Brain microdialysis and its application for the study of animal behaviour.
Microdialysis is a sampling method that is used to determine the extracellular concentration of neurotransmitters in the brain. The method can be applied to conscious and unrestrained animals and is very suitable for the study of the chemistry of endogenous behaviour. This article reviews the contribution that microdialysis made to our understanding of the chemistry of behaviour. Methodological and practical considerations such as the implantation time and the use of guide cannulas are reviewed. The question whether neurotransmitters and related metabolites in dialysates reflect true synaptic release is critically discussed. There is much evidence that dopamine, noradrenaline, acetylcholine and serotonin in dialysates are related to neurotransmission, but there is serious doubt whether this is the case with amino acid transmitters such as GABA, glutamate and aspartate. Until now far over 100 papers appeared that used microdialysis in behavioural studies. Behavioural activation, the sleep-awake cycle and diurnal rhythms were subject of several of these studies. Various workers have described neurochemical changes in the brain that are related to feeding. Other studies were concerned with sexual behaviour and the sexual cycle in females. Parturition, maternal behaviour and offspring recognition have been studied in a series of microdialysis studies carried out in sheep. An overview is given of the microdialysis studies that were carried out to understand the biochemistry of stress. In this respect dopamine and noradrenaline have received much attention. A great number of microdialysis studies dealt with the role of dopamine in self-stimulation, reward and aversive emotions. It is concluded that microdialysis is at presently the most versatile and practical method to study the chemistry of behaviour and it is to be expected that it will soon be a routine methodology in behavioural research. Finally, perspectives and possible future developments of the methods are discussed.


Progesterone and synthetic progestin, dienogest, induce apoptosis of human primary cultures of adenomyotic stromal cells.
To investigate the direct effects of progesterone receptor (PR) agonists on proliferation and apoptosis of human adenomyotic cells. Human primary cultures of adenomyotic stromal cells (ASCs) from 24 patients with adenomyosis were co-treated with estradiol (E2) plus the PR agonists, endogenous progesterone (P) or the synthetic progestin dienogest (DNG), which is used to treat endometriosis. In ASCs, anti-proliferative effects and induction of apoptosis were evaluated in the presence or absence of P (10(-8)-10(-6)M) or DNG (10(-8)-10(-6)M) in culture medium containing E2. Cellular proliferation was analyzed with bromodeoxyuridine incorporation and flow cytometry. Apoptosis was detected with annexin V/7-amino-actinomycin D (7-AAD) staining with flow cytometry and cellular caspase 3/7 activity. P and DNG significantly decreased the proportion of cells in the S phase. In addition, both P and DNG increased apoptosis as measured by annexin V-positive/7-AAD -negative cells and caspase 3/7 activity. Both endogenous P and synthetic progestin directly inhibited cellular proliferation and induced apoptosis in human ASCs. These pharmacological features of progestational compounds provide insight into the therapeutic strategy for the treatment of adenomyosis.


Use of medetomidine-ketamine and atipamezole for reversible immobilization of free-ranging hog deer (Axis porcinus) captured in drive nets.
A combination of 0.05 mg/kg medetomidine and 1.5 mg/kg ketamine was used to immobilize nine adult free-ranging hog deer (Axis porcinus) captured in drive nets in the Royal Bardia National Park, Nepal, 22-23 February 2000. The drugs were administered intramuscularly from separate syringes and the mean time (+/-SD) to complete immobilization was 4.6+/-1.0 min. Muscle relaxation was good and no major clinical side effects were seen. Mean values for physiologic parameters, recorded at 10-12 and 18-20 min after drug administration, were 40.6+/-0.5 and 41.1+/-0.6 C, 87+/-5 and 84+/-4%, 107+/-16 and 113+/-16 beats/ min, and 46+/-9 and 40+/-8 breaths/min for rectal temperature, SpO2, pulse rate, and respiratory rate, respectively. All animals received 0.25 mg/ kg atipamezole intramuscularly 20-22 min after administration of medetomidine-ketamine and the mean time to coordinated running was 4.8+/-0.8 min. All animals survived for at least 5 mo post-capture. To reduce stress and to facilitate handling, medetomidine-ketamine and atipamezole are recommended for reversible immobilization of free-ranging hog deer captured in drive nets.


Three new species of Cosmocerca Diesing, 1861 (Nematoda: Cosmocercidae) parasitising frogs Cacosternum boettgeri Boulenger, 1882, Kassina senegalensis Dumeril and Bibron, 1841 and Phrynomantis bifasciatus Smith, 1847 from South Africa.
Cosmocercid nematodes have been documented with much criticism due to the numerous inaccurate descriptions, redescriptions and synonymisation of found species. This is due to indistinguishable characters of females and the lack of male specimens found. Consequently, the species C. ornata is the most commonly found species worldwide and the only species of the genus reported in South Africa. In the present study, we found Cosmocerca in three different amphibian species, namely Cacosternum boettgeri, Kassina senegalensis and Phrynomantis bifasciatus. Based on differences in the shape of the gubernaculum and number of papillae, the found nematodes were assigned to three new species namely C. daly n. sp., C. monicae n. sp. and C. makhadoensis n. sp. Descriptions of species are followed by pairwise and phylogenetic analysis of partial ITS-28S sequences. All three species were found only in their host types from distant localities. Therefore, we hypothesise that host specificity of Cosmocerca from South African amphibians might be rather high and that the presence of C. ornata throughout South Africa is rather doubtful.


Assessing risk of hospital readmissions for improving medical practice.
We compare statistical approaches for predicting the likelihood that individual patients will require readmission to hospital within 30 days of their discharge and for setting quality-control standards in that regard. Logistic regression, neural networks and decision trees are found to have comparable discriminating power when applied to cases that were not used to calibrate the respective models. Significant factors for predicting likelihood of readmission are the patient's medical condition upon admission and discharge, length (days) of the hospital visit, care rendered during the hospital stay, size and role of the medical facility, the type of medical insurance, and the environment into which the patient is discharged. Separately constructed models for major medical specialties (Surgery/Gynecology, Cardiorespiratory, Cardiovascular, Neurology, and Medicine) can improve the ability to identify high-risk patients for possible intervention, while consolidated models (with indicator variables for the specialties) can serve well for assessing overall quality of care.


Comparing Predicted Probability of Hepatocellular Carcinoma in Patients With Cirrhosis With the General Population: An Opportunity to Improve Risk Communication?
Risk scores estimating a patient's probability of a hepatocellular carcinoma (HCC) diagnosis are abundant but are difficult to interpret in isolation. We compared the predicted HCC probability for individuals with cirrhosis and cured hepatitis C with the general population (GP). All patients with cirrhosis achieving sustained viral response (SVR) in Scotland by April 2018 were included (N = 1,803). The predicted 3-year probability of HCC at time of SVR achievement was determined using the aMAP prognostic model. GP data on the total number of incident HCCs in Scotland, stratified by demographics, were obtained from Public Health Scotland. Predicted HCC risk of cirrhosis SVR patients was compared with GP incidence using 2 metrics: (i) incidence ratio: i.e., 3-year predicted probability for a given patient divided by the 3-year probability in GP for the equivalent demographic group and (ii) absolute risk difference: the 3-year predicted probability minus the 3-year probability in the GP. The mean predicted 3-year HCC probability among cirrhosis SVR patients was 3.64% (range: 0.012%-36.12%). Conversely, the 3-year HCC probability in the GP was much lower, ranging from <0.0001% to 0.25% depending on demographics. The mean incidence ratio was 410, ranging from 5 to >10,000. The mean absolute risk difference was 3.61%, ranging from 0.012% to 35.9%. An online HCC-GP comparison calculator for use by patients/clinicians is available at https://thrive-svr.shinyapps.io/RShiny/ . Comparing a patient's predicted HCC probability with the GP is feasible and may help clinicians communicate risk information and encourage screening uptake.


Tumor-associated macrophages and Tregs influence and represent immune cell infiltration of muscle-invasive bladder cancer and predict prognosis.
Muscle-invasive urothelial bladder cancer (MIBC) is associated with limited response rates to systemic therapy, risk of recurrence and death. Tumor infiltrating immune cells have been associated with outcome and response to chemo-and immunotherapy in MIBC. We aimed to profile the immune cells in the tumor microenvironment (TME) to predict prognosis in MIBC and responses to adjuvant chemotherapy. We performed multiplex immunohistochemistry (IHC) profiling and quantification of immune and stromal cells (CD3, CD4, CD8, CD163, FoxP3, PD-1, and CD45, Vimentin, αSMA, PD-L1, Pan-Cytokeratin, Ki67) in 101 patients with MIBC receiving radical cystectomy. We used uni- and multivariate survival analyses to identify cell types predicting prognosis. Samples were subdivided using K-means clustering for Treg and macrophage infiltration resulting in 3 clusters, Cluster 1: Treg high, cluster 2: macrophage high, cluster 3: Treg and macrophage low. Routine CD68 and CD163 IHC were analyzed with QuPath in an extended cohort of 141 MIBC. High concentrations of macrophages were associated with increased risk of death (HR 10.9, 95% CI 2.8-40.5; p < 0.001) and high concentrations of Tregs were associated with decreased risk of death (HR 0.1, 95% CI 0.01-0.7; p = 0.03) in the multivariate Cox-regression model adjusting for adjuvant chemotherapy, tumor and lymph node stage. Patients in the macrophage rich cluster (2) showed the worst OS with and without adjuvant chemotherapy. The Treg rich cluster (1) showed high levels of effector and proliferating immune cells and had the best survival. Cluster 1 and 2 both were rich in PD-1 and PD-L1 expression on tumor and immune cells. Treg and macrophage concentrations in MIBC are independent predictors of prognosis and are important players in the TME. Standard IHC with CD163 for macrophages is feasible to predict prognosis but validation to use immune-cell infiltration, especially to predict response to systemic therapies, is required.


