Colposcopic performance in a birth cohort previously eligible for human papillomavirus vaccination.
Sweden started subsidized quadrivalent human papillomavirus vaccination for girls aged 13 to 17 in 2007. Since 2012, vaccination has been offered to all girls aged 10 to 12 within a school-based vaccination program, with a coverage of 80% or more. In addition, the vaccine has been offered on-demand as catch-up vaccination for girls aged 13 to 18, with a cumulative coverage of 55% to 60%. Since the first women in Sweden eligible for human papillomavirus vaccination entered the cervical screening program, questions on how to evaluate colposcopic findings among vaccinated women have arisen. Evidence is inconsistent on whether colposcopic features for the detection of cervical lesions are influenced by specific human papillomavirus genotypes and what role they can play in the prevention of invasive cervical cancer in vaccinated women. The primary objective of the study was to compare colposcopic evaluation in vaccinated and unvaccinated women entering the organized cervical screening program. Women in the 1994 and 1995 birth cohorts who entered the cervical screening program at age 23 in 1 region in Sweden were identified. Colposcopy was performed within 2 to 4 months after a positive screening result in accordance with national guidelines. Colposcopic performance was evaluated according to national guidelines with the Swede score and colposcopic impression. Punch biopsies were taken from colposcopic lesions and as "random biopsies" in the absence of lesions. These biopsies were used as the gold standard for the analysis. An endocervical sample was analyzed for cytologic findings and detection of 14 high-risk human papillomavirus genotypes. All colposcopic imaging was saved digitally for re-review. Vaccination status was obtained through linkage to national vaccination registries. Results were compared between vaccinated and unvaccinated women. In 2018 and 2019, 160 out of 165 (98%) women with a positive screening result attended colposcopy, of which 90 (56%) were vaccinated and 70 (44%) were unvaccinated. Only 7 out of 90 (5%) women in the vaccinated group were human papillomavirus 16/18-positive, compared with 23 out of 70 (33%) in the unvaccinated group (P<.001). There was a total of 61 out of 160 (38%) women with high-grade lesions-33 out of 90 (37%) in the vaccinated group and 28 out of 70 (40%) in the unvaccinated group (P=.697). There was 64% (21/33) of vaccinated women and 75% (21/28) of unvaccinated women with high-grade squamous intraepithelial lesions who had a Swede score of 6 to 10 (indicating high-grade squamous intraepithelial lesions) (P=.124). The sensitivity was slightly higher for the detection of high-grade squamous intraepithelial lesions in unvaccinated women using both colposcopic tests (Swede score, 0.67 vs 0.75; colposcopic impression, 0.67 vs 0.68), but the difference was not statistically significant. We found no statistically significant difference between the colposcopic evaluation of vaccinated and unvaccinated women, although human papillomavirus vaccination reduced the prevalence of human papillomavirus 16/18 infection in human papillomavirus-vaccinated women. Our results indicate that colposcopic examination is still a useful tool in vaccinated women entering the organized cervical screening program.


Pineal melatonin synthesis is altered in Period1 deficient mice.
Melatonin is an important endocrine signal for darkness in mammals. Transcriptional activation of the arylalkylamine-N-acetyltransferase gene encoding for the penultimate enzyme in melatonin synthesis drives the daily rhythm of the hormone in the pineal gland of rodents. Rhythmic arylalkylamine-N-acetyltransferase expression is controlled by the cAMP-signal transduction pathway and involves the activation of β-adrenergic receptors and the inducible cAMP early repressor. In addition, the rat arylalkylamine-N-acetyltransferase promoter contains an E-box element which can interact with clock proteins. Moreover, the pineal gland of mice shows a circadian rhythm in clock proteins such as the transcriptional repressor Period1, which has been shown to control rhythmic gene expression in a variety of tissues. However, the role of Period1 in the regulation of pineal melatonin synthesis is still unknown. Therefore, circadian rhythms in arylalkylamine-N-acetyltransferase, β-adrenergic receptor, and inducible cAMP early repressor mRNA levels (real time PCR), arylalkylamine-N-acetyltransferase enzyme activity (radiometric assay) and melatonin concentration radio immuno assay (RIA) were analyzed in the pineal gland of mice with a targeted deletion of the Period1 gene (Per1-/-) and the corresponding wildtype. In Per1-/- the amplitude in arylalkylamine-N-acetyltransferase expression was significantly elevated as compared to wildtype. In contrast, β-adrenergic receptor and inducible cAMP early repressor mRNA levels were not affected by the Period1-deficiency. This indicates that the molecular clockwork alters the amplitude of arylalkylamine-N-acetyltransferase expression. In vitro, pineal glands of Per1-/- mice showed a day night difference in arylalkylamine-N-acetyltransferase expression with high levels at night. This suggests that a deficient in Period1 elicits similar effects as the activation of the cAMP-signal transduction pathway in wildtype mice.


Psoriasiform eruptions during Kawasaki disease (KD): A distinct phenotype.
A psoriasis-like eruption develops in a subset of patients with Kawasaki disease (KD). We sought to systematically compare KD-associated psoriasiform eruptions with classic psoriasis and the outcomes of KD in children with and without this rash. This was a retrospective study of 11 KD cases with a psoriasiform eruption matched 1:2 by age, gender, and ethnicity with psoriasis-only and KD-only controls. Genotyping was performed in 10 cases for a deletion of 2 late cornified envelope (LCE) genes, LCE3C_LCE3B-del, associated with increased risk for pediatric-onset psoriasis. Similar to classic psoriasis, KD-associated eruptions were characterized clinically by well-demarcated, scaly pink plaques and histopathologically by intraepidermal neutrophils, suprabasilar keratin 16 expression, and increased Ki-67 expression. They showed less frequent diaper area involvement, more crust and serous exudate, and an enduring remission (91% vs 23% with confirmed resolution; P < .001). Frequency of LCE3C_LCE3B-del and major KD outcomes were similar between cases and controls. The study was limited by the small number of cases, treatment variation, and availability of skin biopsy specimens. Although the overall clinical and histopathologic findings were similar to conventional psoriasis, this appears to be a distinct phenotype with significantly greater propensity for remission. No adverse effect on KD outcomes was noted.


Seroprevalence of Toxoplasma gondii, rubella and Cytomegalovirus among pregnant females in north-western Turkey.
To examine the sera-prevalence rates of Toxoplasma gondii, rubella and Cytomegalovirus (CMV) among pregnant women in different age groups in the context of a comparison with nationwide and international data previously reported. Females of reproductive age attending to our hospital between 1 January 2012 and 1 January 2014 were included in this study. Antibodies against T gondii;~, rubella and CMV were assayed using chemiluminescence immunoassay methods. The test results.were evaluated retrospectively. Of the participants, 2.5 and 43.9% were seropositive for Toxoplasma lgM and lgG, respectively. The corresponding figures for rubella and CMV were 1.5 and 93.8%, and 2 and 91.5%, respectively. The high rates of immunity against rubella and CMV infections among pregnant females in our region call into question the routine screening of pregnant females for these two diseases. On the other hand, the high rate of seronegativity for T gondii warrants such a routine practice.


Acne cream reduces the deep Cutibacterium acnes tissue load before elective open shoulder surgery: a randomized controlled pilot trial.
Cutibacterium acnes is the main pathogen in periprosthetic shoulder infections. In acne vulgaris therapy, benzoyl peroxide-miconazole nitrate cream effectively reduces the superficial C acnes burden of the skin. Its additional potential in the subcutaneous and capsular layers (eg, for prevention of future periprosthetic shoulder infections) is unknown. The aim of this study was to investigate the efficacy of a topical acne vulgaris cream (benzoyl peroxide-miconazole nitrate) to reduce subcutaneous and capsular C acnes in individuals with C acnes skin colonization undergoing open shoulder surgery. A prospective randomized pilot trial was performed, allocating 60 adult patients (1:1) to either a 7-day preoperative application of a commercial acne cream (benzoyl peroxide-miconazole nitrate) on the preoperative skin (intervention group) or no cream (control group) from November 1, 2018, to May 31, 2020. The superficial skin of the shoulder was sampled at enrollment and before incision, and deep subcutaneous and capsular shoulder samples were taken during surgery. Sixty patients (mean age, 59 years; 55% female patients) undergoing primary open shoulder surgery (17 Latarjet procedures and 43 arthroplasties) were included in the study. At baseline, both randomized groups showed the presence of C acnes on the skin at a rate of 60% (18 of 30 patients in intervention group and 19 of 30 patients in control group, P = .79). In patients with C acnes skin colonization, the intervention resulted in a significant reduction in the overall number of intraoperative samples with positive findings compared with the control group (8 of 18 patients vs. 16 of 19 patients, P = .01), especially in capsular samples (0 of 18 patients vs. 4 of 19 patients, P = .04). The topical 7-day preoperative skin application of acne cream (benzoyl peroxide-miconazole nitrate) significantly reduced the intraoperative C acnes load in 56% of the patients in the intervention group compared with 16% of the control patients.


Contribution of TFEB-mediated autophagy to tubulointerstitial fibrosis in mice with adenine-induced chronic kidney disease.
Autophagy has been implicated in the pathogenesis of chronic kidney disease (CKD). Transcription factor EB (TFEB) is a master controller of autophagy. However, the pathophysiological roles of TFEB in modulating autophagy and tubulointerstitial injury in CKD are unknown. This study aimed to determine whether TFEB-mediated autophagy contributed to the tubulointerstitial injury in mice with CKD. After the mice were treated with an adenine diet (0.2 % adenine) for 8 weeks, the development of CKD was observed to be characterised by increased levels of plasma blood urea nitrogen (BUN), creatinine (Cre), tubulointerstitial inflammation and fibrosis. Immunohistochemical and Western blot analysis further revealed that TFEB and autophagy genes were significantly up-regulated in the kidney of the mice with adenine-induced CKD, and this increase was mostly found in the tubular epithelial cells. Interestingly, a similar expression pattern of TFEB-autophagy genes was observed in tubular epithelial cells in the kidney tissue of patients with immunoglobulin A (IgA) nephropathy. Moreover, a pathogenic role of TFEB in adenine-induced CKD was speculated because the pharmacological activation of TFEB by trehalose failed to protect mice from tubulointerstitial injuries. In the epithelioid clone of normal rat kidney cells (NRK-52E), the activation of TFEB by trehalose increased autophagy induction, cell death and inflammatory cytokine (Interleukin-6, IL-6) release. Collectively, these results suggested that the activation of TFEB-mediated autophagy might cause autophagic cell death and inflammation in tubular epithelial cells, contributing to renal fibrosis in adenine-induced CKD. This study provided novel insights into the pathogenic role of TFEB in CKD associated with a high purine diet.


