[Impact of tobacco use on the periodontium--an update (I)--Part 1: Epidemiologic und pathogenetic aspects of tobacco-related periodontal diseases].
This literature review represents the second in a series of articles from the Swiss task force "Smoking--Intervention in the private dental office" on the topic "tobacco use and dental medicine". In this article, the epidemiological background as well as some pathogenetic processes are described and discussed critically for tobacco-related periodontal diseases. Earlier publications confirmed tobacco consumption as a risk factor for periodontal diseases. Over the last few years, oral health research has significantly contributed to the understanding of the mechanisms leading to the deterioration of the hard and soft tissues supporting the teeth. With the recording of the number of cigarettes smoked per day and the amount of years tobacco was used, a dose response relationship was established. Various, potentially significant pathogenic effects of tobacco-related substances may exist on the periodontal tissues, the immune response system or the composition of the oral flora. Moreover, there is reference that tobacco consumption may change the genetically determined susceptibility for periodontal diseases.


The role of carotid artery stenosis in predicting stroke after coronary artery bypass grafting in a Chinese cohort study.
Current guidelines give priority to surgical treatment of carotid artery stenosis (CAS) before coronary artery bypass grafting (CABG), especially in symptomatic patients. Carotid artery stenting is an alternative treatment for narrowing of the carotid arteries. This study sought to demonstrate the role of severe CAS in predicting stroke after CABG and assess the efficacy of carotid artery stenting in preventing postoperative stroke in a Chinese cohort. From 2015 to 2021, 1799 consecutive patients undergoing isolated CABG surgery were retrospectively recruited in a Chinese cohort. The predictive value of severe CAS in postoperative stroke and carotid stenting in preventing postoperative stroke was statistically analyzed. The incidence of postoperative stroke was 1.67%. The incidence of CAS with stenosis ≥ 50% and ≥ 70% was 19.2% and 6.9%. After propensity matching, the incidence of stroke was 8.0% in the severe CAS group and 0% in the non-severe CAS group. We successfully established an optimal predictive nomogram for predicting severe CAS in patients undergoing CABG. Carotid artery stenting was found ineffective in preventing postoperative stroke. The present study provides the incidence of CAS and postoperative stroke in a Chinese cohort, identifies severe CAS as an independent risk factor for postoperative stroke after CABG, constructs a nomogram predicting the incidence of severe CAS, and evaluates the effectiveness of carotid artery stenting in preventing postoperative stroke after CABG.


Perceptions and implications of violence from care home residents with dementia: a review and commentary.
This paper presents a critical review of the literature related to the violence staff in care homes experience from people with dementia. It attempts to identify the psychological consequences abuse has on care workers and the implications this has for practice. Abuse in the form of violence or aggression against healthcare professionals is not new. However, when this is from residents with dementia in care homes it is considered to be part of the job. Consequently it is largely underreported and ignored which masks its true extent. The magnitude of violence in care homes crosses cultural boundaries. Fear of being blamed, job insecurity and resignation that abuse should be accepted as part of the job is unique to this care setting. The cumulative effect of psychological abuse leads to emotional exhaustion and depersonalisation which results in care workers emotionally and physically withdrawing from residents. Being subjected to abuse, feeling undervalued, unsupported and lacking essential skills may compromise a workforces' ability to provide person-centred care. A rising ageing population and prevalence of dementia will place demands on commissioners and providers to deliver high quality care. Consistent recording and reporting procedures, dementia specific training and infrastructures to support staff is therefore crucial.


Design and Implementation of an ETL-Process to Transfer Wound-Related Data into a Standardized Common Data Model.
For observational studies, which are relevant especially for chronic conditions like chronic wounds, the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) offers a standardized database schema. In this study an ETL process for the transition of wound related data was developed. After understanding the data in general and mapping the relevant codes to concepts available in OMOP, the ETL process was implemented. In a first step, a generic algorithm to convert data to a csv format was implemented in Java. The resulting csv file was then processed within KNIME to be loaded into an OMOP CDM conformant database. During the whole ETL process, HL7 FHIR CodeSystem and ConceptMap resources were used for coding and mapping. First clinical test cases to retrieve data were successfully processed as an example to demonstrate the feasibility and usefulness. They concerned wound size at the first visit and the main issues of patients in the wound quality of life questionnaire (n = 24). In general, the ETL process worked well, yet some challenges arose, like post coordinated SNOMED codes or conditions, which might occur more than once.