Cost-effectiveness of consensus guideline based management of pancreatic cysts: The sensitivity and specificity required for guidelines to be cost-effective.
Detection of cystic lesions of the pancreas has outpaced our ability to stratify low-grade cystic lesions from those at greater risk for pancreatic cancer, raising a concern for overtreatment. We developed a Markov decision model to determine the cost-effectiveness of guideline-based management for asymptomatic pancreatic cysts. Incremental costs per quality-adjusted life year gained and survival were calculated for current management guidelines. A sensitivity analysis estimated the effect on cost-effectiveness and mortality if overtreatment of low-grade cysts is avoided, and the sensitivity and specificity thresholds required of methods of cyst stratification to improve costs expended. "Surveillance" using current management guidelines had an incremental cost-effectiveness ratio of $171,143/quality adjusted life year compared with no surveillance or operative treatment ("do nothing"). An incremental cost-effectiveness ratio for surveillance decreases to $80,707/quality adjusted life year if the operative overtreatment of low-grade cysts was avoided. Assuming a societal willingness-to-pay of $100,000/quality adjusted life year, the diagnostic specificity for high-risk cysts must be >67% for surveillance to be preferred over surgery and "do nothing." Changes in sensitivity alone cannot make surveillance cost-effective. Most importantly, survival in surveillance is worse than "do nothing" for 3 years after cyst diagnosis, although long-term survival is improved. The disadvantage is eliminated when overtreatment of low-grade cysts is avoided. Current management of pancreatic cystic lesions is not cost-effective and may increase mortality owing to overtreatment of low-grade cysts. The specificity for risk stratification for high-risk cysts must be greater than 67% to make surveillance cost-effective.


Canine bladder response to red and green light whole bladder photodynamic therapy.
A normal canine bladder model was used to compare the effects of red and green light whole bladder photodynamic therapy (PDT). Eighteen dogs were treated with Photofrin 1 mg/kg and whole bladder irradiation with red or green light at doses ranging from 20 to 60 J/cm2. Toxicity was assessed using cystometry, cystoscopy, and histopathology. Green light produced more significant vesical toxicity than red light, and this toxicity tended to vary with the light dose administered. Whole bladder PDT with green light at doses greater than 20 J/cm2 resulted in permanent reductions in bladder capacity. Conversely, a green light dose of 20 J/cm2 and red light doses ranging from 20 to 60 J/cm2 did not produce any significant permanent reductions in bladder capacity. Thus, while green light may be more toxic to the bladder than red light, there are distinct combinations of red or green light and Photofrin which can be used in the canine bladder to achieve mucosal degradation without causing permanent vesical dysfunction.


Two distinct populations of primary cytotoxic cells infiltrating into allografted tumor rejection sites: infiltration of macrophages cytotoxic against allografted tumor precedes that of multiple sets of cytotoxic T lymphocytes with distinct specificity to alloantigens.
It has been reported that the rejection of tumor allografts is mainly mediated by cytotoxic T lymphocytes (CTLs). Here, we characterized the cytotoxic effector cells of C57BL/6 (B6; H-2b) mice infiltrating into the rejection site of the i.p. allografted Meth A fibrosarcoma (or P815 mastocytoma) cells of H-2d origin. Two types of cytotoxic cells (i.e., CD8+ CTLs and macrophages (M phi s)) were identified by flow cytometric fractionation of the infiltrates or by specific in vitro elimination of cells either with antibody (Ab)-coated beads or with an Ab-plus complement. Of particular interest, these effector cells showed distinct and unique target specificities. First, the CTLs were inactive against transplanted tumor (e.g., Meth A) cells, whereas they were cytotoxic against donor-related concanavalin A (Con A) blasts as well as CTLL-2 (H-2b) cells transfected with a class I gene of H-2d origin. A cold target competition assay suggested that the CTLs were composed of multiple sets of T cells, each of which specifically recognized different allo-antigens. Second, the M phi s lysed the allografted tumor cells but were inert toward the Con A blasts and the CTLL-2 transfectants. Unexpectedly, the infiltration of M phi s preceded the infiltration of CTLs by several days during the course of rejection. These results indicate that two distinct populations of unique cytotoxic cells (i.e., CTLs and M phi s) are induced in the allografted tumor rejection site, and that the infiltration of cytotoxic M phi s responsible for rejection precedes that of the CTLs cytotoxic against cells expressing donor-related allo-antigens.


The influence of age on posterior pelvic floor dysfunction in women with obstructed defecation syndrome.
Knowledge of risk factors is particularly useful to prevent or manage pelvic floor dysfunction but although a number of such factors have been proposed, results remain inconsistent. The purpose of this study was to evaluate the impact of aging on the incidence of posterior pelvic floor disorders in women with obstructed defecation syndrome evaluated using echodefecography. A total of 334 patients with obstructed defecation were evaluated using echodefecography in order to quantify posterior pelvic floor dysfunction (rectocele, intussusception, mucosal prolapse, paradoxical contraction or non-relaxation of the puborectalis muscle, and grade III enterocele/sigmoidocele). Patients were grouped according to the age (Group I = patients up to 50 years of age; Group II = patients over 50 years of age) to evaluate the isolated and associated incidence of dysfunctions. To evaluate the relationship between dysfunction and age-related changes, patients were also stratified into decades. Group I included 196 patients and Group II included 138. The incidence of significant rectocele, intussusception, rectocele associated with intussusception, rectocele associated with mucosal prolapse and 3 associated disorders was higher in Group II, whereas anismus was more prevalent in Group I. The incidence of significant rectocele, intussusception, mucosal prolapse and grade III enterocele/sigmoidocele was found to increase with age. Conversely, anismus decreased with age. Aging was shown to influence the incidence of posterior pelvic floor disorders (rectocele, intussusception, mucosa prolapse and enterocele/sigmoidocele), but not the incidence of anismus, in women with obstructed defecation syndrome.


The Association between Vitamin D Deficiency and Changes in Cognitive Functions in Chinese Older Adults: A Prospective Cohort Study.
Along with the problem of population aging, the prevalence of dementia is gradually increasing. Associations between vitamin D deficiency (VDD) and cognitive functions remain unclear. We aimed to determine the relationship between VDD and changes in cognitive performance in community-dwelling older adults. In this longitudinal cohort study, participants aged ≥65 years were enrolled in March, 2016. The serum level of 25-hydroxy-vitamin D was analyzed by liquid-chromatography-tandem-- mass-spectrometry at baseline. VDD was defined as less than 20 ng/mL. All participants completed a health status questionnaire. Cognitive functions were evaluated by the Wechsler Adult Intelligence Scale-Revised in China at baseline and each visit. The linear mixed-effects model was utilized to examine the association between baseline VDD and changes in cognitive functions. In total, 866 participants were included in our study, with a mean duration of 3 years. VDD was markedly associated with lower full intelligence quotient (FIQ) (β: -3.355, 95% confidence interval [CI]:-4.165,-2.545), verbal intelligence quotient (VIQ) (β: -3.420, 95%CI: -4.193,-2.647), performance intelligence quotient (PIQ) (β: -2.610, 95%CI: -3.683,-1.537), comprehension (β: -0.630, 95%CI: -1.022,-0.238), information (β: -0.354, 95%CI: -0.699,-0.008), arithmetic (β: -1.065, 95%CI: -1.228,-0.902), digit span (β: -0.370, 95%CI: -0.547,-0.192), vocabulary (β: -0.789, 95%CI: -1.084,-0.493), picture completion (β: -0.391, 95%CI: -0.761,-0.022), block design (β: -0.412, 95%CI: -0.697,-0.127), picture arrangement (β: -0.542, 95%CI: -0.909,-0.174), and object assembly (β: -0.492, 95%CI: -0.818,-0.165) than those with adequacy. A higher frequency of VDD was associated with lower scores of FIQ, VIQ, PIQ and subtests on memory and executive function. Future randomized controlled trials are warranted to further verify the conclusions.


Combining rim area to disc area asymmetry ratio and Moorfields regression analysis of confocal scanning laser ophthalmoscopy for glaucoma screening.
To determine the utility of combining rim area to disc area asymmetry ratio (RADAAR) and Moorfields regression analysis (MRA) to detect primary open-angle glaucoma (POAG) using confocal scanning laser ophthalmoscopy (CSLO) (Heidelberg retina tomograph 3 (HRT3)) in high-risk populations. Cross-sectional study. Subjects with high risk for developing POAG. Subjects underwent HRT, frequency doubling technology perimetry (FDT), and complete ophthalmic examination. Based on an ophthalmologic examination and FDT results of the worse eye, subjects were classified into 4 categories: normal, possible glaucoma, probable glaucoma, and definite glaucoma. Main outcome measures included sensitivities (Se), specificities (Sp), positive and negative predictive values (PPV, NPV), and positive and negative likelihood ratios (PLR, NLR) of the MRA, RADAAR, and combined MRA- RADAAR tests. Of 375 subjects, 11 were classified as having definite glaucoma. Depending on the reference standard, range results for Se, Sp, PPV, NPV, PLR, and NLR were, respectively, 57.7% to 100%; 55.1% to 85.4%; 6.3% to 39%; 92.6% to 100%; 1.97 to 4.9; 0 to 0.49 for MRA; 11.5% to 27.3%; 98.1% to 98.8%; 30% to 60%; 87.4% to 97.8%; 9.29 to 14.1; and 0.74 to 0.89 for RADAAR; and 57.7% to 90.9%; 81.3% to 85.1%; 12.8% to 38.5%; 92.6% to 99.7%; 3.87 to 4.85; 0.11 to 0.50 for combination MRA-RADAAR. When using HRT in populations at high risk for glaucoma, RADAAR had a higher specificity than MRA in identifying glaucoma. When patients were classified as borderline on MRA, combining RADAAR values decreased the number of false-positives as well, and may be recommended when high specificity is required.


Understanding h-prune biology in the fight against cancer.
The h-prune protein is a member of the DHH protein superfamily, and its overexpression in breast, colorectal and gastric cancers correlates with depth of invasion and degree of lymph-node metastasis. Taken together with the observation that h-prune is highly expressed in metastatic breast cancer, this suggests that h-prune can be used as a marker for the identification of subsets of cancer patients with highly aggressive tumours. H-prune possesses a phosphodiesterase (cAMP-PDE) activity, and inhibition of PDE activity with dipyridamole suppresses cell motility. H-prune interacts with nm23-H1, GSK-3beta and gelsolin. Although a correlation between an h-prune PDE activity and cellular motility has been shown, GSK-3beta does not affect the PDE activity of h-prune. Inhibition of the interactions between h-prune and GSK-3beta and nm23-H1 additively suppresses the migration of colon cancer and breast cancer cells, thus suggesting that h-prune regulates cell motility by two different means of action: through its PDE activity and in its interactions with protein partners. Therefore, the identification of highly specific inhibitors of h-prune should be useful in the development of drugs to treat cancer metastasis.


The effect of marital status on glioma patient survival: analysis of 617 cases: A SEER-based study.
To study the effect of marital status on survival outcome in people diagnosed with glioma, not otherwise specified using the Surveillance, Epidemiology, and End Results (SEER) database.We chose patients diagnosed with glioma between 2000 and 2014 from the SEER database and recorded their disease-related data. We then analyzed overall 5-year cause-specific survival with respect to different marital statuses. There were 617 patients (262 women and 355 men). Of these, 54.0% (n = 333), 24.6% (n = 152), 8.6% (n = 53), and 12.8% (n = 79) were married, single, divorced (or separated), and widowed, respectively. The 5-year cause-specific survival was 39.30%, 64.50%, 60.40%, and 10.10% in the married, single, divorce (or separated), and widowed groups, respectively. The widowed group had substantially higher risk of glioma-related death than did the married group (hazard ratio 1.77, 95% confidence interval 1.337-2.344, P < .001). Being widowed provided higher risk of glioma mortality compared than did marital statuses. Widowed people should be given more support and psychological intervention by society.