12-month-olds' phonotactic knowledge guides their word-object mappings.
This study examined whether 12-month-olds will accept words that differ phonologically and phonetically from their native language as object labels in an associative learning task. Sixty infants were presented with sets of English word-object (N = 30), Japanese word-object (N = 15), or Czech word-object (N = 15) pairings until they habituated. Infants associated CVCV English, CCVC English, and CVCV Japanese words, but not CCVC Czech words, with novel objects. These results demonstrate that by 12 months of age, infants are beginning to apply their language-specific knowledge to their acceptance of word forms. That is, they will not map words that violate the phonotactics of their native language to objects.


[Fibromyalgia].
The characteristic symptoms of fibromyalgia are chronic widespread musculoskeletal pain in various parts of the body and abnormal tenderness at 18 specified tender points. Associated symptoms often reported include stiffness, sleep disorders, fatigue, and problems with concentration. The prevalence is about 3.5% for women and 0.5% for men. The impact of the disease is considerable both for those directly affected (restriction in activities of daily living and in ability to take part in family, professional, and social life) and for society as a whole (direct and indirect costs). The disease usually has a chronic course. An abnormality of the central pain-processing mechanisms is highly relevant for the pathogenesis. In addition to early diagnosis and intensive patient education, pharmacotherapy, exercise therapy, behavior therapy, and multidisciplinary treatment are particularly important for the management of fibromyalgia.


[Influence of floor disinfection on microbial and particulate burden measured under low turbulance air flow in ophthalmological operation theatres].
The necessity for routine disinfection of floors between two surgical procedures or disinfection only after visible contamination was assessed in two identical ophthalmological operating theatres equipped with laminar air flow ventilation. Over a period of four weeks, one of the two tested operating rooms was disinfected after every surgical procedure, and the other only in the case of visible contamination. This regimen was inverted every week. To compare the air quality, particle count and total bacteria count were measured inside and outside the laminar air flow. Additionally, bacteria count was measured in the operating field, consisting of the operating table and the instrument tray. Patients were monitored for surgical site infection over a period of one year after operation. No difference in particle count or number of viable bacteria was found between the two investigated procedures. Also, no wound infections were observed after one year of surveillance for surgical site infection. It appears that frequent cleaning disinfection of floors is not necessary if a laminar air flow ventilation system is installed. Under these conditions, targeted disinfection of visibly soiled surfaces appears to be sufficient. Generally, the duration of surgical procedures should be kept as short as possible.


Body image and depression in endometriosis: Examining self-esteem and rumination as mediators.
Endometriosis is a chronic systemic disease affecting 1 in 10 people assigned female at birth, that can result in appearance-based and functional bodily changes which can negatively impact body image. Empirical evidence supports the body dissatisfaction-driven hypothesis that negative body image leads to greater depressive symptoms; but potential underlying mechanisms are under-researched. This prospective study investigated the mediating role of two theoretically-derived intervening factors, self-esteem and rumination, in individuals living with endometriosis who typically report high rates of body image concerns and depressive symptoms. Initially, 996 participants completed the first online survey (T0) assessing demographic, medical and psychological factors. Of these, 451 completed surveys at 1-month (T1) and 2-months (T2) follow-up assessing self-esteem, rumination and depression. Bootstrapped analyses with full-information maximum likelihood estimation indicated that poor body image (T0) predicted greater depressive symptoms over time (T2). Self-esteem (T1), but not rumination (T1), mediated the body image-depression relationship. These results provide support for the body dissatisfaction-driven hypothesis and further identify that self-esteem is a key meditating factor. This highlights the importance of addressing self-esteem in body image focused interventions.


Peripheral blood NK cells expressing HLA-G, IL-10 and TGF-β in healthy donors and breast cancer patients.
Human natural killer (NK) cells are not only professional cytotoxic cells integrated into effector branch of innate immunity, but they are also regulatory cells, managing different immune processes. Immunoregulatory NK cells, expressing HLA-G and IL-10, have been generated in vitro from human hematopoietic progenitors and found in vivo among decidual NK cells of pregnant women. Human peripheral blood NK cells have been shown to acquire suppressive properties after HLA-G uptake during trogocytosis. Moreover, it has been shown that circulating NK cells contain a trace amount of cells producing TGF-β and IL-10, which exert a suppressive influence upon innate and adaptive immunity. In this study, we report on a minor subset of peripheral blood HLA-G(+) NK cells possessing suppressive activity toward effector functions of NK cells. Further we demonstrate an increased number of circulating HLA-G(+), IL-10(+), and TGF-β(+) NK cells in breast cancer patients which might impair efficiency of anti-tumor immunity.


Nonpeptide oxytocin antagonists: potent, orally bioavailable analogs of L-371,257 containing a 1-R-(pyridyl)ethyl ether terminus.
Structure-activity studies on the oxytocin antagonist 1 (L-371,257) have identified a new series of high affinity, receptor-selective OT antagonists in which the N-acetyl-4-piperidinyl ether terminus in 1 has been replaced with a 1-(aryl)ethoxy group.


[Transposition of pedicled adrenal gland for the treatment of adrenal medullary hyperplasia].
To investigate the operative modes for adrenal medullary hyperplasia. 8 cases of adrenal medullary hyperplasia were treated with transposition of pedicled adrenal gland. The inferior and the medial blood vessel of adrenal gland were ligated. The superior blood vessel of adrenal gland was formed a 5.0- 6.0 cm pedicle and dragged to the subcutaneous of dorsum. After follow-up for an average of 2 years, only 1 of the 8 patients did not recover as a result of psychosis and others had no symptoms but normal endocrine results. Transposition of the pedicled adrenal gland is a simple and satisfied way to treat patients with adrenal medullary hyperplasia.


The effects of sign design features on bicycle pictorial symbols for bicycling facility signs.
The inanimate bicycle symbol has long been used to indicate the animate activity of bicycling facility signs. In contrast, either the inanimate bicycle symbol or the animate bicycle symbol has been used interchangeably for the standard pavement symbols in bike lanes. This has led to confusion among pedestrians and cyclists alike. The purpose of this study was to examine two different designs (inanimate symbol vs. animate symbol) involved in the evaluation of perceived preference and glance legibility, and investigate sign design features on bicycle pictorial symbols. Thirty-five participants compared current bicycle signs (inanimate symbols) to alternative designs (animate symbols) in a controlled laboratory setting. The results indicated that the alternative designs (animate symbols) showed better performance in both preference and glance legibility tests. Conceptual compatibility, familiarity, and perceptual affordances were found to be important factors as well.


Improved high-performance liquid chromatographic method for analysis of L-carnitine in pharmaceutical formulations.
A reversed-phase high performance liquid chromatographic method for analysis of L-carnitine is described. The improved method is able to provide a high resolution between L-carnitine and crotonoylbetaine, a major impurity and degradation product, and suitable for quantitative analysis of L-carnitine in pharmaceutical formulations, such as solution, tablets, and capsules. The resolution, linearity, accuracy and reproducibility of the method are discussed.


Simulation of axoplasmic transport.
We have analysed a kinetic model of axonal transport by simulating experimental tracer profiles. The existence of three phases of axoplasmic transport is assumed: fast anterograde, slow anterograde and retrograde. Each phase has its characteristic velocity. Transported materials are postulated to shift between these phases. Also catabolism and sequestration of material is allowed for in our model. Thus, we have set up equations which contain axonal transport, diffusion and cross-over terms. The rate constants of material shifts were determined by computer fitting to experimental data. Best-fitted values of the rate constants for transfer of material between the fast and slow phases were both 2 X 10(-5) sec-1, while the rate constants for transfer between the fast and retrograde phases were both 1 X 10(-5) sec-1. The rate constant of material loss from the slow phase to the extracellular space was 1 X 10(-6) sec-1. The material shift between the slow and retrograde phases was negligibly small. These data show that there is exchange of material between the fast and slow phases and between the fast and retrograde phases. However, there is no significant exchange between the slow and retrograde phases. Diffusion was found to have only a minor effect on the profiles. The velocity of the fast anterograde track in cold-blooded animals was predicted to be around 200 mm/day, or, in other words, to be close to experimentally observed values of the fast anterograde component of axonal transport.


Assessment of physical work demands of long-distance industrial gas delivery truck drivers.
The aim of this study was to assess the work-related physical demands of long-distance truck drivers employed by a large gas delivery company in Canada. A total of 15 truck drivers participated in a data collection that included self-reporting assessments, field observations, and direct measurements to describe daily tasks organization, postural demands, physical workload, and force exertions. Truck drivers' work was characterized by long working days ranging from 9.9 to 15.1 h (mean = 11.4 h), with half (49%) of the total working time spent behind the wheel. The overall workload as measured by relative cardiac strain (18.7% RHR) was found excessive for the long term given the shift duration. Peaks of heart rate in excess of 30 beats per minute above the daily average occurred mainly while operating valves and handling heavy hoses during gas deliveries. The task of delivering gas at a client's site required a moderate work rate on average (8.3 mlO2/kg/min) requiring 24.4% or maximum work capacity on average. Based on multiple data sources, this study highlights the risks of over-exertion and of excessive physical fatigue in the truck drivers' work that are coherent with the high prevalence of self-reported musculoskeletal pain in this group of workers.


BMP-4, TGF-β and Smad3 as Modulators of Synovial Fluid Cells Viability.
Objective Our goal was to evaluate the modulation of the synovial fluid cells (SFC) from patients with and without osteoarthritis (OA) by bone morphogenetic protein 4 (BMP-4), Smad-3 and transforming growth factor beta (TGF-β). Methods Synovial fluid was collected from patients submitted to knee arthroscopy or replacement and were centrifuged to isolate cells from the fluid. Cells were cultured for 21 days and characterized as mesenchymal stem cells (MSCs) according to the criteria of the International Society of Cell Therapy. Then, we performed an [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay (MTT) assay after exposing cells with and without OA to TGF-β, Smad3 and BMP-4 pathway inhibitors and to different concentrations of BMP4. Results Exposure to the TGF-β, Smad3 and BMP-4 inhibitors modifies the mitochondrial activity of the SFCs. The activity of the SFCs is modified by influences of increasing concentrations of BMP4, but there is no difference in cellular activity between patients with and without OA. Conclusion TGF-β, Smad3 and BMP-4 modulate the activity of SFCs from patients with and without knee OA.


