma cortisol levels decreased significantly from baseline with BDP 10 mg, but no significant changes in vital signs were observed at the end of treatment. Despite a small sample size and the open comparison with 5-ASA, this multicenter study showed the therapeutic equivalence of BDP 5 and 10 mg/d in alleviating clinical symptoms and improving endoscopic and biopsy scores in patients with mild to moderate UC. BDP 5 mg/d displayed better general tolerability and less reduction of plasma cortisol levels, however, and may be preferable to the higher dose in this indication.


Communication and engagement of community members from ethnic minorities during COVID-19: a scoping review.
This review examined the factors influencing communication and engagement with ethnic and racial minority groups in Australia during the COVID-19 pandemic. It aimed to answer two main questions: (1) what communication problems people from these communities typically faced during the pandemic? and (2) what strategies and recommendations were suggested to enhance communication and engagement for ethnic and racial minorities during the current COVID-19 pandemic and any similar events in the future? Scoping review. PubMed, EMBASE, Cochrane Library, PsychINFO and CINAHL. Grey literature was searched within organisations' websites and a Google search of key terms. We included original research, case studies, reports (including government and charity reports), systematic and scoping articles and literature reviews in English, published from January 2020 to August 2022. Two researchers independently assessed the literature for eligibility and extracted data from the included literature. The selected papers were analysed and summarised into themes relevant to the research questions. The final review included 38 studies combining published academic papers and grey literature. Key themes relating to communication and engagement issues included a lack of trust in authority, a lack of access to information and ineffective communication channels and a lack of timely and culturally responsive materials. To reduce the issues, the papers spoke about the key role of community organisations to provide local support and community leaders as trusted spokespersons. Lastly, key recommendations to reduce inequity and strengthen future pandemic responses focused on the need for collaborations and consultations, increasing the number of bilingual workers and supporting community-led communication efforts. The insights gained from the activities and experiences documented in this review during the COVID-19 pandemic should be incorporated into future decision-making and interventions to enhance communication and engagement strategies.


Non-specific effects of vaccination on child survival? A prospective study in Senegal.
Several studies have shown an association between vaccination and child mortality in developing countries. The present paper examines this issue using data from a Senegalese rural area which has been monitored from 1983 to the present. We analysed two birth cohorts, comprising 7796 and 3573 persons who had received either BCG and DTP (diphtheria-tetanus-pertussis) simultaneously or neither of these vaccines, and who had been followed from birth to 2 years of age. The association between vaccinations and mortality was assessed by Cox proportional hazards model. Mortality ratios for recipients of the BCG/DTP combination were 0.59 (95% CI: 0.46-0.74) for the first cohort and 0.70 (0.50-0.97) for the second cohort. Mortality ratios for measles vaccine recipients were 0.98 (0.75-1.27) for the first cohort and 0.87 (0.57-1.30) for the second cohort. The BCG/DTP combination was associated with a reduction in mortality whereas measles vaccination was not associated with mortality.


Mutation testing with hyperproperties.
We present a new method for model-based mutation-driven test case generation. Mutants are generated by making small syntactical modifications to the model or source code of the system under test. A test case kills a mutant if the behavior of the mutant deviates from the original system when running the test. In this work, we use hyperproperties-which allow to express relations between multiple executions-to formalize different notions of killing for both deterministic as well as non-deterministic models. The resulting hyperproperties are universal in the sense that they apply to arbitrary reactive models and mutants. Moreover, an off-the-shelf model checking tool for hyperproperties can be used to generate test cases. Furthermore, we propose solutions to overcome the limitations of current model checking tools via a model transformation and a bounded SMT encoding. We evaluate our approach on a number of models expressed in two different modeling languages by generating tests using a state-of-the-art mutation testing tool.


Mycorrhiza of the host-specific Lactarius deterrimus on the roots of Picea abies and Arctostaphylos uva-ursi.
The ectomycorrhizal basidiomycete species Lactarius deterrimus Gröger is considered to be a strictly host-specific mycobiont of Picea abies (L.) Karst. However, we identified arbutoid mycorrhiza formed by this fungus on the roots of Arctostaphylos uva-ursi (L.) Spreng. in a mixed stand at the alpine timberline; typical ectomycorrhiza of P. abies were found in close relation. A. uva-ursi is known as an extremely unspecific phytobiont. The mycorrhizae of both associations are described and compared morphologically. The mycorrhiza formed by L. deterrimus on both A. uva-ursi and P. abies show typical ectomycorrhizal features such as a hyphal mantle and a Hartig net. The main difference between the mycorrhizal symbioses with the different phytobionts is the occurrence of intracellular hyphae in the epidermal cells of A. uva-ursi. This emphasizes the importance of the plant partner for mycorrhizal anatomy. This is the first report of a previously considered host-specific ectomycorrhizal fungus in association with A. uva-ursi under natural conditions. The advantages of this loose specificity between the fungus and plant species is discussed.


LncRNA ACART protects cardiomyocytes from apoptosis by activating PPAR-γ/Bcl-2 pathway.
Cardiomyocyte apoptosis is an important process occurred during cardiac ischaemia-reperfusion injury. Long non-coding RNAs (lncRNA) participate in the regulation of various cardiac diseases including ischaemic reperfusion (I/R) injury. In this study, we explored the potential role of lncRNA ACART (anti-cardiomyocyte apoptosis-related transcript) in cardiomyocyte injury and the underlying mechanism for the first time. We found that ACART was significantly down-regulated in cardiac tissue of mice subjected to I/R injury or cultured cardiomyocytes treated with hydrogen peroxide (H2 O2 ). Knockdown of ACART led to significant cardiomyocyte injury as indicated by reduced cell viability and increased apoptosis. In contrast, overexpression of ACART enhanced cell viability and reduced apoptosis of cardiomyocytes treated with H2 O2 . Meanwhile, ACART increased the expression of the B cell lymphoma 2 (Bcl-2) and suppressed the expression of Bcl-2-associated X (Bax) and cytochrome-C (Cyt-C). In addition, PPAR-γ was up-regulated by ACART and inhibition of PPAR-γ abolished the regulatory effects of ACART on cell apoptosis and the expression of Bcl-2, Bax and Cyt-C under H2 O2 treatment. However, the activation of PPAR-γ reversed the effects of ACART inhibition. The results demonstrate that ACART protects cardiomyocyte injury through modulating the expression of Bcl-2, Bax and Cyt-C, which is mediated by PPAR-γ activation. These findings provide a new understanding of the role of lncRNA ACART in regulation of cardiac I/R injury.


The BH3 mimetic HA14-1 enhances 5-fluorouracil-induced autophagy and type II cell death in oesophageal cancer cells.
Resistance to chemotherapeutic agents has been associated with a failure of cancer cells to induce apoptosis. Strategies to restore apoptosis have led to the development of BH3 mimetics, which inhibit anti-apoptotic Bcl-2 family members. We examined the sensitivity of three oesophageal cancer cell lines to 5-fluorouracil (5-FU) alone and in combination with the BH3 mimetic HA14-1. Clonogenic assays, morphology, markers of autophagy and apoptosis were used to assess the involved death mechanisms. In response to 5-FU treatment, OE21 cells induce apoptosis, KYSE450 and KYSE70 cells are more resistant and induce autophagy accompanied by type II cell death. Autophagy induction results in ineffective treatment as substantial numbers of cells survive and re-populate. HA14-1 did not improve 5-FU treatment or reduce colony re-growth in the apoptosis deficient KYSE70 cells. However, the sensitivity of OE21 (apoptotic) and KYSE450 cells (apoptosis deficient/type II cell death) was significantly improved. In OE21 cells, treatment with 5-FU and HA14-1 resulted in augmentation of apoptosis. In KYSE450 cells, the reduction in recovering colonies following combination treatment was due to the enhancement of type II cell death. The efficacy of HA14-1 is cell line dependent and is not reliant on apoptosis induction.


KiSS1 gene as a novel mediator of TGFβ-mediated cell invasion in triple negative breast cancer.
The invasive and metastatic phenotypes of breast cancer correlate with high recurrence rates and poor survival outcomes. Transforming growth factor-β (TGFβ) promotes tumor progression and metastasis in aggressive breast cancer. Here, we identified the kisspeptin KiSS1 as a downstream target of canonical TGFβ/Smad2 pathway in triple negative breast cancer cells. We also found KiSS1 expression to be required for TGFβ-induced cancer cell invasion. Indeed, knockdown expression of KiSS1 blocked TGFβ-mediated cancer cell invasion as well as metalloproteinase (MMP9) expression and activity. Interestingly, Kisspeptin-10 (KP-10), the smallest active form of kisspeptin also stimulates cancer cell invasive behavior through activation of MAPK/Erk pathway. We described a positive feedback loop between KiSS1 and p21 downstream of TGFβ, further contributing to TGFβ-induced cancer cell invasion. Lastly, we explored both the clinical utility of KiSS1 as a lymph node involvement predictive tool and its potential as a therapeutic target. We found KiSS1 high expression to correlate with lymph node positive status. Furthermore, blocking KiSS1 using a specific small peptide antagonist (p234) impaired TGFβ-mediated cell invasion and MMP9 induction. Together, our results define an essential role of KiSS1 in regulating TGFβ pro-invasive effects and define KiSS1 as a therapeutic new target for triple negative breast cancer.


Autologous fat grafting for the treatment of sclerotic lesions and scars.
Microfat grafting is a well-known technique that is underutilized in dermatology. Instead of removing sclerotic tissue, microfat grafting preserves the tissue and uses stem cells for remodeling its structure into normal tissue. We performed a retrospective study of patients treated with microfat grafting for sclerotic and atrophic skin lesions and scars. Seventy-two microfat grafts were performed using the Magalon technique under general anaesthesia for the treatment of sclerotic and atrophic skin lesions. We performed grafts for different indications, such as scars (n=55) and sclerotic and atrophic skin lesions (n=17: Parry-Romberg syndrome, morphea). The main outcome was assessed for satisfaction during follow-up. In addition, an independent committee judged the results based on photographs. Satisfaction levels (e.g. results were judged to be "good") were almost 91% (n=50/55) for scars and 100% (n=17/17) for atrophic and sclerotic skin lesions. Satisfaction levels according to the independent committee were 94.1% for sclerotic and atrophic lesions and nearly 51% for scars. Satisfaction was high after microfat grafting for atrophic and sclerotic skin lesions. Microfat grafting enabled restoration of the skin texture by exploiting stem cell properties. It is an efficient dermatological therapy for sclerotic and atrophic lesions, for which there are few alternative treatments.