Cytogenetics in the management of clonal chromosomal abnormalities of undetermined significance and persistent polyclonal B-cell lymphocytosis: Guidelines from the Groupe Francophone de Cytogénétique Hématologique (GFCH).
Acquired clonal chromosomal abnormalities (CAs) are usually considered to be disease-related. However, when a CA of this type is the only abnormality present (and especially in small clones), the clinical significance is unclear. Here, we review the literature on recurrent CAs whose significance is regularly subject to debate. Our objective was to help with their interpretation and develop guidelines for sex chromosome loss, trisomy 15, trisomy 8, deletion 20q and other isolated non-myelodysplastic neoplasm (MDS)-defining CAs. We suggest that non-MDS-defining CAs correspond to clonal hematopoiesis of indeterminate potential (CHIP) in the absence of cytopenia and clonal cytopenia of undetermined significance (CCUS) in the presence of cytopenia. Lastly, we review the literature on persistent polyclonal binucleated B-cell lymphocytosis; although usually benign, this condition may correspond to a premalignant state.


Gas diffusion electrode setup for catalyst testing in concentrated phosphoric acid at elevated temperatures.
We present a detailed description of the construction and testing of an electrochemical cell setup allowing the investigation of a gas diffusion electrode containing carbon supported high surface area catalysts. The setup is designed for measurements in concentrated phosphoric acid at elevated temperature, i.e., very close to the actual conditions in high temperature proton exchange membrane fuel cells (HT-PEMFCs). The cell consists of a stainless steel flow field and a PEEK plastic cell body comprising the electrochemical cell, which exhibits a three electrode configuration. The cell body and flow field are braced using a KF-25 vacuum flange clamp, which allows an easy assembly of the setup. As demonstrated, the setup can be used to investigate temperature dependent electrochemical processes on high surface area type electrocatalysts, but it also enables quick screening tests of HT-PEMFC catalysts under realistic conditions.


Costunolide alleviates HKSA-induced acute lung injury via inhibition of macrophage activation.
Staphylococcus aureus (S. aureus) infection leads to a severe inflammatory response and causes acute lung injury (ALI), eventually threatening human life. Therefore, it is of importance to find an agent to inhibit inflammation and reduce ALI. Here, we found that costunolide, a sesquiterpene lactone, displays anti-inflammatory effects and ameliorates heat-killed S. aureus (HKSA)-induced pneumonia. Costunolide treatment attenuated HKSA-induced murine ALI in which pulmonary neutrophil infiltration was inhibited, lung edema was decreased, and the production of pro-inflammatory cytokines was significantly reduced. In addition, costunolide dose-dependently inhibited the generation of IL-6, TNF-α, IL-1β, and keratinocyte-derived cytokine (KC), as well as the expression of iNOS, in HKSA-induced macrophages. Furthermore, costunolide attenuated the phosphorylation of p38 MAPK and cAMP response element-binding protein (CREB). Collectively, our findings suggested that costunolide is a promising agent for alleviating bacterial-induced ALI via the inhibition of the MAPK signaling pathways.


Excited-State Dynamics of Dithienylethenes Functionalized for Self-Supramolecular Assembly.
The photoswitching and competitive processes of two photochromic dithienylethenes (DTEs) functionalized at both sides with 2-ureido-4[1H]-pyrimidone (UPy) quadruple hydrogen-bonding recognition patterns have been investigated with NMR experiments, ultrafast spectroscopy, and density functional theory (DFT) calculations. The originality of these molecules is their ability to form large supramolecular assemblies induced by light for the closed form (CF) species while the open form (OF) species exist as small oligomers. Photochromic parameters have been determined and photochemical pathways have been rationalized with clear distinction between the antiparallel (OF-AP) and parallel (OF-P) species. A new photocyclization pathway via triplet manifold has been evidenced. The effect of the supramolecular assembly on the photochemical response is discussed. Unlike the photoreversion process, which is unaffected by supramolecular assembly, rate constants of the photocyclization reaction and intersystem crossing process are sensitive to the presence of small OF oligomers.