Suppression of human melanoma cell growth and metastasis by the melanoma-associated antigen CD63 (ME491).
CD63 has been identified in human melanoma cells by a number of different monoclonal antibodies (MAbs). Studies with MAbs have shown that expression is most marked in naevi and early forms of cutaneous melanoma and reduced in vertical growth phase and metastatic lesions. To investigate further the role of CD63 in progression of melanoma, genomic CD63 was transfected into a CD63-negative human melanoma cell line using an episomal vector. The stable transfected melanoma cells had similar growth rates to control transfected melanoma cells in vitro but much lower growth rates when injected intradermally into athymic nude mice. The CD63-transfected cells also had a reduced number of metastases in the peritoneal cavity and subcutaneous sites when injected intravenously. MAb against CD63 did not influence the growth of CD63-transfected melanoma cells in vitro. Our results confirm previous studies using H-ras-transformed NIH3T3 fibroblasts and suggest that CD63 may have a role as a tumor suppressor gene in human melanoma that acts to limit invasion and progression of melanoma.


Evaluation of quality indicators for nutrition and metabolism in critically ill patients: role of the pharmacist.
To assess compliance in a Spanish intensive care unit (ICU) with 8 of the 13 quality indicators of the Spanish Society of Intensive Medicine and Coronary Units (Sociedad Española de Medicina Intensiva y Unidades Coronarias, SEMICyUC) related to nutrition and metabolism in critically ill patients. The study included all patients over 18 years of age with an ICU stay of >48 hours between January and May 2019. The pharmacist was integrated into the daily activity of the multidisciplinary team of a 20-bed ICU to monitor and carry out the control of the quality indicators of the SEMICyUC. Studied indicators refer to: nutritional risk assessment and nutritional status (three indicators), glycaemic control, calculation of calorie-protein requirements, and use of early enteral nutrition or adequate parenteral nutrition. Compliance with each indicator was measured as the percentage of patients. 110 patients were included and 73 (66.4%) were male. Compliance results were: blood glucose range (90.7%), severe hypoglycaemia (0%), identification of patients at nutritional risk (58.2%) or with possible refeeding syndrome (8.9%), assessment of nutritional status at admission (58.2%), calculation of calorie-protein requirements (77.8%), early enteral nutrition (96.4%), and adequate use of parenteral nutrition (37.8%) CONCLUSION: Compliance with indicators related to glycaemic control and artificial nutrition (enteral and parenteral nutrition) was higher than reference standards, but there is a need to improve compliance with indicators related to nutritional risk and status at ICU admission. The hospital pharmacist integrated into the ICU multidisciplinary team can add value to the nutrition monitoring and quality indicators of the nutritional process of the critical patient, providing safe and effective nutritional therapy to patients.


Validation of a luminescence immunoassay for the detection of PrP(Sc) in brain homogenate.
A luminescence immunoassay (LIA) was developed for the diagnosis of bovine spongiform encephalopathy (BSE) in brain tissue using two different monoclonal antibodies for capture and detection of the protease-resistant fragment of the pathological prion protein (PrP27-30). PrP27-30 currently represents the most reliable marker for the infectious particle (denominated prion) causing transmissible spongiform encephalopathies (TSEs). Internal and official validation studies of this assay are described using brain homogenates from ascertained BSE positive and negative cows. Using more than 300 positive and 1400 negative bovine or ovine samples, an excellent sensitivity and specificity of 100% were demonstrated. More than 1000-fold dilutions of a BSE positive homogenate still resulted in a clear positive signal. In combination with a simple homogenisation procedure for the preparation of the samples, this assay lends itself for large scale screening of cattle and sheep for TSEs using complete automation of the process.


Impact on the Incremental Cost-Effectiveness Ratio of Using Alternatives to EQ-5D in a Markov Model for Multiple Sclerosis.
This study responds to a request in the National Institute for Health and Care Excellence (NICE) guidance to assess the impact of using alternative sources of utility values, applied to multiple sclerosis (MS). Incremental cost-effectiveness ratios (ICERs) were calculated using utility values based on UK and Dutch values of EQ-5D, two UK mappings and one Dutch mapping of EQ-5D and two condition-specific instruments: the UK eight-dimensional Multiple Sclerosis Impact Scale (MSIS-8D) and the Dutch Multiple Sclerosis Impact Scale Preference-Based Measure (MSIS-PBM). Deterministic and Monte-Carlo simulation-based ICERs were estimated for glatiramer acetate versus symptom management using a lifetime Markov model. For both UK and Dutch perspectives, mapped and condition-specific utility values expressed significantly higher quality of life for the worst health state of the model than did EQ-5D. The ICER of glatiramer acetate with EQ-5D was US$182,291 for The Netherlands and US$153,476 for the UK. Ratios for mapped and condition-specific utilities were between 20 and 60 % higher. The overestimation of quality of life of patients with MS by mapped EQ-5D or condition-specific utility values, relative to observed EQ-5D, increases the ICER substantially in a lifetime Markov model.


Application of artificial neural network for prediction of fluoride removal efficiency using neutralized activated red mud from aqueous medium in a continuous fixed bed column.
The present research work approaches the removal of fluoride from aqueous medium using neutralized activated red mud (NARM) in a continuous fixed bed column. Artificial neural network (ANN) technique was applied effectively for optimization of the model for the practicability of the removal process. The consequences of various experimental variables, like bed length, adsorbate concentration, experimental time, and adsorbate solution flow rate are studied to know the breakthrough point and saturation times. The highest removal potentiality of NARM was considered to be 3.815 mg g-1 of F- in the bed height of 15 cm, starting concentration 1 ppm, susceptible time 120 min, adsorbate solution flow rate 0.5 mL min-1, and constant room temperature, respectively. Bohart-Adams and Thomas models were considered to describe the fixed bed column effect to the bed height and adsorbate concentrations. The experimental data were applied to a back propagation (BP) learning algorithm programme with a four-seven-one architecture model. The artificial neural network model was considered to be functioning correctly as absolute relative percentage error throughout the learning period. Differentiation between the predicted outcomes from ANN model and actual results from experimental analysis affords a high degree of correlation (R2 = 0.998) stipulating that the model was able to predict the adsorption efficiency. Experimented adsorbent materials were characterized using different instrumental analysis that is scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDS), Fourier transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD).


Liquid crystal-based sensitive and selective detection of uric acid and uricase in body fluids.
The abnormal levels of uric acid (UA) in body fluids are associated with gout, type (II) diabetes, leukemia, Lesch-Nyhan syndrome, uremia, kidney damage, and cardiovascular diseases. Also, the presence of uricase (UOx) symbolizes genetic disorders and corresponding complications. Therefore, the detection of UA and UOx in the body fluids is significant for clinical diagnosis. 4-Cyano-4'-pentylbiphenyl (5CB, a nematic liquid crystal (LC)) was doped with octadecyl trimethylammonium bromide (OTAB, a cationic surfactant), which formed a self-assembled monolayer at the aqueous/5CB interface. The UOx-catalyzed oxidation of UA yielded H2O2, releasing the single-strand deoxyribonucleic acid (ssDNA) from the nanoceria/ssDNA complex. The interaction of the released ssDNA with OTAB disrupted the monolayer at the aqueous/5CB interface, which resulted in a dark to bright change when observed through a polarized optical microscope. The LC-based sensor allowed the detection of UA with a linear range of 0.01-10 μM and a limit of detection (LOD) of 0.001 μM. The UA detection was also performed in human urine samples and the results were comparable to that of a standard commercial colorimetric method. Similarly, the detection of UOx was performed, with a noted linear range of 20-140 μg/mL. The LOD was as low as 0.34 μg/mL. The detection of UOx was also demonstrated in human serum samples with excellent performance. This method provides a robust sensing platform for the detection of UA and UOx and has potential for applications in clinical analysis.


Genome-wide Mapping of Off-Target Events in Single-Stranded Oligodeoxynucleotide-Mediated Gene Repair Experiments.
Short single-stranded oligodeoxynucleotides are versatile molecular tools used in different applications. They enable gene repair and genome editing, and they are central to the antisense technology. Because the usability of single-stranded oligodeoxynucleotides depends on their efficiencies, as well as their specificities, analyzing their genotoxic off-target activities is important. Thus, we have developed a protocol that follows the fate of a biotin-labeled single-stranded oligodeoxynucleotide in human cells based on its physical incorporation into the targeted genome. Affected chromosomal fragments are enriched and preferably sequenced by nanopore sequencing. This protocol was validated in gene repair experiments without intentionally inducing a DNA double-strand break. For a 21-nucleotide-long phosphorothioate-modified oligodeoxynucleotide, we compiled a broad array of error-free incorporations, point mutations, indels, and structural rearrangements from actively dividing HEK293-derived cells. Additionally, we demonstrated the usefulness of this approach for primary cells by treating human CD34+ hematopoietic stem and progenitor cells with a 100-nucleotide-long unmodified oligodeoxynucleotide directed against the endogenous CYBB locus. This work should pave the way for future genotoxicity analyses. Concerning genome engineering approaches based on nuclease-induced DNA double-strand breaks, this protocol could aid in detecting the unwanted effects caused by the donor fragments themselves.


Safety and immunogenicity of the live-attenuated varicella vaccine in pediatric solid organ transplant recipients: A systematic review and meta-analysis.
This study aimed to synthesize the available evidence on the immunogenicity, safety, and effectiveness of live-attenuated varicella vaccine in solid organ transplant recipients. Medline and EMBASE were searched using predefined search terms to identify relevant studies. The included articles reported varicella vaccine administration in the posttransplant period in children and adults. A pooled proportion of transplant recipients who seroconverted and who developed vaccine-strain varicella and varicella disease was generated. Eighteen articles (14 observational studies and 4 case reports) were included, reporting on 711 transplant recipients who received the varicella vaccine. The pooled proportion was 88.2% (95% confidence interval 78.0%-96.0%, 13 studies) for vaccinees who seroconverted, 0% (0%-1.2%, 13 studies) for vaccine-strain varicella, and 0.8% (0%-4.9%, 9 studies) for varicella disease. Most studies followed clinical guidelines for administering live-attenuated vaccines, with criteria that could include being at least 1 year posttransplant, 2 months postrejection episode, and on low-dose immunosuppressive medications. Varicella vaccination in transplant recipients was overall safe in the included studies, with few cases of vaccine-strain-induced varicella or vaccine failure, and although it was immunogenic, the proportion of recipients who seroconverted was lower than that seen in the general population. Our data support varicella vaccination in select pediatric solid organ transplant recipients.