Elevated transaminases as a predictor of coma in a patient with anorexia nervosa: a case report and review of the literature.
Liver injury is a frequent complication associated with anorexia nervosa, and steatosis of the liver is thought to be the major underlying pathology. However, acute hepatic failure with transaminase levels over 1000 IU/mL and deep coma are very rare complications and the mechanism of pathogenesis is largely unknown. A 37-year-old Japanese woman showed features of acute liver failure and hepatic coma which were not associated with hypoglycemia or hyper-ammonemia. Our patient's consciousness was significantly improved with the recovery of liver function and normalization of transaminase levels after administration of nutritional support. Our case report demonstrates that transaminase levels had an inverse relationship with the consciousness of our patient, although the pathogenesis of coma remains largely unknown. This indicates that transaminase levels can be one of the key predictors of impending coma in patients with anorexia nervosa. Therefore, frequent monitoring of transaminase levels combined with rigorous treatment of the underlying nutritional deficiency and psychiatric disorder are necessary to prevent this severe complication.


Genome-wide association of implantable cardioverter-defibrillator activation with life-threatening arrhythmias.
To identify genetic factors that would be predictive of individuals who require an implantable cardioverter-defibrillator (ICD), we conducted a genome-wide association study among individuals with an ICD who experienced a life-threatening arrhythmia (LTA; cases) vs. those who did not over at least a 3-year period (controls). Most individuals that receive implantable cardioverter-defibrillators never experience a life-threatening arrhythmia. Genetic factors may help identify who is most at risk. Patients with an ICD and extended follow-up were recruited from 34 clinical sites with the goal of oversampling those who had experienced LTA, with a cumulative 607 cases and 297 controls included in the analysis. A total of 1,006 Caucasian patients were enrolled during a time period of 13 months. Arrhythmia status of 904 patients could be confirmed and their genomic data were included in the analysis. In this cohort, there were 704 males, 200 females, and the average age was 73.3 years. We genotyped DNA samples using the Illumina Human660 W Genotyping BeadChip and tested for association between genotype at common variants and the phenotype of having an LTA. We did not find any associations reaching genome-wide significance, with the strongest association at chromosome 13, rs11856574 at P = 5×10⁻⁶. Loci previously implicated in phenotypes such as QT interval (measure of the time between the start of the Q wave and the end of the T wave as measured by electrocardiogram) were not found to be significantly associated with having an LTA. Although powered to detect such associations, we did not find common genetic variants of large effect associated with having a LTA in those of European descent. This indicates that common gene variants cannot be used at this time to guide ICD risk-stratification. ClinicalTrials.gov NCT00664807.


Late onset neuromyelitis optica spectrum disorder with anti-aquaporin 4 and anti-myelin oligodendrocyte glycoprotein antibodies.
This study aimed to evaluate the clinical characteristics and prognosis of late onset (≥50 years) neuromyelitis optica spectrum disorder (LO-NMOSD), and compare them with those of early onset (<50 years) NMOSD (EO-NMOSD) and NMOSD with various antibody serostatuses. From January 2015 to December 2020, 360 anti-aquaporin 4 antibody (AQP4-ab)-positive and 130 anti-myelin oligodendrocyte glycoprotein antibody (MOG-ab)-positive patients presented to the Huashan Hospital, China. We retrospectively reviewed their medical records, including the Expanded Disability Status Scale (EDSS) score at each visit and the annualized relapse rate (ARR). Prognostic outcomes included the time to first relapse, blindness, motor dysfunction, severe motor dysfunction, and death. Correlations between the age at onset, lesion location, and clinical parameters were analyzed. This study included 122 (24.9%) patients with LO-NMOSD, 101 with AQP4-ab and 21 with MOG-ab. Compared with EO-NMOSD patients, those with LO-NMOSD had higher EDSS scores and more frequent disease onset with transverse myelitis, blindness, motor dysfunction, and severe motor dysfunction. Compared with LO-NMOSD patients with MOG-ab, those with AQP4-ab had a worse prognosis. Age at disease onset had a significantly positive correlation with EDSS score at the last follow-up of all NMOSD patients, but a negative correlation with ARR-1 (ARR excluding the first attack, calculated from disease onset to final follow-up) in NMOSD patients with AQP4-ab. Patients with LO-NMOSD, especially those with AQP4-ab, had a worse prognosis compared with patients with EO-NMOSD. Age at disease onset and antibody serostatus predicted blindness and motor dysfunction.


Changes in urinary taurine and hypotaurine excretion after two-thirds hepatectomy in the rat.
This study followed the time course of urinary taurine and hypotaurine excretion after two-thirds hepatectomy in rats. The excretion of both taurine and hypotaurine was elevated during 18 h following the hepatectomy, with maximal excretion during the first 6 h. Twelve and 24 h after partial hepatectomy, the hepatic hypotaurine concentration was increased but liver taurine did not differ significantly from controls. No changes were observed in hypotaurine and taurine concentrations of heart, kidney, lung, muscle tissue and spleen. We postulate that partial hepatectomy induces a rapid increase of hepatic (hypo)taurine synthesis from precursor amino acids. The increased (hypo)taurine concentrations spill over into urine.


Staphylococcal nasal carriage in medical students with varying clinical exposure.
Nasal carriage and antibiotic sensitivities of coagulase-positive and coagulase-negative staphylococci were assessed among medical students of three different years. Although carriage rates did not change, there was a trend towards multiple resistance with increasing hospital exposure. Gentamicin resistance in Staphylococcus albus showed a similar trend. The relevance of these findings to current views on the origin of gentamicin resistance is discussed.


New aspects of isocyanate asthma.
Air concentration of isocyanates are associated with the frequency of induced diseases. Asthma, bronchitis and rhinitis, chronic obstructive lung disease, and allergic alveolitis, respectively, were observed in exposed workers. Inhalation challenge tests with isocyanates found some 14% of symptomatic persons immunologically sensitized. At and above current threshold limit values (10 ppb) there is a risk of lung function deterioration also in asymptomatic workers.


Evaluating and improving the cost-effectiveness of the implantable cardioverter-defibrillator.
The implantable cardioverter defibrillator (ICD) is an expensive, widely used device for severe ventricular arrhythmias. Marginal cost-effectiveness analysis is a technique to examine the incremental cost of treatment strategy in relation to its effectiveness. In this study, we used this technique to analyze the cost-effectiveness of the ICD compared with that of electrophysiology (EP)-guided drug therapy and examined ways in which it may be improved. We analyzed Michigan Medicare discharge abstracts (1989 to 1992) and local physician visit, test, and ICD charges. Effectiveness was from 218 previously described patients with ICDs in whom the time of first event (first appropriate shock or death) was determined and presumed to represent "control" (EP-guided drug therapy) mortality. We assumed a 4-year life cycle for the ICD generator and 3.4% operative mortality and used a 5% discount to prevent value. Data were analyzed in a 1-month cycle Markov decision model over a 6-year horizon, and results were updated to 1993 dollars. ICD effectiveness was an increase in discounted mean life expectancy of 1.72 years. Cost-effectiveness was $31,100/year of life saved (YLS). Results were minimally or modestly sensitive to variations in preoperative mortality; resource use; consideration only of patients with ICDs who were receiving any antiarrhythmic drug or specifically amiodarone; and to a decrease in the percentage of first shocks that would equal death without the ICD until the assumed percentage decreased to < 38%. At ejection fraction of < 0.25 and > or = 0.25, cost-effectiveness was $44,000/YLS and $27,200/YLS, respectively, and without preimplant EP study was $18,100/ YLS.(ABSTRACT TRUNCATED AT 250 WORDS)


Patterns of cystine reduction by fibroblasts from normal and cystinotic children.
The possibility that the enzymatic reduction of cystine involves a multi-enzyme system led to re-evaluation of cystine reduction by fibroblasts from normal and cystinotic patients. Lineweaver-Burk plots of data with extracts of a normal cell line, representative of seven normal cell lines, under conditions of increasing cystine with variable levels of reduced glutathione (GSH) resulted in a two-limbed curve above 100 micronM cystine. Two cell lines from children with nephropathic cystinosis containing 1-6 micronmol half-cystine/g protein gave a family of curves similar to those of the normal. With six fibroblast lines containing more than 6 micronmol half-cystine/g protein, increasing cystine resulted in a family of lines without two-limbed curves. Plots of the data as activity against increasing cystine concentrations at ratios of cystine to GSH of 1:2 and 1:1 showed that two of the three lines from cystinotic subjects reduced cystine at a faster rate than the normal line. The third line from a cystinotic patient reduced cystine at a slightly slower rate when the substrate concentration in the assay was less than 80 micronM cystine. When the cystine to GSH ratio was maintained at 2:1, normal cells showed a linear increase in the rate of cystine reduction up to 100 micronM cystine, no increase in the rate between 100 micronM and 200 micronM cystine, and an increase again when the concentration of cystine was raised above 200 micronM. Such a stepwise phenomenon was absent with six cell lines containing more than 6 micronmol half-cystine/g cellular protein. A possible mechanism of control of cystine reduction is discussed.


[The role of thoracic CT scan, a triage tool for suspected COVID-19 cases].
The SARS-Cov-2 pandemic took health care players across the world by surprise, including caregivers, managers and logisticians. In the absence of a vaccine or a specific therapy, detecting the disease at an early stage and isolating confirmed cases from the rest of the healthy population was soon considered to be essential. The RT-PCR technique was the gold standard method for testing for infection with the virus. It has high specificity but moderate sensitivity. It was difficult to access it during the first weeks of the pandemic. On the basis of the observations of the Chinese and Italian scientific community in particular, the recommendation was to combine use of the RT-PCR with a low-dose thoracic CT scan. In the absence of easy access to the RT-PCR, the use of the lung CT scan for a rapid triage of patients within emergency departments proved effective.