[Helicobacter pylori in patients with bleeding ulcer].
The diagnostic sensitivity of the polymerase chain reaction (PCR) and urease respiratory test (URT) in H. pylori infection are compared. The efficacy of H. pylori eradication in patients with a bleeding peptic ulcer using three-component scheme (De-nol, Clarythromycin, Furazolidon) and a complex medication Pylobact is also compared. Thus, URT, performed within 24 hours after the admission is more effective in patients with bleeding ulcer, then PCR. H. pylori eradication is more successful with Pylobact (93,8%) and has less side-effects in such patients, then the used three-component eradication scheme.


An Investigation of the Relationship Between Retention in First Grade and Performance on High Stakes Tests in 3 Grade.
The association between grade retention in first grade and passing the third grade state accountability tests, the Texas Assessment of Knowledge and Skills (TAKS) reading and math, was investigated in a sample of 769 students who were recruited into the study when they were in first grade. Of these 769 students, 165 were retained in first grade and 604 were promoted. Using propensity matching, we created five imputed datasets (average N=321) in which promoted and retained students were matched on 67 comprehensive covariates. Using GEE models, we obtained the association between retention and passing the 3(rd) grade TAKS reading and math tests. The positive association between retention and math scores was significant while the association was marginally significant for reading scores.


Prematurity and perinatal mortality in pregnancies complicated by maternal Chlamydia trachomatis infections.
In a prospective study of morbidity associated with Chlamydia trachomatis infections during pregnancy, we isolated C trachomatis from the endocervix of 18 (6.7%) of 268 women examined before 19 weeks' gestation. Infected women were significantly younger than noninfected women, and significantly more often unmarried, supported by public assistance, and pregnant for the first time. Among women followed up from 19 weeks' gestation until delivery, the mean duration of gestation was significantly shorter for those with antepartum chlamydial infection. Stillbirth or neonatal death occurred in six (33%) of the 18 pregnancies of infected women compared with eight (3.4%) of the 238 pregnancies of noninfected women followed up from the 19th week of gestation through delivery. Stillbirth or neonatal death occurred ten times more often among Chlamydia-infected women than among uninfected controls matched for age, marital status, socioeconomic status, pregnancy order, and race.


Retrospective comparative study of robot-assisted surgery, laparoscopic surgery, and laparotomy for endometrial cancer in patients with a low risk of recurrence.
Minimally invasive surgeries for endometrial cancer are increasing worldwide. In Japan, some articles have examined surgical outcomes, but only a few have addressed oncological outcomes. This study aims to compare robot surgery, laparoscopic surgery, and laparotomy in terms of surgical and oncological outcomes within a low-risk group for endometrial cancer recurrence. This study included patients with endometrial cancer deemed to be at low risk of recurrence and who underwent surgery between January 2011 and December 2020. We studied 99 patients who underwent robot surgery, 85 patients who underwent laparotomy, and 77 patients who underwent laparoscopic surgery. Surgical and oncological outcomes were compared retrospectively for these groups of patients. The median follow-up period was 47, 61, and 60 months in the laparotomy, laparoscopy, and robotic groups, respectively. The three groups had similar perioperative and pathological data. No significant differences in overall survival and disease-free survival were observed among the groups. Univariate and multivariate analyses conducted on the overall study population for disease-free survival and overall survival showed that the surgical approach did not have any influence. Minimally invasive surgery groups had longer operating times compared to the laparotomy group, but they had significantly less blood loss. The number of resected pelvic lymph nodes was similar, and the complication rate was not significant. Robot-assisted surgery and laparoscopic surgery were found to be less invasive and showed similar oncologic outcomes compared to laparotomy surgery for endometrial cancer in patients with a low risk of recurrence.


The relationship between childhood sexual abuse and adult mental health among undergraduates: victim gender doesn't matter.
A large body of research has documented the harmful effects of childhood sexual abuse (CSA) on adult mental health among females, but less work has examined this issue among males. This study examined whether gender moderated the relationship between CSA and adult mental health among a mixed-gender sample of 406 undergraduates. A Pearson chi-square test indicated that a significantly greater proportion of females (41.6%) than males (30.7%) reported a history of CSA. ANCOVAs tested whether gender, CSA status, and their interaction were related to adult mental health symptomatology as measured by Brief Symptom Inventory gender-normed t scores. Participants with a history of CSA reported significantly higher levels of global mental health problems, hostility, paranoid ideation, and psychoticism. The gender by CSA status interaction was not significant for any scale, indicating that the harmful effects of CSA on adult mental health did not vary by gender.