The accessibility of a new oral motor pacifier to infants.
The aim of the present study was to examine whether infants would accept an oral motor pacifier (OMP). Sixteen infants were examined for their immediate acceptance of an OMP. The pacifier was regarded as accepted, if the child took it in the mouth and kept it there actively, i.e. sucked it in one way or other. Their parents were informed verbally and in writing literally about how to offer the OMP to the child and how to use it. The OMP was presented to the child and the child permitted to insert it into her/his mouth by her/himself or if the child failed to do so, the OMP was gently put to the child's mouth. The subjects' reactions were structurally evaluated in terms of 11 statements. The parents of the children received a structured questionnaire with a space for optional free comments and personal opinions. The median age (6 females, 10 males) was 18 months (mean 19.2 months, s.d. 10.6 and range 2-38 months). The statement scores showed no significant differentiation based on the age of the subject. The parents' reports indicated that 14 (87.5%) of the 18 subjects accepted the OMP, 13 (81.3%) enjoyed watching the pacifier as it was shown to them, and 11 (68.8%) explored it with their fingers while holding it in their hands. The vast majority of the children accepted the new OMP either at the first trial or after a few trials.


Gynaecological and reproductive health of women with telomere biology disorders.
Reproductive health may be adversely impacted in women with dyskeratosis congenita (DC) and related telomere biology disorders (TBD). We evaluated gynaecological problems, fertility, and pregnancy outcomes in 39 females aged 10-81 years who were followed longitudinally in our DC/TBD cohort. Twenty-six had bone marrow failure and 12 underwent haematopoietic cell transplantation. All attained menarche at a normal age. Thirteen women reported menorrhagia; ten used hormonal contraception to reduce bleeding. Nine experienced natural normal-aged menopause. Gynaecological problems (endometriosis = 3, pelvic varicosities = 1, cervical intraepithelial neoplasia = 1, and uterine prolapse = 2) resulted in surgical menopause in seven. Twenty-five of 26 women attempting fertility carried 80 pregnancies with 49 (61%) resulting in livebirths. Ten (38%) women experienced 28 (35%) miscarriages, notably recurrent pregnancy loss in five (19%). Preeclampsia (n = 6, 24%) and progressive cytopenias (n = 10, 40%) resulted in maternal-fetal compromise, including preterm (n = 5) and caesarean deliveries (n = 18, 37%). Gynaecological/reproductive problems were noted mainly in women with autosomal-dominant inheritance; others were still young or died early. Although women with TBDs had normal menarche, fertility, and menopause, gynaecological problems and pregnancy complications leading to caesarean section, preterm delivery, or transfusion support were frequent. Women with TBDs will benefit from multidisciplinary, coordinated care by haematology, gynaecology and maternal-fetal medicine.


Modulation of cell proteome by 25-hydroxycholesterol and 27-hydroxycholesterol: A link between cholesterol metabolism and antiviral defense.
Physiological cholesterol metabolism implies the generation of a series of oxidized derivatives, whose oxysterols are by far the most investigated ones for their potential multifaceted involvement in human pathophysiology. In this regard, noteworthy is the broad antiviral activity displayed by defined side chain oxysterols, in particular 25-hydroxycholesterol (25HC) and 27-hydroxycholesterol (27HC). Although their antiviral mechanism(s) may vary depending on virus/host interaction, these oxysterols share the common feature to hamper viral replication by interacting with cellular proteins. Here reported is the first analysis of the modulation of a cell proteome by these two oxysterols, that, besides yielding additional clues about their potential involvement in the regulation of sterol metabolism, provides novelinsights about the mechanism underlying the inhibition of virus entry and trafficking within infected cells. We show here that both 25HC and 27HC can down-regulate the junction adhesion molecule-A (JAM-A) and the cation independent isoform of mannose-6-phosphate receptor (MPRci), two crucial molecules for the replication of all those viruses that exploit adhesion molecules and the endosomal pathway to enter and diffuse within target cells.


The influence of lobule IX of the cerebellar posterior vermis on the baroreceptor reflex in the decerebrate rabbit.
Stimulation of lobule IX (the uvula) of the cerebellar posterior vermis, either electrically or chemically, has been shown to evoke marked cardiovascular effects in both rabbit and cat. Recent experiments suggest that this stimulation can also reduce the responsiveness of neurons in the nucleus tractus solitarii to baroreceptor inputs. The aim of the present study was thus to determine whether the uvula exerts an influence on the baroreceptor reflex. In order to evoke a reflex bradycardia in decerebrate rabbits, blood pressure was increased by inflating a Swan-Ganz catheter positioned in the descending aorta, and in some rabbits the aortic nerve was also stimulated electrically. In most rabbits, following uvula removal, significantly larger reflex falls in heart rate were observed. In a second group of rabbits, a lesion of cerebellar lobules VI-VIII had no effect on reflex bradycardia. It is concluded that the uvula tonically depresses the cardioinhibitory component of the baroreceptor reflex in the rabbit. The possible functional implications of these results are discussed.


Surgical management of the rheumatoid wrist--fusion or arthroplasty.
Forty-eight patients with 33 wrist fusions and 37 silicone wrist arthroplasties were reviewed and compared. Of those who had arthrodesis 97% showed a good or excellent result. Follow-up time averaged 82 months. All patients had a decrease in pain. Most patients had stronger wrists but complained of decreased dexterity. There were no pseudarthroses. The complication rate was 18%. Of patients in the arthroplasty group, 78% had a good or excellent result. Follow-up time averaged 51 months. Most patients in the arthroplasty group had improved dexterity and adequate wrist strength. Average flexion/extension was 32 degrees/29 degrees. The complication rate was 25%, which included four revisions. Of patients who had arthroplasties, 14% had bone resorption about the stem, and 11% of the patients with arthroplasties had x-ray evidence of settling. Factors that did not influence the result of the arthroplasty were patient age, duration of disease before surgery, finger extensor tendon rupture, preoperative motion, and hand dominance. Factors that were associated with failure and/or a fair result in arthroplasty patients were the use of ambulatory aids, the older and narrower prosthetic design, dislocated wrist preoperatively, and the chronic use of steroids.


Nutritional screening based on the controlling nutritional status (CONUT) score at the time of admission is useful for long-term prognostic prediction in patients with heart failure requiring hospitalization.
The objective of the study was to clarify whether controlling nutritional status (CONUT) is useful for predicting the long-term prognosis of patients hospitalized with heart failure (HF). A total of 482 (57.5%) HF patients from the Ibaraki Cardiovascular Assessment Study-HF (N = 838) were enrolled (298 men, 71.7 ± 13.6 years). At admission, blood samples were collected and nutritional status assessed using CONUT. CONUT scores were defined as follows: 0-1, normal; 2-4, light; 5-8, moderate; and 9-12, severe undernutrition. Accordingly, 352 (73%) patients had light-to-severe nutritional disturbances. In the follow-up period [median 541.5 (range 354-786) days], 109 deaths were observed. A Kaplan-Meier analysis revealed that all-cause deaths occurred more frequently in HF patients with nutritional disturbances [n = 93 (26.4%)] than in those with normal nutrition [n = 16 (12.3%); log-rank p < 0.001]. The Cox proportional hazard analyses revealed that a per point increase in the CONUT score was associated with an increased risk of all-cause death (hazard ratio 1.142; 95% confidence interval, 1.044-1.249) after controlling simultaneously for age, sex, previous history of HF hospitalization, log brain natriuretic peptide, and use of therapeutic agents at admission (tolvaptan and aldosterone antagonists). This study suggests that nutritional screening using CONUT scores is helpful in predicting the long-term prognosis of patients hospitalized with HF in a multicenter registry setting.


Comparison of 18 F-FDG and 68 Ga-FAPI-04 Uptake in Postoperative Re-evaluation of Gastric, Duodenal, and Colorectal Cancers.
To compare the potential efficacy of 68 Ga-FAPI-04 PET/CT with that of 18 F-FDG PET/CT for detecting tumor recurrence and nodal and distant metastases in gastric, duodenal, and colorectal cancers. This single-center retrospective clinical study was performed at the Affiliated Hospital of Southwest Medical University between January 2020 and June 2022. Participants with gastric, duodenal, and colorectal cancers after curative resection underwent both 68 Ga-FAPI-04 and 18 F-FDG PET/CT. Histopathologic examination, morphologic imaging, and/or follow-up imaging served as the reference standards. The SUV max of the tumor recurrence and nodal and distant metastases between 18 F-FDG and 68 Ga-FAPI-04 PET/CT were compared using the paired-sample t test. Forty-one participants with gastric, duodenal, and colorectal cancers were enrolled in the study (median age, 51 years; range, 19-75 years). The sensitivity of 68 Ga-FAPI-04 PET/CT was higher than that of 18 F-FDG PET/CT for detecting tumor recurrence (6 of 6 [100%] vs 4 of 6 [67%]), nodal metastases (92 of 92 [100%] vs 31 of 92 [34%]), and distant metastases (28 of 30 [93%] vs 20 of 30 [67%]). 68 Ga-FAPI-04 PET/CT for tumor re-evaluation showed potential for more accurate performance of gastric, duodenal, and colorectal cancers, thereby improving treatment decision-making.


Long-term health-related quality of life after primary treatment for localized prostate cancer: results from the CaPSURE registry.
Few studies have reported on late declines and long-term health-related quality of life (HRQOL) after prostate cancer (PCa) treatment. We assessed long-term HRQOL following various treatments for localized PCa. This cohort study of HRQOL up to 10 yr after treatment used a prospectively accrued, nationwide PCa registry that collects longitudinal patient-reported HRQOL. Various primary treatments for localized PCa. The Medical Outcomes Studies 36-item Short Form and the University of California, Los Angeles, Prostate Cancer Index characterized physical function, mental health, and sexual, urinary, and bowel function and bother. Repeated measures mixed-model analysis assessed change in HRQOL by treatment over time, and logistic regression was used to measure the likelihood of a clinically significant decline in HRQOL. Among 3294 men, 1139 (34%) underwent nerve-sparing radical prostatectomy (NSRP), 860 (26%) underwent non-NSRP, 684 (21%) underwent brachytherapy, 386 (12%) underwent external beam radiotherapy, 161 (5%) underwent primary androgen deprivation therapy, and 64 (2%) pursued watchful waiting/active surveillance. Median follow-up was 74 mo (interquartile range: 50-102). Most treatments resulted in early declines in HRQOL, with some recovery over the next 1-2 yr and a plateau in scores thereafter. Surgery had the largest impact on sexual function and bother and on urinary function, radiation had the strongest effect on bowel function, and androgen deprivation therapy had the strongest effect on physical function. The main limitation was attrition among the cohort. Although most men experience initial declines in HRQOL in the first 2 yr after treatment, there is little change from 3 to 10 yr and most differences between treatments attenuated over time. Various treatments for prostate cancer result in a distinct constellation of adverse effects on health-related quality of life, which may have a long-term impact. These findings are helpful regarding shared decision making over choice of primary treatment.