Exercise Training Normalizes Timing of Left Ventricular Untwist Rate, but Not Peak Untwist Rate, in Individuals with Type 2 Diabetes and Diastolic Dysfunction: A Pilot Study.
There is limited information regarding the role of left ventricular (LV) twist and the effect of exercise in type 2 diabetes (T2D). The aim of this study was to compare LV twist parameters in patients with T2D versus healthy control subjects and the effects of high-intensity interval exercise (HIIE) and moderate-intensity exercise (MIE) on LV twist in patients with T2D with diastolic dysfunction. This study, which included both prospective and retrospective components, included 47 patients with T2D and diastolic dysfunction and 37 healthy individuals. Patients with T2D were randomized to HIIE (4 × 4 min at 90%-95% of maximal heart rate, three times a week, 120 min/wk; n = 24) or MIE (210 min/wk; n = 23) for 12 weeks and examined with echocardiography (LV twist by speckle-tracking method) at baseline and posttest. The control subjects received no intervention and were matched according to age, gender, and body mass index to those completing the intervention. In total, 37 subjects completed 12 weeks of MIE (n = 17) or HIIE (n = 20). LV peak untwist rate (UTR) was similar in patients with T2D and control subjects (P ˃ .05). At baseline, LV peak UTR, relative to total diastolic period, occurred 5.8 percentage points later in patients with T2D compared with control subjects (P = .004). Time to peak UTR was shortened by 6.5 percentage points (P = .002) and 7.7 percentage points (P < .001) after MIE and HIIE, respectively. Time to peak UTR was similar to that in control subjects after exercise interventions. In patients with T2D and diastolic dysfunction, LV peak UTR was similar, but time to peak LV UTR was delayed compared with control subjects. Twelve weeks of endurance exercise normalized the timing of UTR.


Concomitant PPARα and FXR Activation as a Putative Mechanism of NASH Improvement after Gastric Bypass Surgery: a GEO Datasets Analysis.
Compared to non-surgical weight loss (Diet), weight loss after Roux-en-Y gastric bypass (RYGB) results in greater rates of non-alcoholic steatohepatitis (NASH) resolution. Changes in bile acid physiology and farnesoid X receptor (FXR) signaling are suspected mediators of postoperative NASH improvement. Recent experimental evidence suggests that upregulation of hepatic peroxisome proliferator-activated receptor α (PPARα) activity might also impact NASH improvement. As FXR partly regulates PPARα, we compared resolution of NASH and changes in hepatic PPARα and FXR gene expression following Diet and RYGB. We searched the Gene Expression Omnibus database to identify human studies with liver biopsies containing genomic data and histologic NASH features, at baseline and after Diet or RYGB. Microarray data were extracted for PPARα and FXR gene expression analyses using GEOquery R package v.2.42.0. We identified one study (GSE83452) where patients underwent either Diet (n = 29) or RYGB (n = 25). NASH prevalence was similar at baseline (Diet 76% versus RYGB 60%, P = ns). After 1 year, NASH resolved in 93.3% of RYGB but only in 27.3% of Diet (P < 0.001). Hepatic PPARα and FXR gene expression increased only after RYGB (P < 0.001). These changes were also found when analyzing only patients that resolved NASH (P < 0.01), and patients without NASH at baseline and follow-up (P < 0.05). Compared to Diet, RYGB results in greater NASH resolution with concurrent upregulation of hepatic PPARα and FXR. Our findings point to concurrent PPARα and FXR activation, triggered by RYGB, as a potential mechanism to improve NASH.


Pregnancy zone protein inhibits production of interleukin-2 but does not affect interleukin-2 receptor expression on T cell activation.
The effect of pregnancy zone protein (PZP), which exhibits increased levels in the blood during pregnancy, on T cells was examined. PZP was found to suppress DNA synthesis following stimulation with phytohemagglutinin (PHA), concanavalin A (ConA) or CD3 antigen or in the mixed lymphocyte reaction (MLR). This effect of PZP was mediated by a reduction in interleukin-2 (IL-2) production, and was abolished by exogenous recombinant IL-2 administration. PZP did not affect the proliferation of T cells following stimulation with the calcium ionophore A23187 and phorbol 12-myristate 13-acetate (TPA). These results suggest that PZP acts on the T cell surface and reduces IL-2 production, but not IL-2R expression, and does not directly affect Ca2+ influx or protein kinase C.


Does dietary restriction really increase longevity in Drosophila melanogaster?
It is often accepted that dietary restriction (DR) increases longevity in most species so far tested. Showing the same result in the fruit fly Drosophila melanogaster would be of interest, because this species is widely used in aging research. Some studies have shown that dietary restriction decreases longevity in this species while the opposite result has also been reported. However, some recent results appear to be flawed due to the use of not optimal control rearing conditions. It is argued that, for the time being, it cannot be concluded that dietary restriction increases longevity in D. melanogaster. It has also been shown in other fly species that dietary restriction does not increase longevity.


Effect of haemopoietic stem-cell proliferation regulators on early and late spleen colony-forming cells.
An inhibitor and stimulator of CFU-s proliferation can be obtained from haemopoietic tissue containing, respectively, relatively quiescent CFU-s (e.g. normal bone marrow) and proliferating CFU-s (e.g. regenerating bone marrow). Their effects on the proliferative behaviour of steady-state and regenerating marrow CFU-s, which produce colonies 7, 10 and 12 days post-transplantation have been investigated. The results demonstrate changing sensitivities of CFU-s to inhibitor and stimulator as they progress through a developmental age structure, 'Older' CFU-s (producing early spleen colonies) are more sensitive to stimulator, 'Younger' CFU-s (producing late spleen colonies) are more sensitive to inhibitor.


Assembly of epithelial tight junctions is negatively regulated by Par6.
Epithelial cells display apical-basal polarity, and the apical surface is segregated from the basolateral membranes by a barrier called the tight junction (TJ). TJs are constructed from transmembrane proteins that form cell-cell contacts-claudins, occludin, and junctional adhesion molecule (JAM)-plus peripheral proteins such as ZO-1. The Par proteins (partitioning-defective) Par3 and Par6, plus atypical protein kinase C (aPKC) function in the formation or maintenance of TJs and more generally in metazoan cell polarity establishment. Par6 contains a PDZ domain and a partial CRIB (Cdc42/Rac interactive binding) domain and binds the small GTPase Cdc42. Here, we show that Par6 inhibits TJ assembly in MDCK II epithelial cells after their disruption by Ca(2+) depletion but does not inhibit adherens junction (AJ) formation. Transepithelial resistance and paracellular diffusion assays confirmed that assembly of functional TJs is delayed by Par6 overexpression. Strikingly, the isolated, N-terminal fragment of PKCzeta, which binds Par6, also inhibits TJ assembly. Activated Cdc42 can disrupt TJs, but neither a dominant-negative Cdc42 mutant nor the CRIB domain of gammaPAK (p21-activated kinase), which inhibits Cdc42 function, observably inhibit TJ formation. These results suggest that Cdc42 and Par6 negatively regulate TJ assembly in mammalian epithelial cells.


Uncomplicated pregnancy following oral contraceptive-induced liver hepatoma.
A patient who used oral contraceptives who had had a partial hepatectomy for benign hepatic cell adenoma became pregnant 3 years after surgery. No diagnosed liver complicaions resulted during the pregnancy or the postpartum period.


Intradialytic clearance of opioids: methadone versus hydromorphone.
Opioids are commonly prescribed to patients with chronic pain associated with end-stage renal disease requiring hemodialysis. The stability of opioid analgesia during dialysis may vary among different opioids. No studies to date have corroborated this clinical observation by directly comparing plasma concentrations of different opioids during dialysis. We compared changes in peridialysis plasma concentrations of 2 pharmacokinetically distinct opioids, methadone and hydromorphone (HM). Fourteen dialysis patients with chronic pain received either methadone or HM for at least 2 weeks before beginning the study. Blood samples were obtained immediately before, during, and after hemodialysis in 2 separate dialysis sessions, 1 week apart, and were analyzed for opioid concentrations. Methadone plasma concentrations were more stable during hemodialysis compared to HM: the mean percent change of methadone plasma levels was 14.9% ± 8.2% (± SD) compared with 55.1% ± 8.1% in the HM treatment group, a difference of 40.2% (95% confidence interval 17.14 to 63.14). The mean plasma clearance of methadone was 19.9 ± 8.5 mL/min (± SD) compared with 105.7 ± 8.3 mL/min for HM, a difference of 85.7 mL/min (95% confidence interval 61.9 to 109.1). There were no differences between the 2 opioid groups in pain scores, side effect profile, and quality of life. Methadone therapy was not associated with an increased rate of adverse events. If confirmed by larger clinical studies, methadone could be considered as one of the opioids of choice in dialysis patients.


Deciphering lipid dysregulation in ALS: from mechanisms to translational medicine.
Lipids, defined by low solubility in water and high solubility in nonpolar solvents, can be classified into fatty acids, glycerolipids, glycerophospholipids, sphingolipids, and sterols. Lipids not only regulate integrity and fluidity of biological membranes, but also serve as energy storage and bioactive molecules for signaling. Causal mutations in SPTLC1 (serine palmitoyltransferase long chain subunit 1) gene within the lipogenic pathway have been identified in amyotrophic lateral sclerosis (ALS), a paralytic and fatal motor neuron disease. Furthermore, lipid dysmetabolism within the central nervous system and circulation is associated with ALS. Here, we aim to delineate the diverse roles of different lipid classes and understand how lipid dysmetabolism may contribute to ALS pathogenesis. Among the different lipids, accumulation of ceramides, arachidonic acid, and lysophosphatidylcholine is commonly emerging as detrimental to motor neurons. We end with exploring the potential ALS therapeutics by reducing these toxic lipids.