Pitch discrimination with mixtures of three concurrent harmonic complexes.
In natural listening contexts, especially in music, it is common to hear three or more simultaneous pitches, but few empirical or theoretical studies have addressed how this is achieved. Place and pattern-recognition theories of pitch require at least some harmonics to be spectrally resolved for pitch to be extracted, but it is unclear how often such conditions exist when multiple complex tones are presented together. In three behavioral experiments, mixtures of three concurrent complexes were filtered into a single bandpass spectral region, and the relationship between the fundamental frequencies and spectral region was varied in order to manipulate the extent to which harmonics were resolved either before or after mixing. In experiment 1, listeners discriminated major from minor triads (a difference of 1 semitone in one note of the triad). In experiments 2 and 3, listeners compared the pitch of a probe tone with that of a subsequent target, embedded within two other tones. All three experiments demonstrated above-chance performance, even in conditions where the combinations of harmonic components were unlikely to be resolved after mixing, suggesting that fully resolved harmonics may not be necessary to extract the pitch from multiple simultaneous complexes.


Metabolic syndrome and related variables, insulin resistance, leptin levels, and PPAR-γ2 and leptin gene polymorphisms in a pedigree of subjects with bipolar disorder.
Evidence points to a high prevalence of metabolic dysfunction in bipolar disorder (BD), but few studies have evaluated the relatives of subjects with BD. We conducted a cross-sectional study in an extended family of patients with BD type I. The available relatives of the same family were interviewed (DSM-IV-R) and assessed in fasting conditions for body mass index, constituent variables of the metabolic syndrome (MS), leptin levels, insulin resistance index, and single nucleotide polymorphisms (SNPs) for the leptin receptor and promoter and PPAR-γ2 genes. The frequency of MS was compared with that recorded in the local general population. Ninety-three relatives of three adults with BD were evaluated (30 aged < 18 years, 63 aged > 18 years). The frequency of MS was similar to that of the general population. Significantly higher frequencies of abnormal glucose, total and low density cholesterol (LDL-c) levels (all p < 0.05), waist circumference (p = 0.057), and leptin and insulin resistance values (in adults only) were observed in the family. Adults with the QQ genotype of the leptin receptor displayed higher LDL-c levels than carriers of the R allele. The associations among BD consanguinity, familial hypercholesterolemia, and leptin receptor SNPs reported herein should be replicated and extended in other pedigrees.


Sympathetic α₃β₂-nAChRs mediate cerebral neurogenic nitrergic vasodilation in the swine.
The α(7)-nicotinic ACh receptor (α(7)-nAChR) on sympathetic neurons innervating basilar arteries of pigs crossed bred between Landrace and Yorkshire (LY) is known to mediate nicotine-induced, β-amyloid (Aβ)-sensitive nitrergic neurogenic vasodilation. Preliminary studies, however, demonstrated that nicotine-induced cerebral vasodilation in pigs crossbred among Landrace, Yorkshire, and Duroc (LYD) was insensitive to Aβ and α-bungarotoxin (α-BGTX). We investigated nAChR subtype on sympathetic neurons innervating LYD basilar arteries. Nicotine-induced relaxation of porcine isolated basilar arteries was examined by tissue bath myography, inward currents on nAChR-expressing oocytes by two-electrode voltage recording, and mRNA and protein expression in the superior cervical ganglion (SCG) and middle cervical ganglion (MCG) by reverse transcription PCR and Western blotting. Nicotine-induced basilar arterial relaxation was not affected by Aβ, α-BGTX, and α-conotoxin IMI (α(7)-nAChR antagonists), or α-conotoxin AuIB (α(3)β(4)-nAChR antagonist) but was inhibited by tropinone and tropane (α(3)-containing nAChR antagonists) and α-conotoxin MII (selective α(3)β(2)-nAChR antagonist). Nicotine-induced inward currents in α(3)β(2)-nAChR-expressing oocytes were inhibited by α-conotoxin MII but not by α-BGTX, Aβ, or α-conotoxin AuIB. mRNAs of α(3)-, α(7)-, β(2)-, and β(4)-subunits were expressed in both SCGs and MCGs with significantly higher mRNAs of α(3)-, β(2)-, and β(4)-subunits than that of α(7)-subunit. The Aβ-insensitive sympathetic α(3)β(2)-nAChR mediates nicotine-induced cerebral nitrergic neurogenic vasodilation in LYD pigs. The different finding from Aβ-sensitive α(7)-nAChR in basilar arteries of LY pigs may offer a partial explanation for different sensitivities of individuals to Aβ in causing diminished cerebral nitrergic vasodilation in diseases involving Aβ.