The efficacy of the traditional Korean herbal medicine Tongsayobang for the treatment of irritable bowel syndrome: A protocol for a systematic review and meta-analysis.
Irritable bowel syndrome (IBS) is a functional bowel disorder with symptoms of recurrent abdominal pain associated with a change in stool frequency or appearance that decreases patient quality of life. Conventional Western medicine has limited efficacy in treating IBS. Tongsayobang (TSYB) is a traditional Korean medicine that has been used to treat lower intestinal problems. This study provides a procedure for conducting a systematic review of the efficacy and safety of TSYB for IBS. The main electronic databases will be searched up to May 2021 for randomized controlled trials and quasi-randomized controlled trials evaluating the effect of TSYB or modified TSYB on patients with IBS. The primary outcome will be the overall efficacy rate. The secondary outcome will be data such as IBS-related quality of life, global symptom scores, and adverse events. This study will adopt the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, and will involve a meta-analysis, if possible. The methodological quality of the included studies will be assessed using the Risk of Bias tool from the Cochrane Handbook, version 6.1.0. Ethical approval is not required because this study does not include any participants' personal information. DOI 10.17605/OSF.IO/M32BK (https://osf.io/m32bk).


Changes in U.S. Preventive Services Task Force recommendations: effect on mammography screening in Olmsted County, MN 2004-2013.
We assessed changes in adherence to screening mammography recommendations with the introduction of the new U.S. Preventive Services Task Force (USPSTF) recommendations in 2009. Using the Rochester Epidemiology Project data linkage system, we examined mammography screening from 2004 to 2013 in 31,377 women 40years of age and older residing in Olmsted County, MN before and after the 2009 change in recommendations. Chi-square was used to compare screening rates before and after changes in recommendations overall, by age group, and by baseline adherence. Among women 40 years and older, declines in screening were observed: 69% of the population was adherent in 2004-2005, 61% in 2006-2009 and 53% in 2010-2013. Absolute decreases in screening were observed from pre- to post-change for those ages 40-49 (4%), 50-74 (9%), and those 75+ (19%, all p<0.0001). Relative declines in screening rates were observed among women aged 70-74 years who were non-adherent at baseline and among women who were adherent at baseline, overall, and in each age group (all p<.001). Declines in screening, both absolute and relative, were most pronounced among women who were adherent at baseline. Research is needed to assess factors that influence screening in the context of evolving recommendations.


Resilience, plasticity and robustness in gene expression during aging in the brain of outbred deer mice.
Genes that belong to the same network are frequently co-expressed, but collectively, how the coordination of the whole transcriptome is perturbed during aging remains unclear. To explore this, we calculated the correlation of each gene in the transcriptome with every other, in the brain of young and older outbred deer mice (P. leucopus and P. maniculatus). In about 25 % of the genes, coordination was inversed during aging. Gene Ontology analysis in both species, for the genes that exhibited inverse transcriptomic coordination during aging pointed to alterations in the perception of smell, a known impairment occurring during aging. In P. leucopus, alterations in genes related to cholesterol metabolism were also identified. Among the genes that exhibited the most pronounced inversion in their coordination profiles during aging was THBS4, that encodes for thrombospondin-4, a protein that was recently identified as rejuvenation factor in mice. Relatively to its breadth, abolishment of coordination was more prominent in the long-living P. leucopus than in P. maniculatus but in the latter, the intensity of de-coordination was higher. There sults suggest that aging is associated with more stringent retention of expression profiles for some genes and more abrupt changes in others, while more subtle but widespread changes in gene expression appear protective. Our findings shed light in the mode of the transcriptional changes occurring in the brain during aging and suggest that strategies aiming to broader but more modest changes in gene expression may be preferrable to correct aging-associated deregulation in gene expression.


Expanded cardiac rehabilitation reduces cardiac events over five years.
In people with coronary artery disease, does an expanded cardiac rehabilitation program reduce cardiac deaths, myocardial infarctions, and hospital admissions due to cardiovascular disease? Randomised, controlled trial with intention-to-treat analysis. A University hospital in Sweden. People aged less than 75 years who had had a recent myocardial infarction or coronary artery bypass grafts were eligible to participate. Severe co-morbidities were exclusion criteria. Randomisation of 224 participants allocated 111 to undergo expanded cardiac rehabilitation and 113 to a control group. Both groups received standard cardiac rehabilitation, including physical training, education, group and individual counselling, and support to cease smoking. All participants received appropriate preventive medications. In addition, the intervention group received 20 group sessions of stress management, 3 sessions of cooking and diet counselling by a dietician, and a 5-day stay at a 'patient hotel' with several activities including physical training and information. Although other outcomes were reported at the conclusion of 1-year follow-up, the outcomes at the 5-year follow-up were rates of cardiac events: cardiovascular death, acute myocardial infarction, and readmission to a hospital due to other cardiovascular causes. All participants were followed up via national registers of health and mortality. During the 5-year follow-up, 53 (48%) participants in the expanded cardiac rehabilitation group and 68 (60%) participants in the control group had a cardiac event (hazard ratio 0.69, 95% CI 0.48 to 0.99). This difference was mainly due to only 12 (11%) participants having non-fatal myocardial infarctions in the treatment group versus 23 (20%) in the control group (hazard ratio 0.47, 95% CI 0.21 to 0.97). The number of hospitalisations and the number of days of hospitalisation were both significantly fewer in the treatment group than in the control group. Expanded cardiac rehabilitation after acute myocardial infarction or coronary artery bypass surgery reduces the long-term rate of cardiovascular events by reducing myocardial infarctions and days in hospital for cardiovascular reasons.


[Experience with 38 deltopectoral flaps in reconstructive surgery of the head and neck (author's transl)].
The deltopectoral flap was described by Bakamjian in 1965 for pharyngo-oesophageal reconstruction. Since then, the indications of this excellent flap have been extended and the versatility of the flap has allowed extensive skin and mucous membrane resections in cancerology. The authors have used 38 deltopectoral flaps in 36 patients with difficult reconstructive problems. The results have been good in 31 cases. There were 7 failures.


Nexus between mitochondrial function, iron, copper and glutathione in Parkinson's disease.
Parkinson's disease is neuropathologically characterised by loss of catecholamine neurons in vulnerable brain regions including substantia nigra pars compacta and locus coeruleus. This review discusses how the susceptibility of these regions is defined by their shared biochemical characteristics that differentiate them from other neurons. Parkinson's disease is biochemically characterised by mitochondrial dysfunction, accumulation of iron, diminished copper content and depleted glutathione levels in these regions. This review also discusses this neuropathology, and provides evidence for how these pathological features are mechanistically linked to each other. This leads to the conclusion that disruption of mitochondrial function, or iron, copper or glutathione metabolism in isolation provokes the pathological impairment of them all. This creates a vicious cycle that drives pathology leading to mitochondrial failure and neuronal cell death in vulnerable brain regions.


The obscurance of the greatest sylvatic yellow fever epidemic and the cooperation of the Pan American Health Organization during the COVID-19 pandemic.
Since 2016, Brazil has been in the midst of its largest sylvatic yellow fever epidemic ever, found predominantly outside the Amazon region. Cases originating from Brazil have been reported in France, the Netherlands, Romania, Switzerland, Argentina, and Chile. The epidemic began in the Central-West region of Brazil in 2014, spreading into the Southern region, with significant non-human primate transmission continuing towards Paraguay and Argentina. This report is an integrative review of Pan American Health Organization cooperation during a sylvatic yellow fever epidemic. The Pan American Health Organization has played a central role in handling the yellow fever emergency, collaborating with the Ministry of Health and various research groups in supporting interventions of different response areas. The Pan American Health Organization's technical cooperation included: training and workshops to exchange experiences, carrying out technical cooperation in patient management and epidemiological, entomological, laboratory, and epizootic surveillance, organizing the assistance network, and acquiring strategic inputs. The Pan American Health Organization's technical cooperation supported the Ministry of Health's decision to adopt a single-dose vaccine and use fractional doses to support the vaccination needs of more than 39,000,000 people. The coronavirus disease 2019 pandemic contributed to the failure of reaching the yellow fever vaccination goals and made it difficult to integrate the yellow fever vaccine into recommended areas. Given the ongoing coronavirus disease 2019 pandemic, it is necessary to strengthen measures for the surveillance, prevention, and control of yellow fever with multilateral cooperation between countries.


Potassium requirement for cell division in Anacystis nidulans.
A potassium requirement for growth can be readily demonstrated in the autotrophic blue-green bacterium Anacystis nidulans strain TX20 equivalent to 0.7% of the cellular dry weight. Starvation of this organism for potassium partially dissociates growth from cell division, thereby inducing 50% of the population to form filaments.


Benvitimod inhibits MCM6-meditated proliferation of keratinocytes by regulating the JAK/STAT3 pathway.
Benvitimod (Tapinarof), as a small-molecule topical therapeutical aryl hydrocarbon receptor (AHR)-modulating agent, is in clinical development for treating psoriasis and atopic dermatitis. Benvitimod reduces proinflammatory cytokines in psoriasis by specifically binding and activation of AHR. However, whether benvitimod can inhibit keratinocyte proliferation remains unclear. Minichromosome maintenance protein 6 (MCM6) is a key element of the prereplication complex (pre-RC) assembly which is one of the essential steps in the initiation of DNA replication for cell proliferation. This study aimed to determine whether benvitimod could reduce the excessive proliferation of psoriatic keratinocytes by inhibiting MCM6. We examined the inhibitory effect of benvitimod on MCM6-mediated proliferation of keratinocytes by HaCaT cells in vitro and an IMQ-induced psoriatic model of mice in vivo. Epidermal MCM6 expression was enhanced in the skin lesions of psoriatic patients. The experiments further revealed that MCM6 was required for the proliferation of keratinocytes and governed by the IL-22/STAT3 pathway. In addition, the antiproliferation effect of benvitimod is achieved by the inhibition of p-JAK1 and p-JAK2, which further restrained the activation of STAT3 in keratinocytes. Lastly, benvitimod could repressed imiquimod-induced skin lesions and the expression of epidermal MCM6 and p-STAT3 in mice. Moreover, knockdown of AHR in keratinocytes enhanced the activation of JAK1 and JAK2. The findings reveal that benvitimod could decrease MCM6-mediated proliferation of keratinocytes by affecting the JAK/STAT3 pathway, thereby serving as a new treatment modality for psoriasis.