Relationships between controllers of a system.
Many different arrangements of controllers can be designed to ensure the efficient functioning of a system. Whether the system is a complex piece of machinery or a committee in session, the principles are the same.


Emodin Alleviates Sodium Taurocholate-Induced Pancreatic Ductal Cell Damage by Inhibiting the S100A9/VNN1 Signaling Pathway.
Because the pathogenesis of the disease is unclear, the treatment of patients with acute pancreatitis, especially severe acute pancreatitis, is still a major challenge for clinicians. Emodin is an anthraquinone compound extracted from rhubarb that can alleviate the damage to pancreatic ductal epithelial cells induced by adenosine triphosphate, but whether it has a similar protective effect on sodium taurocholate (STC)-stimulated pancreatic ductal cells and the underlying mechanism has not yet been reported. A model of STC-induced HPDE6-C7 human pancreatic ductal epithelial cell injury was established, and then apoptosis and the levels of reactive oxygen species (ROS), glutathione, gamma-glutamylcysteine synthetase, and inflammatory cytokines were assessed in the presence or absence of emodin pretreatment. S100 calcium binding protein A9 (S100A9) and Vanin1 (VNN1) protein expression was also measured. Emodin significantly increased HPDE6-C7 cell viability, inhibited apoptosis and ROS release, and elevated glutathione levels and gamma-glutamylcysteine synthetase activity. Furthermore, emodin downregulated S100A9 and VNN1 protein expression and inhibited the production of inflammatory factors, such as interleukin (IL)-1β, IL-6, IL-8, and IL-18. Emodin attenuates STC-induced pancreatic ductal cell injury possibly by inhibiting S100A9/VNN1-mediated ROS release. This finding provides evidence for the future development of emodin as a therapeutic agent.


Primary cutaneous spindle cell B cell lymphoma: A report of three cases and review of the literature.
Primary cutaneous spindle cell lymphoma is a rare variant of primary cutaneous B-cell lymphoma (PCBCL). Herein, we present 3 cases of primary cutaneous spindle cell B cell lymphoma, 2 males and one female (age range 66-76years). The patients presented with solitary skin lesions, distributed in the head and neck area and chest. The dominant cell size was in the intermediate to large cell size range. While the main cell type was a spindled one, other cells with a nuclear morphology quite typical for a centroblast were noted and as well careful inspection in the three cases revealed a focal residuum of germinal center-like structures. The spindled cells exhibited a B cell follicle center cell phenotype as revealed by expression of CD20, CD79a, BCL6, and CD10. BCL2 was negative in two cases and positive in one case. The proliferation index exceeded 80%. In one case the neoplastic cells were CD30 positive. Subsequent to a diagnosis in each case of follicle center cell lymphoma, the patients underwent complete excision with no known recurrence. In our review of the literature, a total of 42 other cases were reported showing a similar male predominance with the commonest sites of involvement being the head and neck area and upper back. Other than one patient who died of progressive disease due to treatment refusal and one patient who developed metastatic disease to the liver all patients are alive and well without recurrent or metastatic disease. In summation, our experience along with the reported cases suggest the categorization of primary cutaneous spindle cell B cell lymphoma as a variant of primary cutaneous indolent follicle center lymphoma. It is a neoplasm of middle aged to older adults with a predominance in males which can be treated locally in most cases whereby recurrent and metastatic disease following complete removal is uncommon.


Adjuvant treatment with levamisole in cancer: a review of experimental and clinical data.
Animal and human studies of adjuvant treatment with levamisole in cancer are reviewed and discussed. From the animal data it is concluded that the activity of levamisole is dose-dependent, more effective on slow-growing tumors, affects metastasis formation, preferentially is best when levamisole is used as an adjuvant to the usual cytoreductive treatments and that tumor enhancement is not expected. Clinical findings are put into perspective of the animal data and the most appropriate clinical situations are indicated.


Copper metabolism during acute inflammation: studies on liver and serum copper concentrations in normal and inflamed rats.
1 The concentration of copper in serum and liver was determined by atomic absorption spectrophotometry in a study performed on normal rats of either sex and in female rats with carrageenan-induced pleurisy. 2. In the normal animal, total serum copper concentration is significantly higher in female rats, and appears to be higher in mature animals in females. 3 In normal rats of either sex, liver copper concentration undergoes daily variations which are inversely related to the weight of the organ and which leave constant the total amount of metal in the liver. Moreover a day to day non-cyclic variability of liver copper concentration and liver weight was observed. 4 This first set of data showed that comparison with time control was essential. 5 In the inflamed rat, a significant rise of total serum copper at 22, 48 and 72 h after the induction of inflammation was observed. From 96 h up to 240 h post-injection no significant differences were evident. 6 Total liver copper content did not change in the inflamed rats. 7 During acute inflammation in the rat, the copper needed for the increased synthesis of caeruloplasmin is supplied without depletion of liver copper stores.


Mitochondrial Genetics and Function as Determinants of Bone Phenotype and Aging.
The purpose of this review is to summarize the recently published scientific literature regarding the effects of mitochondrial function and mitochondrial genome mutations on bone phenotype and aging. While aging and sex steroid levels have traditionally been considered the most important risk factors for development of osteoporosis, mitochondrial function and genetics are being increasingly recognized as important determinants of bone health. Recent studies indicate that mitochondrial genome variants found in different human populations determine the risk of complex degenerative diseases. We propose that osteoporosis should be among such diseases. Studies have shown the deleterious effects of mitochondrial DNA mutations and mitochondrial dysfunction on bone homeostasis. Mediators of such effects include oxidative stress, mitochondrial permeability transition, and dysregulation of autophagy. Mitochondrial health plays an important role in bone homeostasis and aging, and understanding underlying mechanisms is critical in leveraging this relationship clinically for therapeutic benefit.


[Tracheal adenoid cystic carcinoma treated by complete carinal reconstruction with the help of an ECMO: about a case].
Primitive tumors of the trachea are rare, accounting for 0.1% of the airway tumors. Cystic adenoid carcinoma (or cylindroma) represents the second most frequent type of tracheal cancers. Histologically speaking, this tumor type is divided in three patterns: cribriform, tubular and solid; it presents a slow growth, perineural invasion and potential local recurrence and metastasis. We presented herein the case of a 56-year-old female suffering from a cystic adenoid carcinoma of the low trachea. She has been treated by carinal resection with negative airway margin and complete reconstruction, with the help of an extra corporeal membrane oxygenation (ECMO).


Knowledge, attitudes, and behavior concerning nutrition and physical activity in Mexican children.
To identify the stages of behavior change and the knowledge, attitudes, and habits concerning nutrition and physical activity in Mexican children. A survey was applied to 48 children from 10 years old to obtain data. Stages of behavior change were classified according to the transtheoretical model. For food habits, 31% were in precontemplation, 17% in contemplation, 10% in preparation, 40% in action, and 2% in maintenance. For physical activity, 12% were in precontemplation, 15% in contemplation, 29% in preparation, 42% in action, and 2% in maintenance. It is important to consider the stages of behavior change to plan strategies of educational models.


Sonolucent space posterior to left atrium: unusual echocardiographic appearance in a cardiac transplant patient.
The usual echocardiographic appearances of the atria in heart transplant patients are well known. We report a case of an 81-year-old man with a 16-year-old cardiac transplant who showed a "new" echocardiographic left atrial abnormality. Two-dimensional echocardiography showed a large sonolucent space behind the donor left atrium (DLA), which was at first perplexing. This space, the distorted and partly displaced recipient left atrium (RLA), could be shown to communicate with the donor left atrium, by the use of unconventional imaging and by optison opacification.


Determination of binding-dioxygen in dioxygen complexes by headspace gas chromatography.
Dioxygen complexes play important roles in organisms' bodies, so the determination of binding-dioxygen has practical significance. A simple and robust method based on headspace gas chromatography was proposed to determine the binding-dioxygen in dioxygen complexes. By measuring the content change of nitrogen gas in a vial, the amount of oxygen released from dixoygen complexes can be determined. The method was validated using potassium chlorate as model sample, and the results exhibited good recoveries (90-99%) with the relative standard deviation less than 8%. It was also used to analyze dioxygen complex of cobalt bis(salicylaldehyde) ethylenediimine and polyamine cobalt complexes prepared by solid-phase reaction.


Zebrafish (Danio rerio) life-cycle exposure to chronic low doses of ethinylestradiol modulates p53 gene transcription within the gonads, but not NER pathways.
Parental full life-cycle exposure to ethinylestradiol (EE₂) significantly affects embryo development and survival. One of the possible mechanisms of action of EE₂ may involve the impairment of an organism's ability to repair DNA damage. DNA repair mechanisms have sophistically evolved to overcome DNA damaging hazards that threaten the integrity of the genome. In the present study, changes in the transcription levels of key genes involved in two of the most thoroughly studied DNA repair systems in mammals were evaluated in adult zebrafish (Danio rerio) gonad upon full life-cycle exposure to chronic environmentally low levels of EE₂ (i.e., 0.5, 1 and 2 ng/L EE₂). Real time PCR was used to analyse the expression levels of nucleotide excision repair genes (NER) as well as the tumor suppressor p53 and downstream selected effectors, i.e., p21 (cyclin-dependent kinase inhibitor), GADD45α (growth arrest and DNA damage induced 45, alpha), bax (bcl2-associated X protein) and p53 key regulator MDM2 (murine double minute 2 protein). NER genes transcription levels in gonads did not differ significantly among treatments. In contrast, the number of transcripts of p53 gene was significantly increased in male gonads at all EE₂ exposure concentrations and in females at 1 ng/L EE₂. Despite the increase in p53 transcripts, transcription levels of p21, GADD45α and bax genes were not affected upon EE₂ treatment, whereas MDM2 gene expression significantly increased in females at the intermediate EE₂ dose (1 ng/L). Overall, the present study indicate that chronic low levels of EE₂ significantly modulates the transcription of p53, a key gene involved in DNA repair, particularly in male zebrafish gonads, which supports the hypothesis of an impact of EE2 in male gonad DNA repair pathways.