The effect of functional differences in the alpha and beta chains on the cooperativity of the osidation reduction reaction of hemoglobin.
Partially oxidized solutions of hemoglobin have been reacted with azide to determine the extent of oxidation, of the alpha and beta chains according to the method of McQuarrie and Gibson (J. Biol. Chem. (1971) 246, 517-522) In 2, 2'2'' nitriloethanol buffer the fraction of oxidized material represented by the beta chains decreases with decreasing extent of total oxidation, of the alpha chains. Upon addition of insitol hexaphosphate, the degree of perferntial oxidation in terms of a two-state model similar to the description of oxygenation by Edelstein (nature(1971) 230, 224-227) but with the incorporation of chain heterogeneity. The results indicate that the pH-dependent cooperativity of the oxidation-reduction reaction can be described in terms of a bell curbe of n versus log l, the allosteric somewhat lower and shifted slightly to the left, due in part to an affnity of beta chains for electrons approximately twince that of alpha chains. Because the curve is shifted to the left, oxidation-reduction equilibria at l values corresponding to pH 6 to lie on the right side of the bell curve where cooperativity the preferntial affity of beta chains for electrons rises to about 4 times that of alpha chains. As a consequence, the coreesponding bell curve is lowered with the Hill coeficient falling to unity or below in the range of l encountered. Thus the principal cause of decreased cooperativity is chain heterogeneity and not stabilization in the t state as suggested by Perutz; under these conditions the molecules of methemoglobin in the t state are only a fractional part of the population.


Multiple Myeloma in Adolescent and Young Adults: An ASCO CancerLinQ and SEER Analysis.
Multiple myeloma (MM) is exceedingly rare in adolescents and young adults (AYAs) < 45 years of age. Real-world data from ASCO's CancerLinQ DiscoveryⓇ (CLQD) MM dataset and SEER were utilized to characterize demographics and outcomes of AYA MM patients in the United States in the modern treatment era. Frequencies of SPMs, VTEs, and infections were assessed, as were OS and cause of death. A total of 1946 AYA MM patients from SEER and 1334 from CancerLinQ were included. In terms of SPMs, AYAs were more likely to develop ALL (RR 2.6, P = .003) and AML (RR 1.7, P = .034), and less likely to develop nonmelanoma skin cancer (RR 0.2, P = .001) and prostate cancer (RR 0.1, P = .013) than MM patients ≥ 45. AYAs were at lower risk of VTE (RR 0.75, P = .002) and slightly higher risk of infections (RR 1.11, P = .002). Median OS among AYA MM patients was significantly longer than MM patients ≥ 45 in both datasets. In the SEER cohort, female sex (HR 0.74, P = .003), non-Hispanic ethnicity (HR 0.73, P = .005), and annual household income ≥ $65,000 per year (HR 0.67, P = .001) were associated with lower hazards of mortality. In the CLQD cohort, OS was significantly influenced by female sex (HR 0.6, P = .048). Race did not have a statistically significant impact OS in either cohort. Most AYAs died of MM (68.3%), other primary malignancy (7.5%, mostly leukemia), and cardiovascular events (5.2%). Infections accounted for 3.2% of deaths. This analysis highlights some unique characteristics of AYA MM patients in the United States in the modern era.


Crystallization inhibitory effects of konjac glucomannan, sodium alginate and xanthan gum on curcumin in supersaturated solution.
Supersaturating drug delivery system (SDDS) is a promising approach to enhance the solubility of hydrophobic functional components. However, SDDS is thermodynamically unstable and crystallization tends to occur. In this work, curcumin was used as a model compound, and the crystallization inhibitory effect of konjac glucomannan (KGM), sodium alginate (SA) and xanthan gum (XTG) on curcumin in supersaturated solution was investigated. Amorphous solubility of curcumin was determined using ultraviolet extinction, fluorescence spectroscopy and dynamic light scattering methods. Nucleation induction time (NIT) and crystal growth rate of curcumin were evaluated using ultraviolet probe in the absence and presence of various natural polysaccharides (NPs). Results showed that amorphous solubility of curcumin was approximately 30 μg/mL in pH 6.8 phosphate buffer. NPs used in this work restrained nucleation or crystal growth of curcumin effectively. The NITs of curcumin in the absence of NPs and in the presence of XTG, KGM and SA (1 μg/mL) were 3.7, 60.7, 20.0 and 8.0 min, respectively. The crystal growth rate of curcumin in the absence of NPs and in the presence of XTG, SA and KGM (1 μg/mL) were 0.0103, 0.00752, 0.00286 and 0.000306 min-1, respectively. The nucleation inhibitory effect of NPs on curcumin was ranked as XTG > KGM > SA. The order of crystal growth inhibition capacity of NPs was KGM > SA > XTG. In conclusion, NPs could be incorporated into SDDS to maintain supersaturation of hydrophobic components for enhanced bioavailability.


Inactivation of p53 sensitizes astrocytic glioma cells to BCNU and temozolomide, but not cisplatin.
p53 inactivation sensitizes U87MG astrocytic glioma cells to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide (TMZ), drugs used clinically to treat high-grade astrocytomas. In this report, we examined the effect of p53 inactivation on the chemosensitivity of two additional human astrocytic glioma cell lines, D54 and A172, in order to assess whether sensitization is a general property of astrocytic tumor cells. Compared to control cells with intact p53 function, derived lines in which p53 was inactivated displayed significantly reduced clonogenic survival after exposure to BCNU and TMZ. Sensitization to both BCNU and TMZ was associated with failure of p21(WAF1) induction, lack of a sustained G2 cell cycle arrest and significant tumor cell death. These findings suggest that enhanced sensitivity to BCNU and TMZ is a general property of human astrocytic glioma cells in which p53 was disrupted. In contrast, p53 inactivation rendered D54 and U87MG cells significantly more resistant to cis-dichlorodiamminoplatinum (CDDP), another chemotherapeutic to which high-grade astrocytomas sometimes respond. These results indicate that p53 status influences the chemosensitivity of astrocytic glioma cells in a drug-type specific manner, a finding that may have implications for the selection of drug treatments for patients with astrocytic gliomas.


Switching to once-weekly insulin icodec versus once-daily insulin glargine U100 in individuals with basal-bolus insulin-treated type 2 diabetes (ONWARDS 4): a phase 3a, randomised, open-label, multicentre, treat-to-target, non-inferiority trial.
Insulin icodec (icodec) is a basal insulin analogue suitable for once-weekly dosing. ONWARDS 4 aimed to assess the efficacy and safety of once-weekly icodec compared with once-daily insulin glargine U100 (glargine U100) in individuals with long-standing type 2 diabetes on a basal-bolus regimen. In this 26-week, phase 3a, randomised, open-label, multicentre, treat-to-target, non-inferiority trial, adults from 80 sites (outpatient clinics and hospital departments) across nine countries (Belgium, India, Italy, Japan, Mexico, the Netherlands, Romania, Russia, and the USA) with type 2 diabetes (glycated haemoglobin [HbA1c] 7·0-10·0%) were randomly assigned (1:1) to receive once-weekly icodec or once-daily glargine U100 combined with 2-4 daily bolus insulin aspart injections. The primary outcome was change in HbA1c from baseline to week 26 (non-inferiority margin of 0·3 percentage points). The primary outcome was evaluated in the full analysis set (ie, all randomly assigned participants). Safety outcomes were evaluated in the safety analysis set (ie, all participants randomly assigned who received at least one dose of trial product). This trial is registered with ClinicalTrials.gov, NCT04880850. Between May 14 and Oct 29, 2021, 746 participants were screened for eligibility, of whom 582 (78%) were randomly assigned (291 [50%] to icodec treatment and 291 [50%] to glargine U100 treatment). Participants had a mean duration of type 2 diabetes of 17·1 years (SD 8·4). At week 26, estimated mean change in HbA1c was -1·16 percentage points in the icodec group (baseline 8·29%) and -1·18 percentage points in the glargine U100 group (baseline 8·31%), showing non-inferiority for icodec versus glargine U100 (estimated treatment difference 0·02 percentage points [95% CI -0·11 to 0·15], p<0·0001). Overall, 171 (59%) of 291 participants in the icodec group and 167 (57%) of 291 participants in the glargine U100 group had an adverse event. 35 serious adverse events were reported in 22 (8%) of 291 participants in the icodec group and 33 serious adverse events were reported in 25 (9%) of 291 participants receiving glargine U100. Overall, combined level 2 and level 3 hypoglycaemia rates were similar between treatment groups. No new safety concerns were identified for icodec. In people with long-standing type 2 diabetes on a basal-bolus regimen, once-weekly icodec showed similar improvements in glycaemic control, with fewer basal insulin injections, lower bolus insulin dose, and with no increase in hypoglycaemic rates compared with once-daily glargine U100. Key strengths of this trial include the use of masked continous glucose monitoring; the high trial completion rate; and the inclusion of a large, diverse, and multinational population. Limitations include the relatively short trial duration and the open-label design. Novo Nordisk.


Group A meningococcal disease in the U.S. Pacific Northwest: epidemiology, clinical features, and effect of a vaccination control program.
In 1975 an outbreak of group A meningococcal disease began in Seattle, Washington, and cases subsequently were recognized throughout the Pacific Northwest. Nearly one-half of the affected persons were Native Americans; two-thirds were alcohol abusers and/or habitués of skid road communities. In Seattle, group A meningococci colonized asymptomatic persons only if these individuals had contact with skid road (P = .006). The epidemic strain may have spread from American Indians in Manitoba, Canada. Traditional migration routes connect the two populations; asymptomatic American Indians on reservations in Washington carried group A meningococci. Vaccination programs were undertaken in four cities but only after cases occurred. In Seattle, vaccination reached 80% of the target population and was associated with a significant decrease in incidence of the disease, but cases recurred after the program ended. The social habits of skid road communities, combined with the "case-triggering" approach to, and premature termination of, vaccination programs, may have resulted in 56% of regional cases occurring after the start of the vaccination program in Seattle.


An unusual cause of headache: a dentigerous cyst in the maxillary sinus.
We report the case of a patient with a dentigerous cyst in the maxillary sinus presenting as two months of intermittent, unilateral, pressure-like headaches. The diagnosis was suspected after an upright Waters' projection radiogram and confirmed histologically after surgical removal. The patient was symptom free one year later.


The Atomic Rearrangement of GaN-Based Multiple Quantum Wells in H2/NH3 Mixed Gas for Improving Structural and Optical Properties.
In this work, three GaN-based multiple quantum well (MQW) samples are grown to investigate the growth techniques of high-quality MQWs at low temperature (750 °C). Instead of conventional temperature ramp-up process, H2/NH3 gas mixture was introduced during the interruption after the growth of InGaN well layers. The influence of hydrogen flux was investigated. The cross-sectional images of MQW via transmission electron microscope show that a significant atomic rearrangement process happens during the hydrogen treatment. Both sharp interfaces of MQW and homogeneous indium distribution are achieved when a proper proportion of hydrogen was used. Moreover, the luminescence efficiency is improved strongly due to suppressed non-radiative recombination process and a better homogeneity of MQWs. Such kind of atomic rearrangement process is mainly caused by the larger diffusion rate of gallium and indium adatoms in H2/NH3 mixed gas, which leads to a lower potential barrier energy to achieve thermodynamic steady state. However, when excessive hydrogen flux is introduced, the MQW will be partly damaged, and the luminescence performance will deteriorate.