Computer-aided planning in orthognathic surgery-systematic review.
The aim of this study was to conduct a systematic review to evaluate the accuracy and benefits of computer-aided planning in orthognathic surgery. The search was performed in PubMed, EMBASE, Cochrane Library, LILACS, and SciELO. The articles identified were assessed independently and in a blinded manner by two authors using selection criteria and eligibility criteria. The database search yielded 375 studies. Following the application of search and eligibility criteria, a final nine studies were included in the systematic review. The level of agreement between the authors in the study selection process was substantial (κ=0.767) and study eligibility was considered excellent (κ=0.863). The accuracy of translation was <1.2mm in the maxilla (vertical) and <1.1mm in the mandible (sagittal), and for rotation was <1.5° in the maxilla (pitch) and <1.8° in the mandible (pitch). Two studies showed a medium potential risk of bias and six studies showed a high potential risk of bias. Computer-aided planning in orthognathic surgery was considered accurate for the studies included in this systematic review. However, the low quality of these studies means that randomized clinical trials are needed to compare computer-aided planning to conventional planning in orthognathic surgery.


GENETIC CONSEQUENCES OF SEED DISPERSAL IN THREE SYMPATRIC FOREST HERBS. II. MICROSPATIAL GENETIC STRUCTURE WITHIN POPULATIONS.
Significant spatial genetic differentiation over short distances was detected by F-statistics and spatial autocorrelation within populations of the temperate forest herbs Cryptotaenia canadensis, Osmorhiza claytonii and Sanicula odorata (Apiaceae). Differences among the three species were consistent with estimates of their seed-dispersal abilities. Populations of Cryptotaenia, with the most limited seed dispersal, are characterized by genetic structure at smaller spatial scales than those of Osmorhiza or Sanicula, as indicated by higher estimates of θ(Fst ), larger autocorrelation coefficients, and correlograms with more distant x-intercepts. Although spatial autocorrelation was somewhat more sensitive to the distribution of rare alleles than F-statistics, the two methods were generally concordant. Genetic structure was more pronounced, and inbreeding coefficients larger, in low-density, patchy populations than in a high-density site. Observed patterns of spatial autocorrelation, particularly for Cryptotaenia, were in agreement with expectations based on simulations of isolation by distance. The magnitude of observed autocorrelations was less than those typically produced in computer-simulation studies, but this discrepancy between empirical and theoretical results probably is derived from a lack of genetic and demographic equilibrium in natural populations. Isolation by distance can be an important evolutionary force organizing spatial genetic structure in plant populations, particularly in predominantly self-fertilizing species such as those studied here.


Colon cancer therapy with calcium phosphate nanoparticles loading bioactive compounds from Euphorbia lathyris: In vitro and in vivo assay.
Amorphous calcium phosphate nanoparticles (ACP NPs) exhibit excellent biocompatibility and biodegradability properties. ACP NPs were functionalized with two coumarin compounds (esculetin and euphorbetin) extracted from Euphorbia lathyris seeds (BC-ACP NPs) showing high loading capacity (0.03% and 0.34% (w/w) for esculetin and euphorbetin, respectively) and adsorption efficiency (2.6% and 33.5%, respectively). BC-ACP NPs, no toxic to human blood cells, showed a more selective cytotoxicity against colorectal cancer (CRC) cells (T-84 cells) (IC50, 71.42 µg/ml) compared to non-tumor (CCD18) cells (IC50, 420.77 µg/ml). Both, the inhibition of carbonic anhydrase and autophagic cell death appeared to be involved in their action mechanism. Interestingly, in vivo treatment with BC-ACPs NPs using two different models of CRC induction showed a significant reduction in tumor volume (62%) and a significant decrease in the number and size of polyps. A poor development of tumor vasculature and invasion of normal tissue were also observed. Moreover, treatment increased the bacterial population of Akkermansia by restoring antioxidant systems in the colonic mucosa of mice. These results show a promising pathway to design innovative and more efficient therapies against CRC based on biomimetic calcium phosphate NPs loaded with natural products.


The use of angiotensin converting enzyme inhibitors in combination with other antihypertensive agents.
Angiotensin converting enzyme (ACE) inhibitors have additive effects with most other antihypertensive agents, but the mechanisms of these interactions vary. With diuretics the interaction with ACE inhibitors can be explained by their contrasting effects on the renin-angiotensin system, while with calcium antagonists it may be attributed to independent mechanisms of action. With beta-blockers there is a variable additive effect, which has been proposed to be due to more complete blockade of the renin-angiotensin system than can be obtained with either type of agent alone.


Early liver transplantation for severe alcohol-related hepatitis not responding to medical treatment: a prospective controlled study.
Early liver transplantation for severe alcohol-related hepatitis is an emerging treatment option. We aimed to assess the risk of alcohol relapse 2 years after early liver transplantation for alcohol-related hepatitis compared with liver transplantation for alcohol-related cirrhosis after at least 6 months of abstinence. We conducted a multicentre, non-randomised, non-inferiority, controlled study in 19 French and Belgian hospitals. All participants were aged 18 years or older. There were three groups of patients recruited prospectively: patients with severe alcohol-related hepatitis who did not respond to medical treatment and were eligible for early liver transplantation according to a new selection scoring system based on social and addiction items that can be quantified in points (early transplantation group); patients with alcohol-related cirrhosis listed for liver transplantation after at least 6 months of abstinence (standard transplantation group); patients with severe alcohol-related hepatitis not responding to medical treatment not eligible for early liver transplantation according to the selection score (not eligible for early transplantation group), this group did not enter any further liver transplantation processes. We also defined a historical control group of patients with severe alcohol-related hepatitis unresponsive to medical therapy and non-transplanted. The primary outcome was the non-inferiority of 2-year rate of alcohol relapse after transplantation in the early transplantation group compared with the standard transplantation group using the alcohol timeline follow back (TLFB) method and a prespecified non-inferiority margin of 10%. Secondary outcomes were the pattern of alcohol relapse, 2-year survival rate post-transplant in the early transplantation group compared with the standard transplantation group, and 2-year overall survival in the early transplantation group compared with patients in the not eligible for early transplantation group and historical controls. This trial is registered with ClinicalTrials.gov, NCT01756794. Between Dec 5, 2012, and June 30, 2016, we included 149 patients with severe alcohol-related hepatitis: 102 in the early transplantation group and 47 in the not eligible for early transplantation group. 129 patients were included in the standard transplantation group. 68 patients in the early transplantation group and 93 patients in the standard transplantation group received a liver transplant. 23 (34%) patients relapsed in the early transplantation group, and 23 (25%) patients relapsed in the standard transplantation group; therefore, the non-inferiority of early transplantation versus standard transplantation was not demonstrated (absolute difference 9·1% [95% CI -∞ to 21·1]; p=0·45). The 2-year rate of high alcohol intake was greater in the early transplantation group than the standard transplantation group (absolute difference 16·7% [95% CI 5·8-27·6]) The time spent drinking alcohol was not different between the two groups (standardised difference 0·24 [95% CI -0·07 to 0·55]), but the time spent drinking a large quantity of alcohol was higher in the early transplantation group than the standard transplantation group (standardised difference 0·50 [95% CI 0·17-0·82]). 2-year post-transplant survival was similar between the early transplantation group and the standard transplantation group (hazard ratio [HR] 0·87 [95% CI 0·33-2·26]); 2-year overall survival was higher in the early transplantation group than the not eligible for early transplantation group and historical controls (HR 0·27 [95% CI 0·16-0·47] and 0·21 [0·13-0·32]). We cannot conclude non-inferiority in terms of rate of alcohol relapse post-transplant between early liver transplantation and standard transplantation. High alcohol intake is more frequent after early liver transplantation. This prospective controlled study confirms the important survival benefit related to early liver transplantation for severe alcohol-related hepatitis; and this study provides objective data on survival and alcohol relapse to tailor the management of patients with severe alcohol-related hepatitis. The present study has been granted by the French Ministry of Health-Programme Hospitalier de Recherche Clinique 2010.


Association study between single nucleotide polymorphisms in the VEGF gene and polycystic ovary syndrome.
To investigate single nucleotide polymorphisms (SNPs) in vascular endothelial growth factor (VEGF) gene that have significant associations with the pathogenesis of polycystic ovary syndrome (PCOS) in a Korean population. Case-control study. University-based hospital. One hundred thirty-four patients with PCOS and 100 healthy women as controls. None. Frequencies of genotypes for SNPs in VEGF gene, which were specifically expressed in a Korean population. After genotypic analysis, we found that among 10 SNPs, one novel SNP at site +9812 and one known SNP at site +13553 have P values lower than .05 (+9812: odds ratio [95% confidence interval] 0.61 [0.39-0.95]; +13553: odds ratio [95% confidence interval] 0.59 [0.37-0.93]) and one haplotype (ht4) also has a P value in the significant range (odds ratio [95% confidence interval] 0.34 [0.16-0.74]). We concluded that one novel SNP at +9812 site, one known SNP at +13553 site, and one selected haplotype in the VEGF gene have a high possibility of significant associations with the pathogenesis of PCOS in a Korean population.


Genome-wide identification and expression profiling of the bZIP gene family in Betula platyphylla and the functional characterization of BpChr04G00610 under low-temperature stress.
The basic leucine zipper (bZIP) gene, which plays a significant role in the regulation of tolerance to biotic/abiotic stresses, has been characterized in many plant species. Betula platyphylla is a significant afforestation species. To elucidate the stress resistance mechanism of birch, previous studies identified some stress resistance genes. However, the genome-wide identification and characterization of bZIP gene family in the birch have not been reported. Here, the 56 BpbZIP genes were identified and classified into 13 groups in birch. Cis-element analysis showed that the promoters of 56 family genes contained 108 elements, of which 16 were shared by 13 groups. There were 8 pairs of fragment repeats and 1 pair of tandem repeats, indicating that duplication may be the major reason for the amplification of the BpbZIP gene family. Tissue-specific of BpbZIP genes showed 18 genes with the highest expression in roots, 15 in flowers, 11 in xylem and 9 in leaves. In addition, five differentially expressed bZIP genes were identified from the RNA-seq data of birch under low-temperature stress, and the co-expressed differentially expressed genes were further screened. The analysis of gene ontology (GO) enrichment of each co-expression regulatory network showed that they were related to membrane lipids and cell walls. Furthermore, the transient overexpression of BpChr04G00610 decreased the ROS scavenging ability of birch under low-temperature stress, suggesting that it may be more sensitive to low-temperature. In conclusion, this study provides a basis for the study of the function of BpbZIP genes.