Binding of phosphate to F-ADP-actin and role of F-ADP-Pi-actin in ATP-actin polymerization.
Our previous work (Carlier, M.-F., and Pantaloni, D. (1986) Biochemistry 25, 7789-7792) had shown that F-ADP-Pi-actin is a major intermediate in ATP-actin polymerization, due to the slow rate of Pi release following ATP cleavage on filaments. To understand the mechanism of ATP-actin polymerization, we have prepared F-ADP-Pi-actin and characterized its kinetic parameters. 32Pi binds to F-ADP-actin with a stoichiometry of 1 mol/mol of F-actin subunit and an equilibrium dissociation constant Kpi of 1.5 mM at pH 7.0 Kpi increases with pH, indicating that the H2PO-4 species binds to F-actin. ADP-Pi-actin subunits dissociate much more slowly from filament ends than ADP-actin subunits; therefore, the stability of filaments in ATP is due to terminal ADP-Pi subunits. The slow rate of dissociation of ADP-Pi-actin also explains the decrease in critical concentration of ADP-actin in the presence of Pi reported by Rickard and Sheterline (Richard, J. E., and Sheterline, P. (1986) J. Mol. Biol. 191, 273-280). The effect of Pi on the rate of actin dissociation from filaments is much more pronounced at the barbed end than at the pointed end. Using gelsolin to block the barbed end, we have shown that the two ends are energetically different in the presence of ATP and saturating Pi, but less different than in the absence of Pi. The results are interpreted within a new model for actin polymerization. It is possible that phosphate binding to F-actin can regulate motile events in muscle and nonmuscle cells.


Arterial transit artifacts observed by arterial spin labeling in Moyamoya disease.
Arterial spin labeling (ASL) is a magnetic resonance imaging (MRI) technique used to assess cerebral perfusion. When tissue perfusion is impaired, such as in Moyamoya disease, a hyperintense band called the arterial transit artifact (ATA) may occur, which interferes with accurate measurements on ASL-MRI. In this study, we evaluated the correlation of ATAs with magnetic resonance angiography (MRA) and single-photon emission computed tomography (SPECT) imaging results in Moyamoya disease. The aim of our study was to elucidate the pathophysiology of ATAs and risk factors for high ATA scores. This retrospective study included 28 patients (56 hemispheres) with Moyamoya disease treated at our institution. MRI, MRA, ASL perfusion, and N-isopropyl-[123I] b-iodoamphetamine (123I-IMP) SPECT were performed. In order to semi-quantitatively evaluate the degree of ATA, the ATA scores were measured according to the number of hyperintense signal bands in the cerebral cortex. The relationship between the ATA scores and clinical and radiological factors were analyzed. Regional cerebral blood flow (rCBF) determined with ASL weakly correlated with that determined by 123I-IMP SPECT (ρ=0.31, p=0.027). There was no significant association between the ATA scores and rCBF values determined with 123I-IMP SPECT (p=0.872, 0.745, 0.743 at PLD1000 (post-labeling delay), 1500, and 2000, respectively). However, there was a significant correlation between ATA scores and MRA scores (ρ=0.427 p=0.001; ρ=0.612 p=0.001; ρ=0.563 p=0.001 at PLD1000, 1500, and 2000, respectively). An analysis of patient background characteristics revealed a significantly higher incidence of high ATA scores in female patients, patients with high MRA scores, and patients with a distinguishable ivy sign. A multivariate analysis confirmed that female sex, high MRA score, and presence of an ivy sign were risk factors for high ATA scores. ATA scores were moderately correlated with MRA scores, and presence of an ivy sign was the most predictive factor for high ATA scores. A high ATA score determined using ASL in a patient with Moyamoya disease might suggest an advanced disease stage and a reduction in cerebrovascular reserve capacity.


The safety of therapeutic monoclonal antibodies: implications for cardiovascular disease and targeting the PCSK9 pathway.
Monoclonal antibodies (mAbs) are established therapies for many conditions, including cancers, autoimmune conditions and infectious diseases. mAbs can offer benefits over conventional pharmacotherapy in terms of potency, dosing frequency and specificity for their target antigen. Mouse-derived antibodies were initially used in humans; however, patients often developed human anti-mouse antibodies, resulting in rapid antibody clearance (and a resulting loss of efficacy) and hypersensitivity reactions. Chimeric, humanized, and fully human antibodies were thus developed, with increasing amounts of human sequence, to reduce immunogenicity. Although generally well tolerated, mAbs may be associated with adverse events (AEs). Many AEs are target-related, and will be specific to the antibody target and the therapeutic area of use. However, off-target AEs, such as hypersensitivity reactions, are observed with many antibodies. Within the realm of cardiovascular medicine, new antibody-based therapies are under investigation to reduce low-density lipoprotein cholesterol (LDL-C) levels. Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma LDL-C levels by increasing degradation of the LDL receptor (LDLR). Therefore, inhibition of the interaction between PCSK9 and the LDLR with mAbs targeting PCSK9 has great potential for patients with hypercholesterolaemia. Early clinical phase studies suggest these mAbs are effective and well tolerated; however, further studies are required to assess their long-term safety.


Aerosol delivery of chemotherapy in an orthotopic model of lung cancer.
The aim of this study was to evaluate the effect on tumour growth of gemcitabine delivered by aerosol in an orthotopic model of lung carcinoma. Large cell carcinoma (NCI-H460) cells were implanted intrabronchially in 24 male BALB/c nude mice on day (d) 0. Aerosols were delivered once a week from d1 to d29 using an endotracheal sprayer. Altogether, 16 animals received gemcitabine at 8 (n=8) and 12 mg.kg-1 (n=8), and eight received a vehicle aerosol. Animals were sacrificed on d36 for histological examination. All animals in the vehicle group developed a large infiltrating carcinoma. Comparatively, four of 13 (31%) animals treated with gemcitabine had no visible tumour and nine of 13 (69%) had a smaller carcinoma with a mean+/-sem largest tumour diameter of 2.05+/-0.7 versus 5+/-0.3 mm in the vehicle group. Gemcitabine was well tolerated at 8 mg.kg-1. At 12 mg.kg-1, three cases of fatal pulmonary oedema were observed, prompting a dose reduction to 8 mg.kg-1 in the remaining animals. A dose effect was observed, with more marked tumour growth inhibition in the animals treated at 12 mg.kg-1 on d1 and d8. In conclusion, in this study, an animal model of aerosolised chemotherapy in lung cancer was developed and demonstrated inhibition of orthotopic tumour growth by aerosol delivery of gemcitabine.


HIV disease progression: depression, stress, and possible mechanisms.
There is much interest in whether depression and stress may explain the wide variability in the disease course of patients infected with human immunodeficiency virus (HIV). This article summarizes the large body of evidence examining whether depression and stress may have an impact on immune- and disease-related parameters in HIV disease. Furthermore, we review what is known about the underlying biological mechanisms of HIV disease, such as alterations in glucocorticoids and catecholamines, which may help explain these psychoimmune relationships. Our review of the literature finds substantial evidence that chronic depression and stressful events may affect HIV disease progression. We know little, however, regarding the biological mechanisms that may account for these relationships. More research is warranted to investigate how depression and stress might impact HIV disease progression and what types of interventions might mitigate the negative impact of chronic depression and trauma.


Molecular mimicry of NMDA receptors may contribute to neuropsychiatric symptoms in severe COVID-19 cases.
Approximately 30% of individuals with severe SARS-CoV-2 infections also develop neurological and psychiatric complaints. In rare cases, the occurrence of autoimmune encephalitis has been reported after SARS-CoV-2 infection. In this systematic review, we have identified eight SARS-CoV-2-associated cases of anti-NMDA receptor encephalitis. All had cerebrospinal fluid antibodies against the NMDA receptor and a recent onset of working memory deficits, altered mental status, or psychiatric symptoms, such as confusion, agitation, auditory hallucination, catatonia and speech dysfunction. All patients received high-dose steroid and immunoglobulin therapeutics and conditions improved in each case. These findings suggest that clinical attention should be paid to warning signs of autoimmune encephalitis in severe COVID-19 cases. If characteristic features of autoimmune encephalitis are present, autoantibody diagnostics should be performed and confirmed cases should be treated with immunotherapy to minimize neurological impairments.


Primary percutaneous coronary intervention on split left coronary artery: Two case reports.
The split left coronary artery (LCA) is an anomaly of coronary arteries connection related to the aorta, presenting more often in patients who underwent invasive coronary angiography compared to coronary computed tomography angiography. Although this anomaly causes no hemodynamic impairment, failure to recognize may lead to incorrect diagnosis and prolonged procedures during acute myocardial infarction resulting in serious complications. We report 2 cases of split left coronary artery presenting with acute myocardial infarction who underwent primary percutaneous coronary interventions (pPCI) with excellent outcomes. In the both cases, electrocardiogram demonstrated ST-segment elevation and cardiac biomarkers were increased. Also, before coronary angiography in both patients echocardiographic examination was performed revealing hypokinesis who corresponded with the territory of occluded coronary arteries. During invasive further coronary examinations split left artery was found, besides the culprit lesion in the left anterior descending artery (LAD). Successful percutaneous stenting was performed on LAD achieving TIMI flow grade 3 in both cases. Prompt recognition of split LCA in the setting of acute myocardial infarction during pPCI, it is essential to achieve appropriate treatment and avoid potential clinical consequences.


Decoding dopamine signaling.
Dopamine is a key neurotransmitter that is important for many physiological functions including motor control, mood, and the reward pathway. In this issue of Cell, the laboratories of Marc Caron and Li-Huei Tsai identify two very different molecules--beta-arrestin 2 and Par-4, respectively--that unexpectedly are involved in dopamine signaling via the D2 receptor. These two new signaling pathways mediate the actions of dopamine on behavior and facilitate crosstalk between different signaling pathways that are activated by binding of dopamine to the D2 receptor.