An inducible lentiviral guide RNA platform enables the identification of tumor-essential genes and tumor-promoting mutations in vivo.
The CRISPR/Cas9 technology enables the introduction of genomic alterations into almost any organism; however, systems for efficient and inducible gene modification have been lacking, especially for deletion of essential genes. Here, we describe a drug-inducible small guide RNA (sgRNA) vector system allowing for ubiquitous and efficient gene deletion in murine and human cells. This system mediates the efficient, temporally controlled deletion of MCL-1, both in vitro and in vivo, in human Burkitt lymphoma cell lines that require this anti-apoptotic BCL-2 protein for sustained survival and growth. Unexpectedly, repeated induction of the same sgRNA generated similar inactivating mutations in the human Mcl-1 gene due to low mutation variability exerted by the accompanying non-homologous end-joining (NHEJ) process. Finally, we were able to generate hematopoietic cell compartment-restricted Trp53-knockout mice, leading to the identification of cancer-promoting mutants of this critical tumor suppressor.


Cocaine abstinence during the "critical period" of a contingency management trial predicts future abstinence in people with cocaine use disorder.
Contingency Management (CM) is being piloted as a treatment for stimulant use disorder in several US states, highlighting the need for treatment optimization. One important goal of optimization is decreasing drug use during the early stages of treatment, which has predicted success in other interventions. However, this "critical period" has not been reported in CM trials. The purpose of this analysis was to determine if, after accounting for baseline abstinence and incentive condition, abstinence in a CM trial for people with Cocaine Use Disorder (CUD) could be predicted by cocaine use during a first-week critical period. Eighty-seven participants with CUD were randomized to receive contingent high or low value incentives for cocaine abstinence or were in a non-contingent control group. Generalized estimating equations (GEE) were used to analyze urine test results over 36 timepoints during the 12-week intervention. To assess for a critical period, the first three visits were included in the GEE as a covariate for remaining urine test results. Participants who provided more negative samples during the critical period were significantly more likely to produce a negative urine sample during the remainder of the trial, though some effects of group remained after controlling for the critical period. These results indicate that a critical period exists for CM trials, and it can explain a substantial amount of future performance. Early contact with an abstinence-contingent high magnitude alternative reinforcer may explain additional performance beyond the critical period, further justifying the use of high magnitude alternative reinforcers.


Recurrence of hepatocellular carcinoma after liver transplant: patterns and prognosis.
Very little is known about the natural history, effects of therapy, and survival after recurrence of hepatocellular carcinoma (HCC) after liver transplantation. All adult patients undergoing liver transplant from September 19, 1988, until September 19, 2002, were reviewed. Only patients with histologically proven HCC in the explant who subsequently developed recurrence were included in further analysis. The endpoints analyzed were survival from time of transplant and survival from time of recurrence. Recipient demographics and laboratory values, technique of transplant (whole cadaver, split, or living donor), and tumor characteristics were analyzed. The time to, location of, and any medical or surgical treatment of recurrences also were considered. Of the 311 patients with HCC in the explant, 57 (18.3%) eventually were diagnosed with recurrent tumor after transplant. Median time to recurrence was 12.3. Five-year survival was significantly lower for patients with recurrence (22%) than for patients without recurrence (64%)(P < 0.0001). Multivariate analysis demonstrated that the size and differentiation of the original tumor, as well as the presence of bone recurrence, were independently associated with survival from transplant in patients with recurrence. When survival from the time of recurrence was analyzed, multivariate analysis showed that the absence of bone metastases, recurrence more than 12 months from transplant, and surgical treatment of the recurrence were independently associated with significantly longer survival. In conclusion, recurrence of HCC significantly shortens survival after transplant. Nonetheless, some patients with recurrence can be expected to live for a considerable period of time. Recurrent disease should be treated surgically when possible, because surgery is independently associated with longer survival.