Atorvastatin calcium in combination with methylprednisolone for the treatment of multiple sclerosis relapse.
This study aimed to investigate the efficacy of combined atorvastatin calcium and methylprednisolone for the treatment of multiple sclerosis relapse. Patients with multiple sclerosis (MS) at the relapse phase were randomized to receive either combined treatment of atorvastatin calcium and methylprednisolone (n = 19) or methylprednisolone alone (n = 19). Expanded Disability Status Scale (EDSS) was administered at baseline, 1 week, 2 weeks, 4 weeks, 3 months, and 6 months after treatment initiation. The number and volume of brain lesions were evaluated using magnetic resonance imaging at baseline and 6 months. The levels of IL-13, IL-35, IFN-γ, and IL-10 in the cerebrospinal fluid were examined using the enzyme-linked immunosorbent assay method. There was no significant difference in EDSS scores at 1, 2, and 4 weeks. At 3 and 6 months, the combined treatment group showed significantly lower EDSS scores than the monotherapy group (P < 0.05). The number and volume of brain lesions in the combined treatment group were significantly lower than the monotherapy group at 6 months (P < 0.001). The mean time to relapse was significantly extended in the combined treatment group than the monotherapy group (P < 0.001). At 2 and 4 weeks, the combined treatment group had significantly higher levels of IL-13, IL-35, and IL-10 in the cerebrospinal fluid than the monotherapy group (P < 0.05), but significantly lower level of IFN-γ (P < 0.001). The levels of IL-13 and IL-10 in the combined treatment group were positively correlated with EDSS scores (r = 0.632, P = 0.001; r = 0.731, P = 0.002). Combined treatment with atorvastatin calcium and methylprednisolone can improve the outcomes of MS relapse compared with glucocorticosteroid alone.


Sister chromatid differentiation and exchanges in adult mudminnows (Umbra limi) after in vivo exposure to 5-bromodeoxyuridine.
An in vivo system for the detection of sister chromatid exchange (SCE) in the central mudminnow, Umbra limi, is presented. Sister chromatid differential (SCD) and SCE were demonstrated by fluorescent and Giemsa procedures 5 to 6 days after the fish were injected with 500 mug/g of BrdU. The exchange rate was found to be 2.64 SCEs metaphase in the intestines and 2.42 SCEs/metaphase in the gills. SCE analysis in U. limi should be a useful tool for measuring the mutagenicity of water-borne chemicals.


Theoretical Calculations and Experiments on the Thermal Properties of Fluorinated Graphene and Its Effects on the Thermal Decomposition of Nitrate Esters.
Fluorinated graphene contains F atoms with high levels of chemical activity, and the application of fluorinated graphene in energetic materials may greatly contribute to the progress of combustion reactions. However, there is a lack of research on the thermal properties of fluorinated graphene and its application on nitrate esters. In this paper, theoretical calculations and experiments were used to study the thermal properties of fluorinated graphene and its application on nitrate esters. The anaerobicity and poor thermal stability of fluorinated graphene were proved by ab initio molecular dynamics (AIMD) calculations and TG-DSC experiments. The ester weakening effect of fluorinated graphene on nitroglycerin was determined via wavefunction analysis, with the greater the fluorination degree, the stronger the ester weakening effect. The existence of fluorinated graphene can significantly increase the heat dissipation of the composites, which was concluded by TG-DSC experiments and TG-DSC-MS-FTIR. The research in this article provides an important reference for the application of fluorinated graphene in energetic materials.


Effects of chronic administration of doxorubicin on myocardial beta-adrenergic receptors.
The effects of multiple doses of doxorubicin (DXR) on myocardial beta-adrenergic receptor density and dissociation constant were investigated in male Sprague Dawley rats. The rats received DXR (2 mg/kg) or vehicle weekly by the SC route for 13 weeks. One group of DXR-treated rats plus corresponding controls were sacrificed at 14 weeks, one week after the last dose. Another group of DXR-treated rats plus corresponding controls were sacrificed at 19 weeks, six weeks after the last dose. The myocardial beta-adrenergic receptor was characterized by radio-ligand binding studies using [125I]iodocyanopindolol. Beta--receptor densities in DXR-treated rats of 7.0 and 7.4 fm/mg protein were unchanged from control levels of 7.2 fm/mg protein at both 14 and 19 weeks, respectively. Receptor dissociation constants in DXR-treated rats of 36.7 and 36.9 pM were increased over control levels of 24.6 and 30.0 pM at 14 and 19 weeks, respectively. However, the change in dissociation constant is only significant at 14 weeks. The increased dissociation constants suggest diminished agonist binding affinity of the myocardial beta-receptor. This impaired response of the receptor to catecholamines would tend to diminish the ability of myocardium to adequately respond to adrenergic stimuli.


Comparison of Laboratory and Non-Laboratory-Based 2019 World Health Organization Cardiovascular Risk Charts in the Bhutanese Population.
The World Health Organization (WHO) recommends the use of color-coded cardiovascular disease (CVD) risk charts for CVD management. This study evaluated the agreement between the laboratory and non-laboratory 10-year CVD risks based on 2019 WHO CVD risk-prediction charts. The agreement of CVD risk scores among 40- to 69-year-old Bhutanese population stratified by gender and age groups (<60 and ≥60 years) was determined via weighted kappa statistics. In the general population, there was substantial agreement between the two CVD risk score charts for all ages and <60 years but a moderate agreement for participants aged ≥60 years. In males, substantial agreement was observed in all ages and in <60 years and moderate agreement in ≥60 years. In females, both the predictions showed substantial agreement in all ages and <60, but a moderate agreement for ≥60 years. The non-laboratory-based risk charts can be used interchangeably with laboratory-based charts for predicting 10-year CVD risk in resource-constrained countries like Bhutan.


Asynchronous ligand binding and proton release in a root effect hemoglobin.
CO binding to the Root effect hemoglobin of menhaden, Brevoortia tyrannus, has been studied by flash photolysis and equilibrium measurements in [bis(2-hydroxyethyl)amino]Tris(hydroxymethyl)methane and Tris buffers, containing 0.2 M NaCl, between pH 6.0 and 8.0. The equilibrium and kinetic data were analyzed according to the two-state model, extended to include chain differences. The calculated value of the allosteric constant, L, varied from 3 X 10(6) at pH 6.0 to 20 at pH 8.0, lower at each pH value than that computed for phosphate buffer. In addition, the intrinsic rate constants of both T and R states were found to vary with pH. The kinetics of CO binding and of proton release, followed by absorbance changes in the pH indicator dye phenol red, were observed in 0.2 M NaCl, at pH values ranging from 6.3 to 7.8. Proton release lags behind CO binding across this pH range, the larger lags occurring at lower pH; this suggests that some proton release is associated with quaternary conformational change. The CO binding progress curves in unbuffered solution were simulated by the two-state model; in these calculations the value of L was systematically changed during the course of the reaction. The time courses of reaction intermediates, obtained from these computations, were then used to represent the kinetics of proton release. A simple model, assuming that proton release accompanies quaternary conformational transition but a modified model, incorporating pH dependence of the intrinsic T and R state affinities, describes proton release across the pH range studied.


Developmental role of fatty acid-binding proteins in mouse brain.
While the functions of the cytoplasmic fatty acid-binding proteins (FABPs) are not well defined, one possibility in neural tissue is in establishing and maintaining the high levels of polyunsaturated fatty acids in membrane lipids characteristic of this tissue and thought essential for normal function. We investigated the reactivity of a protein in developing mouse brain to antiserum prepared against rat heart (H)-FABP. By immunoblot analysis, levels of H-FABP in brain were nearly undetectable until fetal day 17-19, after which levels increased until at least postnatal day 14. Levels of H-FABP were lower in the adult mouse brain, suggesting a function for the protein during differentiation of neural tissue. In immunohistochemical studies with postnatal day 14 mouse brain, the most intensely stained area was the choroid plexus. H-FABP also localized to regions of the somatosensory cortex and to the spinal trigeminal nucleus. In addition, H-FABP was present in the thalamus, entorhinal and piriform cortex, and throughout the pontine and medullary nuclei. Tracts related to the auditory system, including ventral cochlear nucleus and lateral lemniscus, also were H-FABP-positive. In cerebellum, the molecular layer was heavily labeled in cells and processes; in the granule cell layer, there was punctate staining suggestive of mossy fiber terminals. Small cells adjacent to Purkinje cells were intensely stained, while the Purkinje cells were negative. We conclude that H-FABP in brain participates in neurite formation and synapse maturation, and may be related to the similar pattern of expression of GABA related markers.


The impact of 2018 ASCO-CAP HER2 testing guidelines on breast cancer HER2 results. An audit of 2132 consecutive cases evaluated by immunohistochemistry and in situ hybridization.
The 2018 iteration of the ASCO-CAP HER2 testing guidelines proposes significant changes with an emphasis on the integration of concurrent immunohistochemistry (IHC) and in situ hybridization (ISH). We wished to evaluate the impact of these changes on clinical practice. Between Jan 2012 to Feb 2017, 2132 consecutive invasive breast carcinomas were evaluated with IHC and ISH for HER2. The sample tested was the breast primary or axillary nodes in all but 57 (2.7%) distant metastases. For 1824 cases with both dual-probe ISH and IHC results, the ISH subgroup was 1: 299 (16.4%), 2: 19 (1.0%), 1.0%, 3: 6 (0.3%), 4: 48 (2.6%) and 5: 1452 (79.6%). Ultimately 21% of group 2 and 4 cases and 80% of group 4 cases were positive. The change in HER2 status between the 2018 vs 2013 was: amplified in 323 (15.2%) vs 15.5%; not amplified in 1804 (84.6%) vs 82.2%; equivocal in 0 vs 2.3% previously. In 22 of 2127 cases (1.03%) the 2013 and 2018 results were discordant, all in groups 2-4. The discrepant cases included 15 of 331 (4.5%) of 2013 amplified cancers, now negative (all in groups 2 or 3) and 7 of 1796 (0.4%) 2013 nonamplified cases, now positive (all in group 4). Because of routine testing with both IHC and ISH, we found 6 of 1147 (0.52%) IHC negative (0 or 1+) cases were amplified by ISH. Further, 19 of 289 (6.6%) of IHC 3+ cases were nonamplified by ISH, circumstances not covered by these guidelines. In summary at the population level, the 2018 ASCO-CAP guidelines have a 99% agreement with the 2013 results. A major advantage is the abolishment of the clinically problematic equivocal category. Routine performance of both IHC and ISH uncovers a small proportion of cancers whose HER2 status is not addressed by these guidelines.