Incrusted cystitis after intravesical mitomycin C treatment.
Bladder wall calcification is a rare complication of intravesical therapy of superficial bladder cancer with Mitomycin C. A review of the literature revealed 2 other cases. We report a new case and discuss the pathogenic mechanism of this consequence of the intravesical treatment with Mitomycin C.


Molecular cloning using immune sera of a 22-kDal minor outer membrane protein of Vibrio cholerae.
Using antisera prepared against live Vibrio cholerae we have selected several recombinant DNA clones, plasmids pPM440, pPM450 and pPM460, encoding the gene for a 22-kDal V. cholerae peptidoglycan-associated-outer-membrane protein. This is a minor protein in V. cholerae but is expressed in large amounts when the cloned gene is present in Escherichia coli K-12, where it is exposed on the cell surface as judged by ELISA. We have localized the gene within the cloned DNA by transposon mutagenesis and deletion analysis followed by analysis of whole cells and minicells to identify the plasmid-encoded proteins. The DNA region encoding the protein seems to be conserved between El Tor and Classical strains as judged by Southern DNA hybridization.


Current perspectives on tigecycline resistance in Enterobacteriaceae: susceptibility testing issues and mechanisms of resistance.
During the past decades, rates of multidrug-resistant (MDR) and carbapenem-resistant (CR) Enterobacteriaceae clinical isolates, mainly Klebsiella spp., Escherichia coli, Enterobacter spp., Proteus spp. and Serratia marcescens, have increased, considerably restricting effective antimicrobial treatments. Tigecycline, the first member of the glycylcyclines, has been approved by the US Food and Drug Administration (FDA) for the treatment of complicated skin and soft-tissue, complicated intra-abdominal and community-acquired bacterial respiratory infections and is increasingly administered against MDR Enterobacteriaceae. Although resistance has gradually appeared, tigecycline still remains relatively active among Enterobacteriaceae, with resistance rates largely <10% in most wide-scale surveillance studies. Tigecycline resistance has been reported in some studies to be elevated among extended-spectrum β-lactamase (ESBL)-producing, MDR, extensively drug-resistant and CR isolates. Broth microdilution (BMD) is the reference method for tigecycline susceptibility testing, but disagreements have been reported between the methods applied for routine tigecycline susceptibility testing. Therefore, confirmation of daily tigecycline susceptibility testing with BMD appears important in order to avoid misclassification of isolates. Various mechanisms have been reported to confer tigecycline resistance, with RND-type transporters, mainly the AcrAB efflux pump, playing an important role. Other pumps and various control pathways are also implicated in tigecycline resistance. Overall, tigecycline is a potent therapeutic option for enterobacterial infections. Accurate detection of tigecycline susceptibility status and surveillance of resistant organisms in the hospital environment is necessary in order to optimise its use and to preserve tigecycline in our therapeutic arsenal.


Glial polyp (glioma) of the uterine cervix, report of a case with demonstration of glial fibrillary acidic protein.
A case of glial tissue in a polypoid structure of the uterine cervix is presented; the presence of glial fibrillary acidic protein was demonstrated by immunoperoxidase, confirming the astrocytic nature of the tissue. The main hypotheses to explain this unusual finding are discussed.


Omentoplasty in the management of filarial lymphoedema.
A trial of omentoplasty was carried out on 20 patients with unilateral filarial lymphoedema to assess its role in the reduction of oedema volume after failed lymphonodo-venous shunt (LNVS) or as a primary procedure. Omentoplasty was done through a midline laparotomy. The omentum was mobilized from the colon, preserving both gastroepiploic vessels, and transferred to the thigh either through the lower end of the laparotomy incision or through a separate stab and placed subcutaneously in the upper third of the thigh. There was no operative mortality. Morbidity was mainly incisional hernia and superficial wound infection. Fourteen of 18 patients had more than 25% reduction in oedema volume during the immediate postoperative period, and 5 of the 18 had more than 50% reduction. However, there was a gradual loss of response with time. Age, gender, grade of lymphoedema, duration, and previous surgery did not influence the outcome. The incidence of incisional hernia could be reduced by transferring the omentum through the midline. There was a statistically significant reduction in postoperative adenolymphangitis attacks whether or not the oedema volume was reduced. In some patients the oedema was reduced sufficiently to permit subcutaneous excision of the lymphoedematous tissue. There appears to be a definite but limited role for omentoplasty in patients who have failed LNVS.


[Transdermal buprenorphine for acute postoperative pain: a systematic review].
Postoperative pain is still a major concern in several surgical procedures. Multimodal analgesia is best for postoperative pain management; however, opioid therapy is still the main treatment for pain after surgical procedures. Transdermal buprenorphine is a partial μ agonist opioid widely used for chronic pain syndromes, with limited evidence for acute postoperative pain. A systematic review of studies examining transdermal buprenorphine for acute pain management after surgery was conducted. Data from PubMed, Embase, The Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL via EBSCOhost, and LILACS were reviewed, including randomized clinical trials that evaluated total postoperative pain, postoperative analgesic consumption, drug-related side effects and patient satisfaction with analgesia regimen. Data from nine studies (615 patients) were included in this review. Most studies initiated transdermal buprenorphine use 6 to 48 hours before surgery, maintaining use from 1 to 8 days after the procedure. Most studies showed lower or similar postoperative pain scores, postoperative analgesic consumption and patient satisfaction comparing buprenorphine to placebo, tramadol, celecoxib, flurbiprofen and parecoxib. The incidence of side effects varied between studies, with most showing no increase in drug-related side effects with buprenorphine use, except one study, which compared buprenorphine to oral tramadol, and one to transdermal fentanyl. However, most results were derived from evidence with an overall high or unclear risk of bias. Although more studies are necessary, initial results show that transdermal buprenorphine seems to be an effective and safe opioid choice for management of acute postoperative pain.


The timing of initiation of DNA synthesis in Paramecium tetraurelia is established during the preceding cell cycle as cells become committed to cell division.
The timing of initiation of DNA synthesis (IDS) in Paramecium is established before cell division at a point located at about 0.75 in the preceding cell cycle. This point occurs about 90 min prior to fission and coincides with the point at which cells become committed to cell division. The location of the point at which the timing of IDS is set was deduced from a series of nutrient-shift experiments. Changes in nutrient level lead to changes in the duration of the subsequent G1 interval when they occur more than 90 min prior to fission. Perturbation of the cell cycle so that the timing of commitment to cell division is altered, results in a parallel shift in the point at which the timing of IDS is established.


Effect of cholinergic denervation on hepatic fibrosis induced by carbon tetrachloride in rats.
Various factors involved in the development of liver fibrosis, including hepatic stellate cells (HSCs), cholinergic nervous activity and fibrogenetic cytokines. The present study aims to investigate the role of cholinergic regulation in the promoting of liver fibrogenesis relating to bone morphogenetic protein-6 (BMP-6) and/or transforming growth factor-beta1 (TGFbeta1). We treated carbon tetrachloride (CCl(4)) into rats for eight weeks to induce liver fibrosis and arranged these rats for cholinergic denervation, hepatic branch vagotomy or atropine administration. Acetylcholinesterase (AChE) staining showed the distribution of cholinergic nerve around fibrosis scaring septa. The immunohistochemical staining for alpha smooth muscle actin (alphaSMA) indicated the less HSCs in CCl(4) treated rat liver with cholinergic denervation as compared to the sham-operated CCl(4) treated rats. It seems that cholinergic nerve not only innervates around the fibrosis area but also promotes HSCs. We also detected TGFbeta1 and BMP-6 expressions using RT-PCR and immunohistochemistry. The obtained results show that cholinergic denerveration decreases BMP-6 and TGF-beta1 expressions in CCl(4) induced liver fibrosis of rats. In conclusion, cholinergic nerve may influence HSCs in addition to the lowering of BMP-6 and TGF-beta1 gene expressions to modify liver fibrosis.


Feminizing adrenocortical tumors in male patients: adenoma versus carcinoma.
We report a case of a feminizing adrenocortical adenoma in a 8-year-old boy and feminizing carcinoma in a 25-year-old man. Because diagnosis of adrenal malignancy in such tumors by histopathological criteria is not always conclusive, a clinicoradiological approach may be used in the evaluation.


Mushroom Carboxymethylated β-d-Glucan Functions as a Macrophage-Targeting Carrier for Iron Oxide Nanoparticles and an Inducer of Proinflammatory Macrophage Polarization for Immunotherapy.
β-d-glucans have the potential of serving as both macrophage-targeted carriers and immune stimulators via inducing trained immunity in macrophages. In this study, a carboxymethylated β-glucan from mushroom sclerotium of Pleurotus tuber-regium (CMPTR) was combined with iron oxide nanoparticles (IONPs) to form nanocomplexes (CMPTR/IONPs) with particle size around 193 ± 7 nm, which could exert a concerted effect on inducing proinflammatory M1 phenotype macrophages for immunotherapy. This nanocomplex exhibited good stability and low cytotoxicity (over 80% cellular viability of RAW 264.7 and THP-1) and higher cellular uptake by murine macrophages compared with B16F10 cells (p < 0.05). CMPTR/IONPs could convert M2-like bone marrow-derived macrophages into M1 phenotypes with upregulated expression of pro-inflammatory cytokines (IL12 and TNF-α, p < 0.05) and reduced immune-suppressive cytokines (IL10 and TGF-β, p < 0.05). Such polarization was mediated by the combined signaling regulatory factors, including IONP-stimulated IRF5 and CMPTR-triggered TLRs-NF-κB pathways (p < 0.05). Accordingly, CMPTR could have a dual function as a macrophage-targeting carrier for IONPs and an immunostimulant to induce inflammatory M1 macrophage polarization for immunotherapy.