Functional analysis of the p53 pathway in response to ionizing radiation in uveal melanoma.
Uveal melanomas are notoriously radioresistant and thus necessitate treatment with extremely high radiation doses that often cause ocular complications. The p53 tumor suppressor pathway is a major mediator of the cellular response to radiation-induced DNA damage, suggesting that this pathway may be defective in uveal melanoma. The current study was conducted to analyze the functional integrity of the p53 pathway in primary uveal melanoma cells. The p53 gene was sequenced in three primary uveal melanoma cells lines. Cultured primary uveal melanoma cells (MM28, MM50, Mel202, Mel270, and Mel290), MCF7 breast carcinoma cells, normal uveal melanocytes (UM47), and normal human diploid fibroblasts (NHDFs) were irradiated at 250 kVp and 12 mA at a dose rate of 1.08 Gy/min for a total dose of up to 20 Gy. Cell viability was analyzed with trypan blue exclusion. Western blot analysis was used to analyze the expression of p53, p53-phospho-Ser15, p21, Bax, PUMA, and Bcl-x(L). No p53 gene mutations were found in MM28, MM50, or Mel270 cells. Upstream signaling to p53 was intact, with normal induction of p53 and phosphorylation of p53-Ser15, in all five cell lines. Radiation-induced downstream activation of p21 was defective in MM28 and MM50 cells, and activation of Bax was defective in MM50 and Mel290 cells. MM28, MM50, and Mel202 cells failed to deamidate Bcl-x(L) in response to radiation-induced DNA damage. Overall, four of the five uveal melanoma cell lines exhibited at least one downstream defect in the p53 pathway. Expression of p53 and upstream signaling to p53 in response to radiation-induced DNA damage appear to be intact in most uveal melanomas. In contrast, functional defects in the p53 pathway downstream of p53 activation appear to be common. Further elucidation of p53 pathway abnormalities in uveal melanoma may allow therapeutic interventions to increase the radiosensitivity of the tumors.


Twinning in families of triplets.
A study was conducted on twinning in relatives of consecutive triplet sets in the Aland Islands in the years 1740-1939. The incidence of twinning in sibships of triplets was extremely high, 80/1000 (56/1000 before and 143/1000 after the triplet maternity). In Finland as a whole, 1905-1954, the twinning rate was among mothers of triplets 38/1000, ie, about 2.6 times the rate in general population, and was higher after (48/1000) than before the triplet maternity (34/1000). In the sibships of fathers of triplets there was a low rate of twinning (below 10/1000) both of same-sexed (SS) and of opposite-sexed (OS) triplets. Among sibships of mothers of OS triplets the twinning rate was 18/1000 and among mothers' sibships of SS triplets 26/1000. The series of triplet families from both Aland and Finland as a whole indicate a considerably higher frequency of twinning on the maternal than on the paternal side. The sibships of OS triplets in Finland have higher twinning rates than sibships of SS triplets (50/1000 vs 27/1000). In sibships of triplets, not only the DZ but also the MZ twinning rates were approximately twice as high as those in the general population. The triplet rates in Finland were increasingly strong with maternal age and were in the last century among mothers of 30-39 years of age considerably higher than among mothers from this century. This, in combination with higher mean parity, may explain the high rates of multiple maternities in sibships of triplets in the past. The rate of triplet maternities seems to be more sensitive to sociodemographic changes than the rate of twin maternities. Mothers of triplets in Finland had a high frequency (more than 40%) of prenuptially conceived firstborn children. This, and a short protogenesic interval indicate that triplet-prone mothers are more fecundable, ie, they conceive with greater ease and/or may have a better physical condition than other women for completing a gestation with multiple embryos.


What gets on the nerves of cardiac patients? Pathophysiological changes in cardiac innervation.
The autonomic nervous system regulates cardiac function by balancing the actions of sympathetic and parasympathetic inputs to the heart. Intrinsic cardiac neurocircuits integrate these autonomic signals to fine-tune cardiac control, and sensory feedback loops regulate autonomic transmission in the face of external stimuli. These interconnected neural systems allow the heart to adapt to constantly changing circumstances that range from simple fluctuations in body position to running a marathon. The cardiac reflexes that serve to maintain homeostasis in health are disrupted in many disease states. This is often characterized by increased sympathetic and decreased parasympathetic transmission. Studies of cardiovascular disease reveal remodelling of cardiac neurocircuits at several functional and anatomical levels. Central circuits change so that sympathetic pathways become hyperactive, while parasympathetic circuits exhibit decreased activity. Peripheral sensory nerves also become hyperactive in disease, which increases patients' risk for poor cardiac outcomes. Injury and disease also alter the types of neurotransmitters and neuropeptides released by autonomic nerves in the heart, and can lead to regional hyperinnervation (increased nerve density) or denervation (decreased nerve density) of cardiac tissue. The mechanisms responsible for neural remodelling are not fully understood, but neurotrophins and inflammatory cytokines are likely involved. Areas of active investigation include the role of immune cells and inflammation in neural remodelling, as well as the role of glia in modulating peripheral neuronal activity. Our growing understanding of autonomic dysfunction in disease has facilitated development of new therapeutic strategies to improve health outcomes.