Posttraumatic stress disorder symptoms and neurocognitive functioning in fire fighters: The mediating role of sleep problems and resilience.
Firefighters are often exposed to terrible and dangerous scenes due to their duties, and thus have a high risk of developing posttraumatic stress disorder(PTSD). The purpose of the study is to examine the relationship between PTSD symptoms, sleep problems, resilience and neurocognitive functioning of firefighters, and to identify the sequential mediating effects of sleep problems and resilience on the relationship between PTSD symptoms and neurocognitive functioning (especially psychomotor speed and processing speed). Data were collected from 325 firefighters in eight fire departments in four regions of Korea. Subjects performed neurocognitive function tests and completed the following questionnaires: Primary Care PTSD Screening, Pittsburgh Sleep Quality Index-K and Connor-Davidson Resilience Scale-2. The correlation and dual mediation effects were analysed using SPSS 22.0 program and PROCESS macro 3.4 program. PTSD symptoms, neurocognitive functioning, sleep problems and resilience were significantly correlated with each other. In the sequential mediation model, the relationship between PTSD and psychomotor speed/processing speed was sequentially mediated by sleep problems and resilience after adjusting for demographic variables. The PTSD symptoms of firefighters were related to a sequential link between sleep problems, low resilience and decreased neurocognitive function. These findings could serve as a basis for more effective and integrated interventional strategies for facilitating better neurocognitive functioning in firefighters.


In silico analysis of DND1 and its co-expressed genes in human cancers.
Dead-End (DND1) is an RNA-binding protein involved in translational regulation. Defects in DND1 gene causes germ cell tumors and sterility in rodents. Experimental studies with human somatic cancer cells indicate that DND1 has anti-proliferative and pro-apoptotic function in some while oncogenic function in other cells. We examined The Cancer Genome Atlas data for gene alterations and gene expression changes in DND1 in a variety of human cancers. We found that DND1 is amplified, deleted or mutated in multiple human cancers. In different cancers, DND1 alteration correlates with increased diagnosis age of patients, shift in tumor spectrum or change of tumor sites and in some cases is significantly associated with worse survival for cancer patients. For 15 cancers, we retrieved expression data of thousands of genes that co-expressed with DND1. We found that these cancers contain different percentage of genes that are positively or negatively co-expressed with DND1. Ingenuity Pathway Analysis was performed to explore the biological implications of these genes. More than 10 canonical pathways were identified and each cancer type exhibits unique pathway profiles. Comparison analysis across all 15 cancer types showed that some cancers exhibit strikingly similar profiles of DND1-correlated signaling pathway activation or suppression. Our data reinforce the notion that the biological role of DND1 is cell-type specific and suggest that DND1 may play opposing role by exerting anti-proliferative effects in some cancer cells while being pro-proliferative in others. Our study provides valuable insights to direct experimental investigations of DND1 function in somatic cancers.


ScvO2 changes after red-blood-cell transfusion for anaemia in cardiothoracic and vascular ICU patients: an observational study.
Haemoglobin threshold for transfusion has been significantly decreased, but haemoglobin plasma concentration may not be sufficient to assess the need of red-blood-cell (RBC) transfusion. Central venous oxygen saturation (ScvO2 ) is a clue of metabolic matching between O2 transport and consumption, which could help to assess when transfusion is appropriate once anaemia has been diagnosed in ICU patients. Adult patients admitted consecutively to a cardiothoracic and vascular ICU were included in a prospective, observational and single-centre study over a 6-month period (September 2014 to February 2015), provided they were transfused with RBC. Patients with active bleeding or in unstable condition were excluded. Haemoglobin and ScvO2 were collected through a central venous catheter before and after transfusion. In order to identify a ScvO2 threshold, analysis of ScvO2 changes after transfusion was performed. Fifty-three patients received 100 RBC transfusions. Haemoglobin at the time of transfusion was 7·2 g/dl [6·8-7·7], while ScvO2 was 66·9% [60-73]. A 5% increase in ScvO2 after transfusion has the best specificity and positive predictive values, with a ScvO2 threshold of 65%. After transfusion (RBC units, 2 [1-2]), ScvO2 increased only in patients with ScvO2 ≤65%, from 58% [53-62] to 69% [64-73] (P < 0·001). In anaemic patients, RBC transfusion induced a significant increase in ScvO2 , provided it was low before transfusion. A 65% cut-off value of ScvO2 before transfusion showed good specificity and good positive predictive value for a 5% increase after transfusion.


Voltage-gated calcium channels are not involved in generation and propagation of spreading depression (SD) in the brainstem of immature rats.
Spreading depression (SD) can be elicited in the brainstem of rats younger than 13 days when excitability is enhanced by acetate superfusion [F. Richter, S. Rupprecht, A. Lehmenkühler, H.-G. Schaible, Spreading depression can be elicited in brain stem in immature but not adult rats, J. Neurophysiol. 90 (2003) 2163--2170]. To investigate whether voltage-gated calcium channels (VGCCs) modify initiation and propagation of SD in this type of tissue, we applied specific blockers to L-, T-, P/Q-, and N-type VGCCs locally or systemically. SD-related d.c. potentials and concomitant increases in extracellular potassium concentration ([K(+)](e)) were unaffected by the L- and T-type VGCC blocker flunarizine that was applied either systemically (up to 2mg/kg body weight) or by superfusion onto the brainstem (40 microM). In addition, local application of the P/Q-type VGCC blocker omega-agatoxin (1 microM) or of the N-type VGCC blocker omega-conotoxin (1 microM) to the brainstem surface did not influence SD. The results indicate that VGCCs do not modify the generation or propagation of SDs in the brainstem of the immature rat. Blockade of N-type VGCCs disturbed the normal breathing rhythm. Application of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) (250-1000 microM) that elicited SD in the immature cortex, failed to elicit SD in the immature brainstem. In summary, it is likely that K(+) initiates and propagates brainstem SDs.


The interplay of microRNAs and transcription factors in autophagy regulation in nonalcoholic fatty liver disease.
The autophagy-lysosomal degradation system has an important role in maintaining liver homeostasis by removing unnecessary intracellular components. Impaired autophagy has been linked to nonalcoholic fatty liver disease (NAFLD), which includes hepatitis, steatosis, fibrosis, and cirrhosis. Thus, gaining an understanding of the mechanisms that regulate autophagy and how autophagy contributes to the development and progression of NAFLD has become the focus of recent studies. Autophagy regulation has been thought to be primarily regulated by cytoplasmic processes; however, recent studies have shown that microRNAs (miRNAs) and transcription factors (TFs) also act as key regulators of autophagy by targeting autophagy-related genes. In this review, we summarize the miRNAs and TFs that regulate the autophagy pathway in NAFLD. We further focus on the transcriptional and posttranscriptional regulation of autophagy and discuss the complex regulatory networks involving these regulators in autophagy. Finally, we highlight the potential of targeting miRNAs and TFs involved in the regulation of autophagy for the treatment of NAFLD.


Non functioning interstitial cell carcinoma of testis.
The authors add an additional case to the 13 cases of malignant interstitial cell tumor of the testis previously reported in the literature. It has been thought that the hallmark of metastatic interstitial cell tumor of the testis is endocrinopathy secondary to production of hormones by the tumor. In the case reported here there were no clinical or chemical manifestations of any endocrinopathy, making this case unique.


Management of traumatic injuries to the facial nerve.
Penetrating and nonpenetrating trauma to the head and neck produces myriad injuries to the facial nerve. This article presents a rationale of management of neural injury, emphasizing extracranial and intratemporal trauma and techniques of neurorrhaphy.


Evaluation of a commercial staphylococcal bacterin for management of idiopathic recurrent superficial pyoderma in dogs.
Twenty-one dogs with idiopathic superficial recurrent pyoderma were entered into a double-blind, placebo-controlled study to evaluate the efficacy of a commercial staphylococcal bacterin. The study spanned an 18-week period. All dogs were administered sodium oxacillin orally for the initial 6 weeks of the study. Dogs were given the bacterin or placebo SC, twice weekly at 3- or 4-day intervals, beginning at week 0 and continuing for 18 weeks. Dogs given antibiotics plus the bacterin (n = 13) had a significantly (P less than 0.05) better treatment response than those given antibiotic plus placebo.


Hereditary sensory autonomic neuropathy caused by a mutation in dystonin.
In 4 infants with a new lethal autonomic sensory neuropathy with clinical features similar to familial dysautonomia as well as contractures, we identified a deleterious mutation in the DST gene, using homozygosity mapping followed by exome sequencing. DST encodes dystonin, a cytoskeleton linker protein, and the mutation results in an unstable transcript. Interestingly, dystonin is significantly more abundant in cells of familial dysautonomia patients with IKBKAP (I-κ-B kinase complex-associated protein) mutation compared to fibroblasts of controls, suggesting that upregulation of dystonin is responsible for the milder course in familial dysautonomia. Homozygosity mapping followed by exome sequencing is a successful approach to identify mutated genes in rare monogenic disorders.


Role of the RNA-binding protein ZC3H41 in the regulation of ribosomal protein messenger RNAs in trypanosomes.
Trypanosomes are single-celled eukaryotes that rely heavily on post-transcriptional mechanisms to regulate gene expression. RNA-binding proteins play essential roles in regulating the fate, abundance and translation of messenger RNAs (mRNAs). Among these, zinc finger proteins of the cysteine3histidine (CCCH) class have been shown to be key players in cellular processes as diverse as differentiation, regulation of the cell cycle and translation. ZC3H41 is an essential zinc finger protein that has been described as a component of spliced leader RNA granules and nutritional stress granules, but its role in RNA metabolism is unknown. Cell cycle analysis in ZC3H41- and Z41AP-depleted cells was carried out using 4',6-diamidino-2-phenylindole staining, microscopic examination and flow cytometry. The identification of ZC3H41 protein partners was done using tandem affinity purification and mass spectrometry. Next-generation sequencing was used to evaluate the effect of ZC3H41 depletion on the transcriptome of procyclic Trypanosoma brucei cells, and also to identify the cohort of mRNAs associated with the ZC3H41/Z41AP complex. Levels of 5S ribosomal RNA (rRNA) species in ZC3H41- and Z41AP-depleted cells were assessed by quantitative reverse transcription-polymerase chain reaction. Surface sensing of translation assays were used to monitor global translation. We showed that depletion of the zinc finger protein ZC3H41 resulted in marked cell cycle defects and abnormal cell morphologies. ZC3H41 was found associated with an essential protein, which we named Z41AP, forming a stable heterodimer, and also with proteins of the poly(A)-binding protein 1 complex. The identification of mRNAs associated with the ZC3H41/Z41AP complex revealed that it is primarily composed of ribosomal protein mRNAs, and that binding to target transcripts is diminished upon nutritional stress. In addition, we observed that mRNAs encoding several proteins involved in the maturation of 5S rRNA are also associated with the ZC3H41/Z41AP complex. Finally, we showed that depletion of either ZC3H41 or Z41AP led to the accumulation of 5S rRNA precursors and a decrease of protein translation. We propose that ZC3H41 and Z41AP play important roles in controlling the fate of ribosomal components in response to environmental cues.