Lifespan of human lymphocytes estimated during a six year cytogenetic follow-up of individuals accidentally exposed in the 1987 radiological accident in Brazil.
Following the radiological accident which occurred in the city of Goiania (Brazil), in September 1987, a cytogenetic follow-up of 15 exposed patients was started, aiming to observe the mean lifetime of lymphocytes containing dicentric and ring aberrations. The results suggest that the disappearance rate of unstable aberrations follows a two-term exponential function. Up to 470 days after exposure, there is a rapid fall in the aberration frequency. After 470 days, the disappearance rate is very slow. These results may reflect different subpopulations of human lymphocytes, with different lifespans. The estimated average half-time of elimination of dicentrics and rings among the highly exposed group (doses above 1 Gy) was 110 days for the initial period after the exposure (up to 470 days). This value is significantly shorter than the usually accepted value of 3 years reported in the literature. Statistical analysis of possible correlations between the individual half-times and biological parameters, such as sex, age, leukopenia level shown during the critical period, absorbed dose (initial frequency of chromosomal aberrations) and the administration of the bone marrow stimulating factor (rHuGM-CSF) was performed. None of these parameters showed a correlation with the half-time of disappearance of chromosomal aberrations. For the individuals who had received less than 1 Gy the disappearance of aberrations was slower, with a half-time of 160 days during the period up to 470 days after exposure. Mean disappearance functions of unstable chromosome aberrations were inferred, to be applied in accident situations in which there is a blood sampling delay.


Multi-locus phylogeny reveals instances of mitochondrial introgression and unrecognized diversity in Kenyan barbs (Cyprininae: Smiliogastrini).
The phylogenetics and taxonomic status of small African barbs (Cyprininae: Smiliogastrini) remains unresolved despite the recent decision to elevate the genus name Enteromius for the group. The main barrier to understanding the origin of African small barbs and evolutionary relationships within the group is the poor resolution of phylogenies published to date. These phylogenies usually rely on mitochondrial markers and have limited taxon sampling. Here we investigate the phylogenetic relationships of small barbs of Kenya utilizing cytochrome b, Growth Hormone (GH) intron 2, and RAG1 markers from multiple populations of many species in the region. This multi-locus study produced well-supported phylogenies and revealed additional issues that complicate understanding the relationships among East African barbs. We observed widespread mtDNA introgression within the Kenyan barbs, highlighting the need to include nuclear markers in phylogenetic studies of the group. The GH intron 2 resolved heterospecific individuals and aided in inferring the species level phylogeny. The study reveals unrecognized diversity within the group, including within species reported to occur throughout East Africa, and it provides the groundwork for future taxonomic work in the region and across Africa.


Prevalence and determinants of active trachoma among preschool-aged children in Dembia District, Northwest Ethiopia.
Trachoma is an infectious eye disease caused by Chlamydia trachomatis, which is the leading infectious cause of blindness worldwide. In areas where trachoma is endemic, active trachoma is common among preschool-aged children, with varying magnitude. This study aimed to estimate the prevalence of active trachoma and associated risk factors among preschool-aged children in Dembia District, northwest Ethiopia. A community-based cross-sectional survey was conducted among preschool-aged children of northwest Ethiopia. Multistage systematic random sampling was used to select 695 subjects. Trained clinical optometrists subjected each child to an ocular examination and assessed the presence of active trachoma. Face to face interview using pretested and structured questionnaire were conducted to collect data on possible risk factors. Trachoma cases were graded following a World Health Organization simplified grading scheme. All statistical analysis was carried out using the SPSS software version 20. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were used to identify factors associated with active trachoma. Of the 681 preschool-aged children studied, 18% (95% CI: 15.4% - 21.1%) had a prevalence of active trachoma. Children who had clean faces (absence of nasal and ocular discharges) had a lower chance of having active trachoma [aOR = 0.55, 95% CI: 0.37 - 0.82]. The odds of having active trachoma decreased with an increase in the distance to a water point [aOR = 0.51, 95% CI: 0.33 - 0.78]. Similarly, no or poor utilization of liquid waste disposal in the child's household was associated with an increased chance of having active trachoma [aOR = 3.83, 95% CI: 1.26 - 11.61]. The prevalence of active trachoma in these preschool-aged children was found to be high and needs special interventions that focus on educating families about proper face washing, liquid waste disposal, and improving safe water supply near the households.


Enzymatic analysis of the pathways of glucose catabolism and gluconeogenesis in Pseudomonas citronellolis.
Extracts of Pseudomonas citronellolis cells grown on glucose or gluconate possessed all the enzymes of the Entner-Doudoroff pathway. Gluconokinase and either or both 6-phosphogluconate dehydratase and KDPG aldolase were induced by growth on these substrates. Glucose and gluconate dehydrogenases and 6-phosphofructokinase were not detected. Thus catabolism of glucose proceeds via an inducible Entner-Doudoroff pathway. Metabolism of glyceraldehyde 3-phosphate apparently proceeded via glyceraldehyde 3-phosphate dehydrogenase, phosphoglycerate kinase, phosphoglycerate mutase, enolase and pyruvate kinase. These same enzymes plus triose phosphate isomerase were present in lactate-grown cells indicating that synthesis of triose phosphates from gluconeogenic substrates also occurs via this pathway. Extracts of lactate grown-cells possessed fructose diphosphatase and phosphohexoisomerase but apparently lacked fructose diphosphate aldolase thus indicating either the presence of an aldolase with unusual properties or requirements or an alternative pathway for the conversion of triose phosphate to fructose disphosphate. Cells contained two species of glyceraldehyde 3-phosphate dehydrogenase, one an NAD-dependent enzyme which predominated when the organism was grown on glycolytic substrates and the other, an NADP-dependent enzyme which predominated when the organism was grown on gluconeogenic substrates.


Detection of large cell component in small cell lung carcinoma by combined cytologic and histologic examinations and its clinical implication.
In the classification recently proposed by the Pathology Committee of International Association for the Study of Lung Cancer, small cell lung carcinoma (SCLC) was divided into three subtypes: pure SCLC, mixed small cell/large cell carcinoma (mixed SC/LC), and combined SCLC. To examine the clinical utility of this classification, histologic specimens, cytologic specimens obtained by brushing or fine-needle aspiration, and sputum cytologic specimens from 430 patients with SCLC were reviewed. When the subtype of SCLC was determined from the biopsy specimen, cytologic specimen obtained by brushing or fine-needle aspiration, and sputum cytologic specimen, the frequency of mixed SC/LC was 25 of 299 (8.4%), 75 of 400 (18.8%), and 8 of 232 (3.4%), respectively. Whatever the diagnostic method, patients with mixed SC/LC showed a poorer response to treatment and worse prognosis than those with pure SCLC: a median survival of 144 days versus 285 days when classified with the use of biopsy specimens; 160 days versus 275 days with cytologic specimens obtained by brushing or fine-needle aspiration; and 47 days versus 259 days with sputum cytologic specimens, respectively. These findings showed that mixed SC/LC should be separated from pure SCLC as a distinctive group and that cytologic studies of specimens obtained by brushing or fine-needle aspiration were sensitive and useful procedures for this purpose.


Effects of endocrine disrupters on the expression of growth hormone and prolactin mRNA in the rainbow trout pituitary.
It is now widely accepted that chemical pollutants in the environment can interfere with the endocrine system of animals, thus affecting development and reproduction. Some of these endocrine disrupters (EDs) can have estrogenic or antiestrogenic effects. Most studies to date have focused on the effects of EDs on the reproductive system and sex hormones and only limited information exists on how EDs may affect pituitary gland function. A rainbow trout (Oncorhynchus mykiss) pituitary gland culture system was used for studying the effects of EDs on growth hormone (GH) and prolactin (PRL) mRNA expression. We determined that the pituitary glands actively synthesized and secreted GH and PRL over the experimental time-course. In addition, we found that treatment with 17beta-estradiol (positive control) increased levels of GH and PRL mRNA, in a concentration-dependent manner. Treatment of pituitary glands with 500 and 1000 nM of a xenoestrogen, o,p'-DDT (o,p'-dichlorodiphenyltrichloroethane), resulted in a significant induction of GH and PRL mRNA, with a 20-fold increase for PRL and 3-fold increase for GH following treatment with 1000 nM o,p'-DDT. Co-incubation of pituitary glands with ICI 182 780 (a selective estrogen receptor antagonist) and o,p'-DDT resulted in inhibition of PRL mRNA levels; however, the stimulatory effect of DDT on GH mRNA was not seen in this experiment, nor was the inhibitory effect of ICI 182 780 observed with GH mRNA. To the contrary, ICI 182 780 (2.5 nM) had a stimulatory effect on GH mRNA levels. TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), which is known to exert antiestrogenic effects, had an estrogenic-like effect that resulted in a concentration-dependent increase in the levels of GH and PRL mRNA. Co-incubation of pituitaries with TCDD and alpha-napthoflavone (ANF), which is an inhibitor of the aryl hydrocarbon receptor (AhR), caused an inhibition of TCDD-induced PRL mRNA at the higher and lower concentrations, but these effects were less consistent on GH mRNA levels. However, the responses of PRL and GH mRNA to co-incubation with TCDD and ANF, at the various concentrations, were bi-phasic wherein stimulation was seen at the low concentrations and inhibition at the high concentrations. Combined, these results suggest that o,p'-DDT and TCDD are xenoestrogens and that their effects on the expression of GH and PRL genes in the rainbow trout pituitary are modulated, in part, through the ER and AhR, respectively.


[Identification of the first human Leptospira strain in the island of La Réunion].
The first Leptospira strain of the island of La Réunion isolated from a patient hospitalized at Saint-Pierre, is identified L. Icterohaemorrhagiae icterohaemorrhagiae. The importance and severity of leptospiroses in the island of La Réunion are to be emphasized.