[190 years of clinical endoscopy: Philipp Bozzini, an almost forgotten pioneer].
190 years ago Philipp Bozzini published his invention of a "light guide". With this idea the basic of the modern endoscopy was established.


A chimeric Sindbis-based vaccine protects cynomolgus macaques against a lethal aerosol challenge of eastern equine encephalitis virus.
Eastern equine encephalitis virus (EEEV) is a mosquito-borne alphavirus that causes sporadic, often fatal disease outbreaks in humans and equids, and is also a biological threat agent. Two chimeric vaccine candidates were constructed using a cDNA clone with a Sindbis virus (SINV) backbone and structural protein genes from either a North (SIN/NAEEEV) or South American (SIN/SAEEEV) strain of EEEV. The vaccine candidates were tested in a nonhuman primate (NHP) model of eastern equine encephalitis (EEE). Cynomolgus macaques were either sham-vaccinated, or vaccinated with a single dose of either SIN/NAEEEV or SIN/SAEEEV. After vaccination, animals were challenged by aerosol with a virulent North American strain of EEEV (NA EEEV). The SIN/NAEEEV vaccine provided significant protection, and most vaccinated animals survived EEEV challenge (82%) with little evidence of disease, whereas most SIN/SAEEEV-vaccinated (83%) and control (100%) animals died. Protected animals exhibited minimal changes in temperature and cardiovascular rhythm, whereas unprotected animals showed profound hyperthermia and changes in heart rate postexposure. Acute inflammation and neuronal necrosis were consistent with EEEV-induced encephalitis in unprotected animals, whereas no encephalitis-related histopathologic changes were observed in the SIN/NAEEEV-vaccinated animals. These results demonstrate that the chimeric SIN/NAEEEV vaccine candidate protects against an aerosol EEEV exposure.


Meningioma.
Meningiomas are mostly benign tumours originating from the arachnoid cap cells, represent 13-26% of all intracranial tumours. They are more common in older age and in females. Deletion in NF2 gene and exposure to ionizing radiation are established risk factors, while the role of sex hormones is yet not clarified. Five-year survival for typical meningiomas exceeds 80%, but is poorer (5-year survival <60%) in malignant and atypical meningiomas. Papillary and haemangiopericytic morphology, large tumour size, high mitotic index, absence of progesterone receptors, deletions and loss of heterozygosity are poor prognostic factors. Complete surgical excision is the standard treatment. Radiotherapy is currently used in the clinical practice in atypical, malignant or recurrent meningioma at a total dose of 45-60Gy. However, the role of adjuvant irradiation is still controversial and has to be compared in a randomised prospective setting with a policy of watchful waiting. Radiosurgery has gained more and more importance in the management of meningiomas, especially in meningiomas that cannot be completely resected as for many skull base meningiomas. Medical therapy for patients with recurrent, progressive and symptomatic disease after repeated surgery, radiosurgery and radiotherapy is investigational. Hormonal therapy with progesterone antagonists has shown modest results, while chemotherapy with hydroxyurea appears moderately active.


Galactose-Deficient IgA1 Deposits in Clear Cell Renal Cell Carcinoma-Related Henoch-Schönlein Purpura Nephritis.
Recent studies suggest that galactose-deficient IgA1 (Gd-IgA1) plays a role in the pathogenesis of primary IgA nephropathy (IgAN) and Henoch-Schönlein purpura nephritis (HSPN). Furthermore, immunostaining of KM55, an antibody that identifies Gd-IgA1, may be helpful to differentiate primary IgAN and HSPN from secondary causes of glomerular IgA deposition. We report sequential kidney biopsies of a malignancy-associated HSPN, showing intense glomerular mesangial IgA deposition at the initial kidney biopsy and dramatic decrease in disappearance of glomerular deposits after tumor removal. We demonstrate that the glomerular IgA deposition contains Gd-IgA1, detected by immunostaining of KM55, with similar distribution and intensity to IgA. This suggests that renal Gd-IgA1 deposition may play a role in the pathogenesis of malignancy-associated HSPN.


Novel integrated workflow allows production and in-depth quality assessment of multifactorial reprogrammed skeletal muscle cells from human stem cells.
Skeletal muscle tissue engineering aims at generating biological substitutes that restore, maintain or improve normal muscle function; however, the quality of cells produced by current protocols remains insufficient. Here, we developed a multifactor-based protocol that combines adenovector (AdV)-mediated MYOD expression, small molecule inhibitor and growth factor treatment, and electrical pulse stimulation (EPS) to efficiently reprogram different types of human-derived multipotent stem cells into physiologically functional skeletal muscle cells (SMCs). The protocol was complemented through a novel in silico workflow that allows for in-depth estimation and potentially optimization of the quality of generated muscle tissue, based on the transcriptomes of transdifferentiated cells. We additionally patch-clamped phenotypic SMCs to associate their bioelectrical characteristics with their transcriptome reprogramming. Overall, we set up a comprehensive and dynamic approach at the nexus of viral vector-based technology, bioinformatics, and electrophysiology that facilitates production of high-quality skeletal muscle cells and can guide iterative cycles to improve myo-differentiation protocols.


[Ultrastructural mechanisms of the effect of myelopeptides on brain lesions in rats receiving endotoxin and the role of receptor-mediated endocytosis].
It has been demonstrated that myelopeptide is capable of preventing some ultrastructural alterations that take place in the brain in response to intravenous lipopolysaccharide injection by neuronal receptor blockade.


Inflammatory bowel disease in chronic granulomatous disease: An emerging problem over a twenty years' experience.
Chronic granulomatous disease (CGD) is a primary immunodeficiency of phagocytes, characterized by life-threatening infections and hyperinflammation. Due to survival improvement, inflammatory bowel disease (IBD) is becoming increasingly relevant. Here, we report our 20 year experience. We retrospectively analyzed clinic, endoscopic, and histologic features, as well as the management of CGD-IBD patients referred to the Bambino Gesù Children's Hospital in Rome, Italy. Of 20 patients with CGD, 9 presented with CGD-IBD at diagnosis and/or during follow-up. Symptoms occurred at a median age of 16 years (range 3.2-42), with a median delay of 6 months for endoscopic confirmation. Patients mainly complained of nonspecific diarrhea (55%), with discrepancy between symptom paucity and severe endoscopic appearance, mainly represented by extensive colonic involvement (44%). Histology revealed at least 2 characteristic features (epithelioid granulomas, pigmented macrophages, and increased eosinophils) in 78% of patients. Eight of 9 patients received oral mesalamine, and 5 required systemic steroids. One patient received azathioprine due to steroid dependence. No patient required biological therapy or surgery. Clinical remission was obtained in all patients, but the majority complained of mild relapses. Two episodes of severe infection occurred early after steroid therapy. Penetrance of CGD-IBD increases with age. Clinical manifestations may be subtle, and clinicians should have a low threshold to recommend endoscopy. Treatment with NSAIDs and/or steroids achieves a good response, but relapses usually occur. Infection surveillance is mandatory during treatment, to prevent opportunistic infections. A close collaboration between pediatric immunologists and gastroenterologists is pivotal, including combined follow-up.


Case series of Rapidly growing Mycobacterial Post-operative surgical site infection in kidney transplant recipients.
Case series of Rapidly growing Mycobacterial Post-operative wound infection with Mycobacterium Abscessus and/or Mycobacterium Chelone in 4 cases of kidney transplant adult recipient who presented within 6 months of transplant. We report 4 cases of Renal transplant recipients with post-surgical site infection with NTM-69-year-old with post-surgical wound infection with microbiologically proven Mycobacterium Abscessus who discontinued treatment and further presented with intra-abdominal abscess. Next case was 61 years male presented with nodular swellings at surgical site with US findings of intra-abdominal muscle abscess was tested culture positive for Mycobacterium Chelonae and Abscessus.Third case was 34 years male presented with surgical wound infection which was positive for AFB by ZN stain. Lastly,46 years old male patient known hypertensive and E.S.R.D, had culture proven Mycobacterium Abscessus surgical wound infection. All the four cases had their renal transplant at Philippines at different centres. Nontuberculous mycobacteria infection is important cause of morbidity in kidney transplant recipient and high index of suspicion with early diagnosis and treatment is crucial for successful outcome.


Randomised clinical trial: the synbiotic food supplement Probiotical vs. placebo for acute gastroenteritis in children.
Some probiotic strains reduce the duration of acute diarrhoea. As a result of strain and product specificity, each product needs support by clinical data. In children with acute diarrhoea, to test the efficacy of the synbiotic food supplement Probiotical (Streptoccoccus thermophilus, Lactobacillus rhamnosus, Lactobacillus acidophilus, Bifidobacterium lactis, Bifidobacterium infantis, fructo-oligosaccharides). The primary end-points were duration of diarrhoea and the number of children that had a normalised stool consistency. A total of 111 children with acute diarrhoea (median age 40 months) were included in this randomised, prospective placebo-controlled parallel clinical trial in primary health care. All children were treated with oral rehydration solution ad libitum and with the synbiotic (n=57) or placebo (n = 54). The median duration of diarrhoea was 3 days (IQ 25-75: 2-4 days) in the Probiotical group, compared with 4 days (IQ 25-75: 4-5 days) in the placebo group (P<0.005). The number of children with normal stool consistency (defined as stool Bristol score ≤4) was higher in the synbiotic group on days 2 and 3 [21 vs. 2% (P<0.001) and 50 vs. 24% (P<0.001) respectively]. Less additional medication (antipyretics, antiemetics, antibiotics) was administered in the synbiotic group. Physicians were globally more satisfied with the synbiotic food supplement treatment than with placebo (P=0.005). One patient in the placebo group was hospitalised. The median duration of diarrhoea was significantly 1 day shorter in the synbiotic than in the placebo group, associated with decreased prescription of additional medications.