Ultrasonic modulation of tissue optical properties in ex vivo porcine skin to improve transmitted transdermal laser intensity.
Applications of light-based energy devices involving optical targets within the dermis frequently experience negative side-effects resultant from surface scattering and excess optical absorption by epidermal melanin. As a broadband optical absorber, melanin decreases the efficacy of light-based treatments throughout the ultraviolet, visible, and near-infrared spectra while also generating additional heat within the surface tissue that can lead to inflammation or tissue damage. Consequently, procedures may be performed using greater energy densities to ensure that the target receives a clinically relevant dose of light; however, such practices are limited, as doing so tends to exacerbate the detrimental complications resulting from melanin absorption of treatment light. The technique presented herein represents an alternative method of operation aimed at increasing epidermal energy fluence while mitigating excess absorption by unintended chromophores. The approach involves the application of continuously pulsed ultrasound to modulate the tissue's optical properties and thereby improve light transmission through the epidermis. To demonstrate the change in optical properties, pulsed light at a wavelength of 532 nm from a Q-switched Nd:YAG laser was transmitted into 4 mm thick samples of porcine skin, comprised of both epidermal and dermal tissue. The light was transmitted using an optical waveguide, which allowed for an ultrasonic transducer to be incorporated for simultaneous paraxial pulsation in parallel with laser operation. Light transmitted through the tissue was measured by a photodiode attached to an integrating sphere. Increasing the driving voltage of ultrasonic pulsation resulted in an increase in mean transmitted optical power of up to a factor of 1.742 ± 0.0526 times the control, wherein no ultrasound was applied, after which the optical power increase plateaued to an average amplification factor of 1.733 ± 0.549 times the control. The increase implies a reduction in light either back-scattered or absorbed within the tissue, which would allow for a greater proportion of incident energy to be delivered to the clinical target, thereby improving procedural efficacy and potentially reducing the severity of detrimental side-effects. Apparatus Lasers Surg. Med. 49:666-674, 2017. © 2017 Wiley Periodicals, Inc.


Geographical distribution of reference value of aging people's left ventricular end systolic diameter based on the support vector regression.
The aim of this paper is to analyze the geographical distribution of reference value of aging people's left ventricular end systolic diameter (LVDs), and to provide a scientific basis for clinical examination. The study is focus on the relationship between reference value of left ventricular end systolic diameter of aging people and 14 geographical factors, selecting 2495 samples of left ventricular end systolic diameter (LVDs) of aging people in 71 units of China, in which including 1620 men and 875 women. By using the Moran's I index to make sure the relationship between the reference values and spatial geographical factors, extracting 5 geographical factors which have significant correlation with left ventricular end systolic diameter for building the support vector regression, detecting by the method of paired sample t test to make sure the consistency between predicted and measured values, finally, makes the distribution map through the disjunctive kriging interpolation method and fits the three-dimensional trend of normal reference value. It is found that the correlation between the extracted geographical factors and the reference value of left ventricular end systolic diameter is quite significant, the 5 indexes respectively are latitude, annual mean air temperature, annual mean relative humidity, annual precipitation amount, annual range of air temperature, the predicted values and the observed ones are in good conformity, there is no significant difference at 95% degree of confidence. The overall trend of predicted values increases from west to east, increases first and then decreases from north to south. If geographical values are obtained in one region, the reference value of left ventricular end systolic diameter of aging people in this region can be obtained by using the support vector regression model. It could be more scientific to formulate the different distributions on the basis of synthesizing the physiological and the geographical factors. -Use Moran's index to analyze the spatial correlation. -Choose support vector machine to build model that overcome complexity of variables. -Test normal distribution of predicted data to guarantee the interpolation results. -Through trend analysis to explain the changes of reference value clearly.


Determination of health fatalism and the factors affecting health fatalism in patients with epilepsy in the North of Turkey.
In individuals with epilepsy, health fatalism can affect their perceptions of health and their responses to solutions offered, both positively and negatively. This study aimed to investigate health fatalism in people with epilepsy in Turkey and the factors that influence their health fatalism. This descriptive and cross-sectional study was conducted between December 2019 and April 2020 with 100 epilepsy patients who were referred to a neurology outpatient clinic in the North of Turkey. The data for the study were collected using a descriptive information form and the Health Fatalism Scale (HES). The total mean score on the Health Fatalism Scale for the study participants was found to be 56,16 ± 15,71. Significant association was found between health fatalism and educational status (p < 0,05), polytherapy (p < 0,05), and frequency of seizures (p < 0,001). In this study, individuals with epilepsy expressed high levels of fatalism in their health beliefs. It was found that illiterate individuals with epilepsy held more fatalistic beliefs. In addition, it was found that participants who used polytherapy and those who had frequent seizures also had higher levels of fatalistic health beliefs.


Treatment of pulmonary sequestration by video-assisted thoracic surgery (VATS).
Pulmonary sequestration is a rare malformation of the respiratory tract that accounts for 0.15-6.4% of all congenital lung anomalies. Treatment requires resection of the lesion, provided that there is no technical contraindication. The lesion should first be evaluated using video thoracoscopy and then resected whenever possible by video-assisted thoracic surgery (VATS). We report a case of extralobar pulmonary sequestration in a 48-year-old woman. She underwent lobectomy by VATS and achieved an excellent outcome.


Treatment of adenovirus pneumonia with cidofovir in pediatric lung transplant recipients.
Adenovirus pneumonia results in significant morbidity and mortality in lung transplant recipients. Cidofovir allows for directed therapy but can result in nephrotoxicity. We report our experience with cidofovir for the treatment of adenovirus pneumonia in pediatric lung transplant recipients. In a retrospective review, we identified four cases of culture-proven adenovirus pneumonia in children who underwent lung transplantation at Texas Children's Hospital (TCH). All patients received cidofovir 1 mg/kg every other day or three times a week for a total of 4 weeks. Probenecid and intravenous hydration were administered in conjunction with the cidofovir. Intravenous immunoglobulin (IVIg) was given as adjunctive therapy, and immunosuppression was not modified during the treatment course. The four cases of adenovirus pneumonia comprised 4 of the 54 (7%) lung transplantations performed at TCH from 2002 to 2006, and all were in children <3 years of age. All patients developed pneumonia within 2 months after transplantation. With cidofovir treatment, three of the four children survived. Among the survivors, two developed early bronchiolitis obliterans within 1 year after transplant, and one has continued to have good graft function at 2 years after transplant. All patients maintained normal renal function throughout the treatment course. Pediatric lung transplant recipients <3 years of age are at increased risk of adenovirus pneumonia early after transplantation. Cidofovir, when used in the modified dosing regimen and in combination with IVIg and renal protection measures, is a safe and potentially effective treatment option for adenovirus pneumonia in lung transplant recipients.


Diagnostic tools used for melanoma: A survey of Australian general practitioners and dermatologists.
Diagnostic tools such as dermoscopy, sequential digital dermoscopy imaging (SDDI), total body photography (TBP) and automated diagnostic tools are available to assist in early melanoma diagnosis. The use, accessibility and barriers of dermoscopy have been well studied; however, there are few similar studies regarding SDDI, TBP and automated diagnostic tools. We aim to understand the use of these diagnostic aids amongst Australian general practitioners (GPs) and dermatologists. Between June 2019 and January 2020, GPs and dermatologists across Australia were invited to participate in an online survey. Surveys were distributed through GP and dermatology organisations. A total of 227 survey responses were received, 175 from GPs and 52 from dermatologists. Amongst GPs, 44.6% worked in a skin cancer clinic. Dermoscopy was used at least occasionally by 98.9% of all GPs. SDDI was used by 93.6% of skin cancer GPs, 80.8% of dermatologists and 45.3% of generalist GPs. TBP was used or recommended by 77.1% of generalist GPs, 82.3% of skin cancer GPs and 86.5% of dermatologists. The most common barriers to the use of TBP were cost, limited accessibility, poor patient compliance, and time required for both patients and doctors. Very few clinicians reported using automated diagnostic tools. There was an interest in future diagnostic aids for melanoma in 88% of GPs and dermatologists. Dermoscopy, SDDI and TBP were commonly used by responding Australian skin cancer GPs and dermatologists in this survey. Automated diagnostic tools were not reported to be used routinely. Several barriers were identified for use of TBP.


"You have (rotator cuff related) shoulder pain, and to treat it, I recommend exercise." A scoping review of the possible mechanisms underpinning exercise therapy.
Exercise is considered to be both essential and at the forefront of the management of rotator cuff-related shoulder pain (RCRSP). Despite this, many fail to substantially improve with exercise-based treatment. Hence, expanding the current knowledge about the possible mechanisms of exercise for RCRSP is critical. To synthesise the range of mechanisms proposed for exercise in people with RCRSP. Scoping review METHODS: A systematic search of the Physiotherapy Evidence Database (PEDro) was conducted from inception to July 3, 2022. Two reviewers conducted the search and screening process and one reviewer extracted the data from each study. Randomised clinical trials using exercise for the management of RCRSP of any duration were included. The PEDro search terms used were "fitness training", "strength training", "stretching, mobilisation, manipulation, massage", "upper arm, shoulder, or shoulder girdle", "pain", and "musculoskeletal". Data were analysed using quantitative and qualitative approaches. 626 studies were identified and 110 were included in the review. Thirty-two unique mechanisms of exercise were suggested by clinical trialists, from which 4 themes emerged: 1) neuromuscular 2) tissue factors 3) neuro-endocrine-immune 4) psychological. Neuromuscular mechanisms were proposed most often (n = 156, 77%). Overall, biomedical mechanisms of exercise were proposed in 95% of cases. The causal explanation for the beneficial effect of exercise for RCRSP in clinical research is dominated by biomedical mechanisms, despite a lack of supporting evidence. Future research should consider testing the mechanisms identified in this review using mediation analysis to progress knowledge on how exercise might work for RCRSP.