Assessing the impact of watershed characteristics and management on nutrient concentrations in tropical rivers using a machine learning method.
Excessive loadings of terrestrial nitrogen and phosphorus, as well as their imbalances with silicon, have been recognized as one of the major causes of water quality and ecosystem deterioration in receiving waters. In this study, a periodic water quality monitoring was conducted in the rivers and streams of a tropical island (Ishigaki Island, Japan) to identify the factors controlling the concentrations of dissolved inorganic nitrogen (DIN), total phosphorus (TP) and dissolved silicon (DSi) with a special focus on the catchment characteristics (e.g., land use, surface geology, topography). Random Forest (RF) machine learning algorithm was employed to develop predictive models for nutrient concentrations from the catchment properties. The developed models could predict nutrient concentrations with sufficient accuracy, demonstrating that the studied nutrients are strongly affected by catchment properties. Agricultural land uses (e.g., livestock barn, sugarcane field) were ranked as the most important parameters for DIN and TP, while broadleaf forest was the most influential factor for DSi. Using the RF models, the contributions of DIN originating from sugarcane fields (i.e., fertilizers) and barns (i.e., manure) to riverine DIN were estimated, which were up to 60% in total in the studied river basins. Furthermore, the yield of DIN from sugarcane fields, calculated as the concentration of DIN derived from sugarcane fields divided by the percent area of sugarcane fields, strongly positively correlated with the areal coverage of limestone, suggesting that fertilizer-derived DIN is more prone to leaching out from cropland soil to groundwater and rivers in catchments with a higher dominance of calcareous geology. These results, including the methodology employed, have implications for water quality assessment and management in inland and coastal waters not only at the study site but also other regions.


IL-4 protects the B-cell lymphoma cell line CH31 from anti-IgM-induced growth arrest and apoptosis: contribution of the PI-3 kinase/AKT pathway.
Interleukin-4 (IL-4) promotes lymphocyte survival and protects primary lymphomas from apoptosis. Previous studies reported differential requirements for the signal transducer and activator of transcription 6 (STAT6) and IRS2/phosphatidylinositol 3 kinase (PI-3K) signaling pathways in mediating the IL-4-induced protection from Fas-mediated apoptosis. In this study, we characterized IL-4-activated signals that suppress anti-IgM-mediated apoptosis and growth arrest of CH31, a model B-cell lymphoma line. In CH31, anti-IgM treatment leads to the loss of mitochondrial membrane potential, phospho-Akt, phospho-CDK2, and c-myc protein. These losses are followed by massive induction of p27(Kip1) protein expression, cell cycle arrest, and apoptosis. Strikingly, IL-4 treatment prevented or reversed these changes. Furthermore, IL-4 suppressed the activation of caspases 9 and 3, and, in contrast to previous reports, induced the phosphorylation (deactivation) of BAD. IL-4 treatment also induced expression of BclxL, a STAT6-dependent gene. Pharmacologic inhibitors and dominant inhibitory forms of PI-3K and Akt abrogated the anti-apoptotic function of IL-4. These results suggest that the IL-4 receptor activates several signaling pathways, with the Akt pathway playing a major role in suppression of the apoptotic program activated by anti-IgM.


Mutations affecting conformation or sequence of neutralizing epitopes identified by reactivity of viable plaques segregate from syn and ts domains of HSV-1(F) gB gene.
Three classes of HSV-1(F) mutants expressing a resistance phenotype to two highly potent-type common monoclonal antibodies, H126-5 and H233, to glycoprotein B (gB) were selected. Class 1 mutants, selected for resistance to neutralization from nonmutagenized virus stocks, expressed a gB which reacted in biotin-avidin-enhanced surface immunoassays and in immune precipitation tests with the selecting antibodies. Class 2 and 3 mutants were selected for nonreactivity in the biotin-avidin-enhanced surface immunoassay from BUdR-mutagenized, preneutralized virus stocks, but differ in that the selecting antibodies immune precipitated the gB of Class 2 but not that of Class 3. Mutants expressing a resistance phenotype to one monoclonal antibody (H126-5 or H233) invariably retained reactivity in all tests with the heterologous antibody, and recombinants resistant to both antibodies were produced by cotransfection of intact DNA of one mutant with a cloned DNA fragment from another mutant. Class 1 mutations were mapped by marker transfer to a 1734-bp DNA fragment. Class 2 and 3 mutations were mapped to a region defined by a maximum of 377 bp and a minimum of 46 bp, in a biotin-avidin-enhanced surface immunoassay with a panel of DNA fragments of HSV-1(F) BamHI G carrying staggered deletions across the region encoding gB. This region does not overlap the neutralizing antibody determinant site mapped by T.C. Holland, R.M. Sandri-Goldin, L.E. Holland, S.D. Marlin, M. Levine, and J. Glorioso (1983, J. Virol. 46, 649-652) and is located 3' to the ts lesion of HSV-1(HFEM)tsB5 and 5' to the syn3 locus of that virus. It was concluded that (i) inasmuch as the biotin-avidin-enhanced surface immunoassay does not destroy the virus contained in the plaque, it is a rapid and convenient method for both identification and selection of mutants reactive and nonreactive to specific monoclonal antibodies. (ii) gB may contain multiple domains carrying epitopic sites of neutralizing monoclonal antibodies. (iii) The resistance phenotype may arise from mutations which alter the conformation or the amino acid sequence of the epitope. These mutations might be differentiable on the basis of reactivity of mutated gB with selecting monoclonal antibody in nondenaturing and denaturing environments, respectively.


Disparate kinetics of change in responses to electrical stimulation at the thoracic and lumbar level during fatiguing isometric knee extension.
The present study compared the fatigue-induced change of matched-amplitude thoracic evoked potential (TMEP) and lumbar evoked potential (LEP) following electrical stimulation. Ten participants performed a 3 × 3 min isometric knee extension contraction separated by 4 min of recovery at the level of EMG required to produce 50% maximal voluntary contraction (MVC) force at baseline. The TMEP and LEP were evoked during the ongoing contraction at baseline and every minute into the fatiguing protocol and during recovery. Both responses were also assessed during a transcranial magnetic stimulation (TMS) evoked silent period to elicit a TMS-TMEP and TMS-LEP to assess responses without the confounding influence of descending drive. The results displayed disparate kinetics of the TMS-TMEP and TMS-LEP throughout the fatiguing protocol. The TMS-TMEP was reduced at all time points during exercise (P < 0.001), whereas the TMS-LEP was reduced at 2 min into set 1 and 1 min into sets 2 and 3 (P ≤ 0.04). TMS-LEPs were higher than the TMS-TMEPs at most time points (P ≤ 0.04). No change was observed in the TMEP or LEP. When evoked during the silent period, the reduction in TMEP is greater than the LEP during fatiguing isometric exercise. The disparate kinetics of change suggest that differential mechanisms are responsible for evoked responses to thoracic and lumbar stimulation. More research is required to identify the mechanisms responsible for the TMEP and LEP before precise inferences can be made on what fatigue-induced changes in these variables reflect.NEW & NOTEWORTHY Assessing spinal excitability using lumbar stimulation when measuring responses in lower limbs has been suggested as an alternative method that could circumvent the issues associated with thoracic stimulation. The present study compared responses to the two types of stimuli throughout a fatiguing protocol and demonstrated that lumbar evoked responses differ substantially from thoracic responses when measured in the absence of voluntary drive. These findings suggest that different mechanisms are responsible for evoked responses to thoracic and lumbar stimuli.


Natural molecule coatings modify the fate of cerium dioxide nanoparticles in water and their ecotoxicity to Daphnia magna.
The ongoing development of nanotechnology has raised concerns regarding the potential risk of nanoparticles (NPs) to the environment, particularly aquatic ecosystems. A relevant aspect that drives NP toxicity is represented by the abiotic and biotic processes occurring in natural matrices that modify NP properties, ultimately affecting their interactions with biological targets. Therefore, the objective of this study was to perform an ecotoxicological evaluation of CeO2NPs with different surface modifications representative of NP bio-interactions with molecules naturally occurring in the water environment, to identify the role of biomolecule coatings on nanoceria toxicity to aquatic organisms. Ad hoc synthesis of CeO2NPs with different coating agents, such as Alginate and Chitosan, was performed. The ecotoxicity of the coated CeO2NPs was assessed on the marine bacteria Aliivibrio fischeri, through the Microtox® assay, and with the freshwater crustacean Daphnia magna. Daphnids at the age of 8 days were exposed for 48 h, and several toxicity endpoints were evaluated, from the molecular level to the entire organism. Specifically, we applied a suite of biomarkers of oxidative stress and neurotoxicity and assessed the effects on behaviour through the evaluation of swimming performance. The different coatings affected the hydrodynamic behaviour and colloidal stability of the CeO2NPs in exposure media. In tap water, NPs coated with Chitosan derivative were more stable, while the coating with Alginate enhanced the aggregation and sedimentation rate. The coatings also significantly influenced the toxic effects of CeO2NPs. Specifically, in D. magna the CeO2NPs coated with Alginate triggered oxidative stress, while behavioural assays showed that CeO2NPs coated with Chitosan induced hyperactivity. Our findings emphasize the role of environmental modification in determining the NP effects on aquatic organisms.


A polymorphism in plasma platelet-activating factor acetylhydrolase is involved in resistance to immunoglobulin treatment in Kawasaki disease.
To investigate whether reduced levels of plasma platelet-activating factor acetylhydrolase (PAF-AH) as a result of a genetic polymorphism are involved in the pathogenesis of Kawasaki disease (KD). The frequency of a V279F polymorphism (G/T transversion) in the PAF-AH gene was quantified in 76 Japanese children with KD and 112 healthy Japanese adults using the allele-specific polymerase chain reaction (PCR). Associations between genotype, clinical features, and resistance to intravenous immunoglobulin (IVIG) were investigated in the patients with KD. Plasma PAF-AH activity was measured by using [3H]-acetyl-PAF. There were no significant differences in genotype frequency between patients and controls (P = .51). Compared with the GG (normal genotype) group, significantly more patients in the GT (heterozygous) +TT (homozygous deficient) group required additional IVIG (52% vs 14%, P = .001). The duration of fever and maximum serum C-reactive protein (CRP) levels also were significantly increased in the GT+TT group (P = .012 and .036, respectively), whereas plasma PAF-AH activity was significantly lower (P <.0001). We conclude that the V279F polymorphism in the plasma PAF-AH gene and consequent enzymatic deficiency is one of the factors for IVIG nonresponse in Japanese patients with acute KD.