Progestin is important for testicular development of male turbot (Scophthalmus maximus) during the annual reproductive cycle through functionally distinct progestin receptors.
In teleost, sex steroid hormones are critical for reproduction. Progestin is known to promote spermiation. To further understand the functions of progestin via its receptors during the annual reproductive cycle in male turbot (Scophthalmus maximus), we observed testicular development, quantified several sex steroid hormones, detected the expression of progestin receptors, and measured various sperm parameters. Results showed that the turbot testicular structure was of the lobular type. During breeding season, a number of spermatocytes (stage III) developed into spermatids (stage IV), then differentiated into sperm during spermiogenesis (stage V), and finally regressed to spermatocytes (stage VI). Concomitant with testicular development, serum progesterone (P4) and 17α,20β-dihydroxy-4-pregnen-3-one (DHP) exhibited higher levels from stage IV to V than other stages. Furthermore, males with higher motility sperm showed higher levels of P4 and DHP compared with fish with lower motility sperm. These results indicated that P4 and DHP might induce spermatogenesis due to seasonal changes. Concurrently, in testes, the nuclear progesterone receptor (pgr) was expressed throughout the reproductive cycle and its level peaked during spermiogenesis while expression of membrane progestin receptor alpha (mPRα) did not change significantly. However, in sperm, mPRα expression was higher than in testes and had a significant positive correlation with curvilinear velocities (VCL), sperm motility, and motility duration. In conclusion, progestin appears to exert a direct pgr-mediated effect on spermiogenesis and improve sperm motility characteristics depending on the abundance of mPRα protein in sperm during spermiation.


The more important role of archaea than bacteria in nitrification of wastewater treatment plants in cold season despite their numerical relationships.
Nitrification failure of wastewater treatment plants (WWTPs) in cold season calls into investigations of the functional ammonia-oxidizing microorganisms (AOMs). In this study, we report the abundance of ammonia-oxidizing archaea (AOA), bacteria (AOB) and complete ammonia-oxidizing (comammox) Nitrospira in 23 municipal WWTPs in cold season, and explore the correlations between AOMs abundance and their relative contribution to nitrification. The copy numbers of AOA and AOB amoA gene ranged from 2.42 × 107 to 2.47 × 109 and 5.54 × 106 to 3.31 × 109 copies/g sludge, respectively. The abundance of amoA gene of Candidatus Nitrospira inopinata, an important strain of comammox Nitrospira, was stable with averaged abundance of 8.47 × 106 copies/g sludge. DNA-based stable isotope probing (DNA-SIP) assays were conducted with three typical WWTPs in which the abundance of AOA was lower than, similar to and higher than that of AOB, respectively. The results showed that considerable 13C-assimilation by AOA was detected during active nitrification in all WWTPs, whereas just a much lesser extent of 13C-incorporation by AOB and comammox Nitrospira was found in one WWTP. High-throughput sequencing with 13C-labeled DNA also showed the higher reads abundance of AOA than AOB and comammox Nitrospira. Nitrososphaera viennensis was the dominant active AOA, while Nitrosomonas oligotropha and Nitrosomonas europaea were identified as active AOB. The results obtained suggest that AOA, rather than AOB and comammox Nitrospira, dominate ammonia oxidation in WWTPs in cold season despite the numerical relationships of AOMs.


The LDL receptor pathway delivers arachidonic acid for eicosanoid formation in cells stimulated by platelet-derived growth factor.
Animal cells can convert 20-carbon polyunsaturated fatty acids into prostaglandins (PGs) and leukotrienes. These locally produced mediators of inflammatory and immunological reactions act in an autocrine or paracrine fashion. Arachidonic acid (AA), the precursor of most PGs and leukotrienes, is present in the form of lipid esters within plasma lipoproteins and cannot be synthesised de novo by animal cells. Therefore, AA or its plant-derived precursor, linoleic acid, must be provided to cells if PGs or leukotrienes are to be formed. Because several classes of lipoproteins, including low-density lipoproteins (LDL), very-low-density lipoproteins, and chylomicron remnants, are taken up by means of the LDL receptor, and because LDL and very-low-density lipoproteins, but not high-density lipoproteins, stimulate PG synthesis, we have suggested previously that PG formation is directly linked to the LDL pathway. Using fibroblasts with the receptor-negative phenotype of familial hypercholesterolaemia and anti-LDL receptor antibodies, we show here that LDL deliver AA for PG production and that an LDL receptor-dependent feedback mechanism inhibits the activity of PGH synthase, the rate-limiting enzyme of PG synthesis. These results indicate that the LDL pathway has a regulatory role in PG synthesis, in addition to its well-known role in the maintenance of cellular cholesterol homeostasis.


Spasticity, weakness, force variability, and sustained spontaneous motor unit discharges of resting spastic-paretic biceps brachii muscles in chronic stroke.
The purpose of our study was to examine relations among spasticity, weakness, force variability, and sustained spontaneous motor unit discharges in spastic-paretic biceps brachii muscles in chronic stroke. Ten chronic stroke subjects produced submaximal isometric elbow flexion force on impaired and non-impaired sides. Intramuscular EMG (iEMG) was recorded from biceps and triceps brachii muscles. We observed sustained spontaneous motor unit discharges in resting biceps on iEMG. Spontaneous discharges increased after voluntary activation only on the impaired side. The impaired side had greater matching errors and greater fluctuations in isometric force. Spontaneous discharges were not related functionally to spasticity, force variability, or weakness. However, greater strength on the impaired side correlated with less force variability. Weakness rather than spasticity is a main factor interfering with voluntary force control in paretic-spastic biceps brachii muscles in chronic stroke.


Stepwise adaptations to low temperature as revealed by multiple mutants of psychrophilic α-amylase from Antarctic Bacterium.
The mutants Mut5 and Mut5CC from a psychrophilic α-amylase bear representative stabilizing interactions found in the heat-stable porcine pancreatic α-amylase but lacking in the cold-active enzyme from an Antarctic bacterium. From an evolutionary perspective, these mutants can be regarded as structural intermediates between the psychrophilic and the mesophilic enzymes. We found that these engineered interactions improve all the investigated parameters related to protein stability as follows: compactness; kinetically driven stability; thermodynamic stability; resistance toward chemical denaturation, and the kinetics of unfolding/refolding. Concomitantly to this improved stability, both mutants have lost the kinetic optimization to low temperature activity displayed by the parent psychrophilic enzyme. These results provide strong experimental support to the hypothesis assuming that the disappearance of stabilizing interactions in psychrophilic enzymes increases the amplitude of concerted motions required by catalysis and the dynamics of active site residues at low temperature, leading to a higher activity.


Bradykinin preconditioning induces protective effects against focal cerebral ischemia in rats.
Bradykinin is recognized to play an important role in heart ischemia tolerance, and it is expressed in ischemic brain. We hypothesized that bradykinin might play a role in the regulation of tolerance to ischemic brain when administered prior to the ischemic episode. We investigated the effects of bradykinin preconditioning on ischemic damage using an in vivo model of 2-h ischemia and 24-h reperfusion focal cerebral ischemia in rats. Prior to ischemia, bradykinin was pumped into the brain via external carotid artery at a dose of 10 microg/kg/min for 15 min. A significant reduction of 41.20% in infarct size was noted in rats pretreated by bradykinin 15 min prior to ischemia. Brain edema and permeability of blood-brain barrier were also decreased. Immunohistochemical and Western blot analysis of brains revealed a significant increase in basic fibroblast growth factor protein levels. The study demonstrated that bradykinin preconditioning induces protection against ischemic brain injury, and this protection is likely due to the protection of cerebral vasculature and the promotion of neuronal survival.


Inspiratory flow rates and volumes with the Aerolizer dry powder inhaler in asthmatic children and adults.
To assess the peak inspiratory flow rate (PIFR) and forced inspiratory vital capacity (FIVC) through the formoterol (Foradil*) Aerolizer* in patients with mild, moderate and severe asthma. PIFR and FIVC were assessed in 33 adults and 32 children using a spirometer alone (baseline), a spirometer with an adaptor, and a spirometer with an adaptor and the Aerolizer inhaler (placebo loaded). Of adult patients using the Aerolizer inhaler, 73% had PIFR values of >100 l/min and 91% had values of >60 l/min. PIFR in adults was reduced from a mean baseline of 283 l/min to 118 l/min through the loaded Aerolizer inhaler. Similarly, 75% of children using the Aerolizer inhaler had PIFR values >80 l/min and 91% had values of > 60 l/min. The mean PIFR in children was reduced from a baseline of 154 l/min to 100 l/min through the loaded Aerolizer inhaler. Only small mean decreases from baseline were observed in FIVC through the loaded Aerolizer inhaler: 8.4% in adults and 3.8% in children. FIVC values of > 2.0 litre were achieved in 82% of adults, and 81% of children achieved FIVC values of >1.5 litre. This study, albeit in a relatively small patient population, suggests that most children and adults with asthma can generate PIFRs of > 60 l/min and FIVCs of > 1.5 litre through the Aerolizer inhaler regardless of their disease severity. Such findings compare extremely favourably with other dry powder inhalers.


Validation of heart rate spot-check protocol to measure circadian variation and heart rate in healthy dogs and dogs with atrial fibrillation.
Alternatives for out-of-clinic heart rate (HR) measurement are required to optimise the management of atrial fibrillation (AF) in dogs. Additionally, the presence of circadian variation (CV) in HR in pet dogs remains unknown. We aimed to identify the number and duration of spot-checks required for an accurate estimation of 24-hour HR in canine AF. Circadian variation in HR was examined in healthy dogs and dogs with AF, and spot-check-derived HR was compared with a CV-derived gold standard. Ambulatory electrocardiogram data from healthy dogs and dogs with AF were retrospectively analysed. Heart rate was calculated from the entire recording and pre-defined periods (spot-checks) of one hour to 30 and 60 s in duration. Circadian variation in HR was determined by cosinor analysis. Bias and limits of agreement of means and median HR with mesor HR were determined by correlation and Bland-Altman analysis. Circadian variation in HR was identified not only in 18/22 healthy dogs and 14/21 AF dogs but only on ambulatory electrocardiogram recordings. Four-hourly spot-checks provided the most accurate estimate of mesor HR in healthy dogs (bias of the median over 30 s 7.70, limits of agreement 7.48), whereas, in dogs with AF, four, six and eight-hourly spot-checks provided reliable estimates of mesor HR (bias within -1.29 and -29.5). Four, six and eight-hourly HR spot-checks can estimate 24-hourly HR in dogs with AF. There was CV in HR in most healthy pet dogs and dogs with AF. Spot-check protocols cannot identify CV in HR.


Study on the influence of industrial intelligence on carbon emission efficiency-empirical analysis of China's Yangtze River Economic Belt.
How to achieve the goal of "carbon peak and carbon neutrality" and explore the compatibility of industrial and ecological civilization is a major challenge for China today. This study analyzes the impact of industrial intelligence on industrial carbon emissions efficiency in 11 provinces of China's Yangtze River Economic Belt, measuring the efficiency of industrial carbon emissions through the non-expected output slacks-based measure (SBM) model, selecting industrial robot penetration to measure the level of industrial intelligence, establishing a two-way fixed model to verify the impact of industrial intelligence on carbon emission efficiency, and testing for intermediary effects and regional heterogeneity. The results show that: (1) the industrial carbon emission efficiency of the 11 provinces shows year-over-year improvement, with significant differences between upstream, midstream, and downstream, where downstream is the highest and upstream is the lowest. (2) The development of industrial intelligence is highly uneven, with the upstream level being the weakest. (3) Industrial intelligence can improve the efficiency of industrial carbon emissions by enhancing green technological innovation and energy use efficiency. (4) The effect of industrial intelligence on industrial carbon emission efficiency also shows regional heterogeneity. Finally, we present policy recommendations. This research provides mathematical and scientific support for achieving carbon reduction targets at an early stage and helps accelerate the construction of a modern, low-carbon China.


Inhibitory effects of anticancer drugs on dextromethorphan-O-demethylase activity in human liver microsomes.
The dextromethorphan-O-demethylase activity determined in human liver microsomes was used to screen various anticancer drugs for their ability to inhibit this cytochrome CYP2D6-dependent activity. Competitive inhibition indicates that the drug binds the enzyme and is potentially subjected to a polymorphic metabolism. Among the 13 anticancer drugs tested, 4 compounds caused competitive inhibition of dextromethorphan-O-demethylation: lomustine (Ki = 7.7 microM), doxorubicin (Ki = 75 microM), vinorelbine (Ki = 22 microM), and vinblastine (Ki = 42 microM). The results of these studies indicate that the metabolism of the drugs concerned is possibly altered in poor metabolizers of debrisoquine and requires further investigation to study their specific routes of biotransformation. The metabolism of these drugs probably involves various biotransformation pathways, among which the CYP2D6-dependent route would be of minor importance. A second hypothesis is that these drugs could be inhibitors of the isozyme without being a substrate.


The long-term outcome of lumbar fusion in the Swedish lumbar spine study.
Current literature suggests that in the long-term, fusion of the lumbar spine in chronic low back pain (CLBP) does not result in an outcome clearly better than structured conservative treatment modes. This study aimed to assess the long-term outcome of lumbar fusion in CLBP, and also to assess methodological problems in long-term randomized controlled trials (RCTs). A prospective randomized study was carried out. A total of 294 patients (144 women and 150 men) with CLBP of at least 2 years' duration were randomized to lumbar fusion or non-specific physiotherapy. The mean follow-up time was 12.8 years (range 9-22). The follow up rate was 85%; exclusion of deceased patients resulted in a follow-up rate of 92%. Global Assessment (GA) of back pain, Oswestry Disability Index (ODI), visual analogue scale (VAS) for back and leg pain, Zung depression scale were determined. Work status, pain medication, and pain frequency were also documented. Standardized outcome questionnaires were obtained before treatment and at long-term follow-up. To optimize control for group changers, four models of data analysis were used according to (1) intention to treat (ITT), (2) "as treated" (AT), (3) per protocol (PP), and (4) if the conservative group automatically classify group changers as unchanged or worse in GA (GCAC). The initial study was sponsored by Acromed (US$50,000-US$100,000). Except for the ITT model, the GA, the primary outcome measure, was significantly better for fusion. The proportion of patients much better or better in the fusion group was 66%, 65%, and 65% in the AT, PP, and GCAC models, respectively. In the conservative group, the same proportions were 31%, 37%, and 22%, respectively. However, the ODI, VAS back pain, work status, pain medication, and pain frequency were similar between the two groups. One can conclude that from the patient's perspective, reflected by the GA, lumbar fusion surgery is a valid treatment option in CLBP. On the other hand, secondary outcome measures such as ODI and work status, best analyzed by the PP model, indicated that substantial disability remained at long-term after fusion as well as after conservative treatment. The lack of objective outcome measures in CLBP and the cross-over problem transforms an RCT to an observational study, that is, Level 2 evidence. The discrepancy between the primary and secondary outcome measures prevents a strong conclusion on whether to recommend fusion in non-specific low back pain.


Acute renal failure in bone marrow transplant patients admitted to the intensive care unit.
Review of bone marrow transplant (BMT) cases admitted to our intensive care unit (ICU) and to compare co-morbidity and outcome of BMT patients developing or not developing acute renal failure (ARF). A case review of BMT patients admitted to the ICU (a 16-bed medico-surgical ICU in a tertiary care teaching institution) over a 4-year period. Between January 1994 and December 1998, 57 among 441 BMT patients (12.9%) were admitted to the ICU, mainly for respiratory distress (58%) and hypotension (32%). Forty-two patients (73.7%) presented ARF as defined as a doubling of serum creatinine. Compared to the 15 other patients, ARF patients had a higher APACHE II score (30 +/- 8 vs. 25 +/- 7, p < 0.05). For ARF vs. non-ARF patients, there was no difference in age (43.8 +/- 10.8 vs. 44.3 +/- 11.1 years), in requirement for mechanical ventilation (76 vs. 73%) and vasopressors (69 vs. 60%), and in prevalence of graft-versus-host disease (19 vs. 13%) or neutropenia (69 vs. 67%), but the prevalence of sepsis (83 vs. 60%) and liver failure (69 vs. 40%) was higher. Maximum serum bilirubin was markedly increased in ARF compared to non-ARF patients (p < 0.005). For both subgroups, no difference in the administration of potential nephrotoxic agents was identified. Usually, ARF was considered multifactorial by clinicians, with ATN being the most frequent diagnosis (55%). Maximum serum creatinine reached a mean of 330 +/- 130 micromol/l. In 74% of cases, ARF occurred concomitantly or after admission to the ICU. Oligoanuria was present in 38%, whereas polyuria was observed in 17%. Fourteen ARF patients (33%) required dialytic support. Mortality rates were significantly different in ARF vs. non-ARF patients (88 vs. 60%, p < 0.05). Predictive factors for the development of ARF were liver failure (odds ratio (OR) 5.9), low serum albumin (OR 1.2) and APACHE II score (OR 1.1), whereas variables predictive of mortality were mechanical ventilation (OR 14.8), ARF (OR 5.8), liver failure (OR 3.7), and APACHE II score (OR 1.2). This study confirms that ARF in BMT patients admitted to the ICU is frequent, multifactorial, related to liver failure, and that its development has a negative impact on outcome.


Development of the basal lamina and extracellular materials in the early chick embryo.
Chick embryos at developmental stages up to primitive streak formation were fixed in a mixture of tannic acid and glutaraldehyde. A basal lamina was present in the unincubated embryo and consisted of a lucent lamina interna and a lamina densa. At the primitive streak stage the lamina densa showed a periodicity of stained elements. Densely stained materials were present on the cell surfaces lining the cavity between the epiblast and endoblast, and on the mesoderm cells within this cavity. Considerable amounts of extracellular material were observed in the cavity. Hyaluronidase treatment removed the cell surface and extracellular material, indicating that hyaluronic acid is a major component. This enzyme disrupted the basal lamina, leaving a fibrillar remnant with no periodic structure. It is therefore suggested that the dense periodicities consist of glycosaminoglycan built on an enzyme-resistant framework which is probably collagen. Enzyme-resistant fibrils, presumably collagen precursors, are present elsewhere within the tissue spaces.


Impact of school-based health centers on children with asthma.
To quantitatively assess the impact of school-based health centers (SBHCs) on hospitalization and emergency department (ED) visits for children with asthma. The study was conducted at four SBHC intervention school districts and two comparable non-SBHC school districts in Greater Cincinnati, Ohio. A longitudinal quasi-experimental time-series repeated measures design was used with a study period from 1997 to 2003. Children with asthma with at least 2 years of continuous enrollment who had medical claims for asthma diagnosis and antiasthmatic medications were selected. The primary data sources were student enrollment data from the schools and the Ohio Medicaid claims database. Generalized estimating equation (GEE) analysis and analysis of covariance were used to assess the intervention effect before and after the SBHC program. Asthma was one of the major diseases for SBHC encounters. Major prescription drugs that SBHC staff managed for children with asthma included albuterol, montelukast, fluticasone, budesonide, and triamcinolone. Of 273 children (196 in SBHC schools and 77 in non-SBHC schools), 42% were female, 41.7% African-Americans, and the average age was 8.2 years. After the opening of the SBHC, relative risks of hospitalization and ED visits in the SBHC group decreased 2.4-fold and 33.5%, respectively. The cost of hospitalization per child decreased significantly over time for children in SBHC schools (F = 4.115, p = .044). After SBHCs opened, cost of hospitalization decreased for African-American children (F = 5.198, p = .023). Costs of ED visits for children in SBHC schools were significantly lower than children in non-SBHC schools (F = 19.8, p < .0001). The risk of hospitalization and ED visits for children with asthma decreased significantly with SBHC programs. The potential cost-savings for hospitalization was estimated as 970 dollars per child.


Role of GABA and opioids in the regulation of the vasopressin response to physical exercise in normal men.
The present study was undertaken in order to establish the possible involvement of GABAergic and/or opioid pathways in the mechanism underlying the arginine-vasopressin (AVP) response to physical exercise. After fasting overnight, seven subjects were tested on four mornings at least 1 week apart. Exercise was performed on a bicycle ergometer. The workload was gradually increased at 3 min intervals until exhaustion and lasted about 15 min in all subjects. Tests were carried out under administration of placebo, the opioid antagonist naloxone (10 mg as an i.v. bolus injection), the GABAergic agonist sodium valproate (600 mg in three divided doses orally) or naloxone plus sodium valproate. Plasma AVP levels rose 4-fold during exercise. The administration of naloxone did not modify, whereas sodium valproate completely abolished the plasma AVP rise during exercise. When naloxone was given together with sodium valproate, AVP rose 3-fold in response to exercise. These data suggest the involvement of a GABAergic mechanism in regulation of the AVP response to physical exercise in men. Furthermore, the data argue against a role of naloxone sensitive endogenous opioids in the control of AVP during exercise, whereas they suggest a partial opioid mediation of the GABAergic inhibitory action.


Using Semantic Web technologies for the generation of domain-specific templates to support clinical study metadata standards.
The Biomedical Research Integrated Domain Group (BRIDG) model is a formal domain analysis model for protocol-driven biomedical research, and serves as a semantic foundation for application and message development in the standards developing organizations (SDOs). The increasing sophistication and complexity of the BRIDG model requires new approaches to the management and utilization of the underlying semantics to harmonize domain-specific standards. The objective of this study is to develop and evaluate a Semantic Web-based approach that integrates the BRIDG model with ISO 21090 data types to generate domain-specific templates to support clinical study metadata standards development. We developed a template generation and visualization system based on an open source Resource Description Framework (RDF) store backend, a SmartGWT-based web user interface, and a "mind map" based tool for the visualization of generated domain-specific templates. We also developed a RESTful Web Service informed by the Clinical Information Modeling Initiative (CIMI) reference model for access to the generated domain-specific templates. A preliminary usability study is performed and all reviewers (n = 3) had very positive responses for the evaluation questions in terms of the usability and the capability of meeting the system requirements (with the average score of 4.6). Semantic Web technologies provide a scalable infrastructure and have great potential to enable computable semantic interoperability of models in the intersection of health care and clinical research.


IL10 -1082, IL10 -819 and IL10 -592 polymorphisms are associated with chronic periodontitis in a Macedonian population.
Genetic polymorphisms in the interleukin 10 (IL10) gene have been reported to influence the host response to microbial challenge by altering levels of cytokine expression. We analyzed nucleotide polymorphisms in the promoter region of the IL10 gene and its relation with periodontal disease in a Macedonian population. The study population consisted of 111 unrelated subjects with chronic periodontitis and 299 healthy controls. DNA was isolated and IL10 genotyping performed by PCR-SSP (Heidelberg kit) for the alleles and genotypes of IL10 -1082, IL10 -819 and IL10 -592. Frequencies of IL10 haplotypes and the haplotype zygotes were also examined. Comparisons between groups were tested using the Pearson's p-value. After Bonferroni adjustment, significant associations were detected between subjects with chronic periodontitis and IL10 genotypes (IL10 -1082/A:G was negative or protective and IL10 -1082/G:G was positive or susceptible). Cytokine polymorphism on the IL10 gene appears to be associated with susceptibility to chronic periodontitis in Macedonians.


Macrodactyly and the epidermal nevus syndrome.
Macrodactyly is an uncommon congenital anomaly that affects the fingers and toes. Speculation as to cause is focused on the association with connective tissue abnormalities, such as neurofibromatosis. We report a highly unusual case of a patient with epidermal nevus syndrome, a specific connective tissue and skeletal disease, who also exhibited bilateral, four finger macrodactyly. Potential causes of linkage between these two specific and unusual syndromes are discussed. Treatment of the epidermal nevus may be nonoperative, differing from the philosophy of aggressive treatment of the similarly appearing premalignant congenital hairy nevus.


TH17 cells and corticosteroid insensitivity in severe asthma.
Asthma is classically described as having either a type 2 (T2) eosinophilic phenotype or a non-T2 neutrophilic phenotype. T2 asthma usually responds to classical bronchodilation therapy and corticosteroid treatment. Non-T2 neutrophilic asthma is often more severe. Patients with non-T2 asthma or late-onset T2 asthma show poor response to the currently available anti-inflammatory therapies. These therapeutic failures result in increased morbidity and cost associated with asthma and pose a major health care problem. Recent evidence suggests that some non-T2 asthma is associated with elevated TH17 cell immune responses. TH17 cells producing Il-17A and IL-17F are involved in the neutrophilic inflammation and airway remodeling processes in severe asthma and have been suggested to contribute to the development of subsets of corticosteroid-insensitive asthma. This review explores the pathologic role of TH17 cells in corticosteroid insensitivity of severe asthma and potential targets to treat this endotype of asthma.


Deposition of lipopigment--a new feature of human splenic sinus endothelium (SSE). Ultrastructural and histochemical study.
Lipopigment (LP) deposition was studied in a series of 36 control and 79 pathological spleens. In the control group the LP deposition in SSE was rudimentary and did not display age-dependence. A varying degree of lysosomal and cytoplasmic siderosis was a frequent finding in haemolytic anemia without any significant LP induction. In the acquired secondary storage syndrome and in some inherited lysosomal enzymopathies, the amount of LP in splenic sinus endothelium (SSE) was significantly increased and in some instances its deposition reached very high values. As deposition was not accompanied by any detectable lysosomal lipid storage phenomenon in pulpar histiocytes, the pigmentogenesis is thought to be by a process resembling that for lipofuscin. In ceroid-lipofuscinosis group the SSE affection was of low degree, as seen in other viscera. The LP deposition seems thus to be a prominent, albeit variable feature of human SSE lysosomal pathology and may represent a monotonous response to various stimuli connected with increased demands on the SSE lysosomal system. Only in some lysosomal enzymopathies, typically in sphingomyelinase deficiency was SSE LP deposited progressively and concurrently with the stored lipid. LP deposition was accompanied by an increase in lysosomal enzyme activities but lacked the alkaline phosphatase induction in SSE described in lipid and mucopolysaccharide storage diseases. This and several other features which are reviewed clearly distinguish SSE from the pulpar histiocytes with which they have been often identified.


Public relations. Part II, Strategies and tactics.
In Part I of this series, the six steps in the public relations process are discussed. They include identifying publics, conducting research, establishing goals, developing and implementing public relations strategies, and evaluating outcomes. In Part II, many of the commonly used public relations strategies and tactics are described.


Oxysterol mediated changes in fatty acid distribution and lipid synthesis in cultured bovine aortic smooth muscle cells.
We studied the actions of oxysterols on fatty acid distribution and lipid synthesis in cultured bovine aortic smooth muscle cells. Cultures were labeled with [1-14C]arachidonate or [1-14C]oleate. During a 24-hr incubation, 25- or 22R-hydroxycholesterol enhanced the incorporation of label into triglycerides, concomitant with a reduction in the labeling of phospholipids. Cholestantriol or 20-hydroxycholesterol had the opposite effects. They caused a higher incorporation of radiolabel into phospholipids and a reduction of labeling of triacylglycerols. Similar changes were seen in cells labeled with [1-14C]acetate. Therefore, we conclude that oxysterols can promote changes in the distribution of fatty acids between neutral lipids and phospholipids through mechanisms that still need to be clarified.


Adversarial Examples Generation for Deep Product Quantization Networks on Image Retrieval.
Deep product quantization networks (DPQNs) have been successfully used in image retrieval tasks, due to their powerful feature extraction ability and high efficiency of encoding high-dimensional visual features. Recent studies show that deep neural networks (DNNs) are vulnerable to input with small and maliciously designed perturbations (a.k.a., adversarial examples) for classification. However, little effort has been devoted to investigating how adversarial examples affect DPQNs, which raises the potential safety hazard when deploying DPQNs in a commercial search engine. To this end, we propose an adversarial example generation framework by generating adversarial query images for DPQN-based retrieval systems. Unlike the adversarial generation for the classic image classification task that heavily relies on ground-truth labels, we alternatively perturb the probability distribution of centroids assignments for a clean query, then we can induce effective non-targeted attacks on DPQNs in white-box and black-box settings. Moreover, we further extend the non-targeted attack to a targeted attack by a novel sample space averaging scheme ([Formula: see text]AS), whose theoretical guarantee is also obtained. Extensive experiments show that our methods can create adversarial examples to successfully mislead the target DPQNs. Besides, we found that our methods both significantly degrade the retrieval performance under a wide variety of experimental settings. The source code is available at https://github.com/Kira0096/PQAG.


Describing Maternal Knowledge of Infant Feeding Practices.
This qualitative study aimed to describe first-time mothers' knowledge of infant feeding practices, including the responsive feeding approach. This descriptive, qualitative study enrolled first-time mothers in the third trimester of pregnancy. Participants were asked plans for infant feeding and knowledge of infant feeding cues and responsive feeding. NVivo version 11 was used to analyze data using thematic analysis. All mothers (n = 30) intended to breastfeed. Hunger cues such as rooting were described; cessation of eating was consistently mentioned as a fullness cue. Mothers were unfamiliar with responsive feeding yet deduced the meaning of feeding in response to infant cues. Readiness for complementary foods was described by infant age and/or health care provider recommendation; developmental readiness was not described. Findings suggest future education and research should focus on responsive feeding and readiness for complementary foods. Finding ways to assist mothers to adhere to recommendations may promote healthy infant growth and prevent childhood obesity.


Hypothermia attenuates NO production in anesthetized rats with endotoxemia.
Sepsis is often associated with upregulation of nitric oxide production and fever, and it is common to control an excessive febrile response with antipyretic therapy and external cooling. Our aim was to evaluate the effect of hypothermia on NO production in a model of septic shock. Rats were anesthetized, ventilated, and instrumented for hemodynamic monitoring and divided into four groups. Normothermic controls (NC) received saline intravenously and were maintained at 37 °C. Hypothermic controls (HC) received saline but were allowed to become hypothermic. Normothermic endotoxic (NE) received Escherichia Coli lipopolysaccharides (LPS) intravenously to induce endotoxic shock and was maintained at 37 °C. Hypothermic endotoxic (HE) received LPS intravenously and was allowed to become hypothermic. Exhaled NO (NOe) was measured from mixed expired gas at time zero and every 30 min, for 5 h. After injection of LPS, NOe increased substantially in the NE group (700 ± 24 ppb), but increased only to 25 ± 2 ppb in the HE group. NOe increased to 90 ± 3 ppb in the NC group, and to 17.6 ± 3.1 ppb in the HC group after 5 h (P < 0.05), whilst blood pressure remained stable. In the HE group, blood pressure fell immediately after injection of the LPS, but thereafter remained stable despite the rise in NOe. In the NE group, the blood pressure fell gradually, and the animals became hypotensive. During the natural course of endotoxemia in anesthetized rats, allowing severe hypothermia to ensue by not actively managing temperature and hemodynamics resulted in significantly reduced expired NO concentrations, lung injury, and prolonged survival. The clinical benefits of such a finding currently remain unclear and merit further investigation.


Repeated measurement of spontaneous and clastogen-induced sister-chromatid exchange.
Sister-chromatid exchanges (SCE), both spontaneous and chemically-induced [bleomycin (BLM), mitomycin-C (MMC), streptonigrin (SN), and 4-nitroquinoline-1-oxide (4NQO)], were studied in the lymphocytes of 24 normal individuals on 2 or 3 different occasions, separated by periods of up to 2 years. For all BLM-induced SCEs, the variation in SCE frequency among the samples from a single individual was significantly greater than the variation between replicate cultures on a given day. These results raise questions concerning the validity of conclusions based on a single observation of chemically-induced SCEs.


Platelets and antiplatelet therapy in ischemic heart disease.
Blood platelets have been shown to play an important role not only in thrombosis, but also in the pathogenesis of coronary artery disease and its complications. Drugs that affect platelets have been shown to reduce mortality in survivors of acute myocardial infarction, to reduce the risk of myocardial infarction in patients with unstable angina, and to preserve the potency of saphenous venous grafts used to bypass obstructed coronary arteries. The drugs may also play a role in the primary prevention of arteriosclerosis and in preventing thrombotic complications following coronary angioplasty.