Metformin as an adjunct therapy for the treatment of moderate to severe acne vulgaris.
The purpose of this literature review is to evaluate the use of metformin as an adjunct therapy in the treatment of moderate-to-severe acne in those not diagnosed with polycystic ovary syndrome (PCOS) or androgen excess. The authors conducted independent literature searches. Results were limited to clinical trials and randomized controlled trials. Studies with participants diagnosed with moderateto-severe acne vulgaris taking metformin versus placebo or other active treatment were included;studies with participants diagnosed with PCOS or androgen excess were excluded. The authors found three studies consistent with the search guidelines that evaluated the effects of metformin as adjunct therapy in moderate to severe acne vulgaris. In eachstudy, metformin was an effective adjunct therapy in the treatment of moderate-to-severe acne vulgaris.


C-reactive protein: an independent predictor of cardiovascular disease in Aboriginal Australians.
We assessed the independent contribution of C-reactive protein to the risk of cardiovascular disease in Aboriginal Australians. High sensitivity CRP levels were measured in 705 Aboriginal participants aged 20-74 years free from CVD at baseline. Participants were followed for a median of 11 years. Cox proportional hazards models were used to assess the association of CRP with the risk of developing CVD events. A total of 114 participants were diagnosed with CVD. Incidence rates were 5.4 and 21.4 per 1,000 person-years for the lower (<3 mg/l) and the higher (>or=3 mg/l) CRP groups, respectively. After adjusting for age, sex, total cholesterol, systolic blood pressure, smoking status, diabetes, BMI and waist circumference, the association between CRP and CVD remained significant, with a hazard ratio of 2.40 (95% CI: 1.25, 4.62) for the higher CRP group relative to the lower CRP group. The population attributable risk was 52% (95% CI: 14%, 74%). CRP is an independent predictor of CVD in Aboriginal people. A large proportion of CVD cases are associated with elevated CRP levels. Therefore, controlling the conditions that cause inflammation may be beneficial to cardiovascular health in Aboriginal communities.


Treating attention-deficit/hyperactivity disorder with a stimulant transdermal patch: the clinical art.
Stimulant medications (amphetamine and methylphenidate) are the best-documented treatments for attention-deficit/hyperactivity disorder, but their short pharmacokinetic and behavioral half-lives have historically produced irksome time-course effects. New drug-delivery systems designed to eliminate the need for frequent dosing include the methylphenidate transdermal system, in which the matrix acts as both the drug reservoir and the skin adhesive. The methylphenidate transdermal system patch, in contrast to long-acting oral preparations, requires a paradigmatic shift in clinical thinking, as well as refinement of clinical management skills. For dosing with the methylphenidate transdermal system patch, clinicians must think in terms of a retrievable form of drug delivery (in milligrams per hour) rather than a fixed nonretrievable dose (in milligrams per dose or milligrams per day). Clinicians and patients can determine the optimal clinical dose by controlling 2 variables: (1) patch size (controlling milligrams per hour) and (2) duration of patch wear. The new paradigm is worth learning, because the patch offers several advantages over oral preparations for some patients, chiefly individualized control over effect duration (determined by when the patch is applied in the morning and removed in the afternoon/evening). Taking full advantage of this treatment option requires educating the patient and parents regarding practical elements of daily use. These elements include patch-site selection, application techniques, management of wear time to optimize the daily time course of clinical benefits, and skin hygiene. This article summarizes clinical principles that physicians may find useful in managing this new addition to the attention-deficit/hyperactivity disorder treatment armamentarium.


[Aromatase inhibitors in the therapy for breast cancer].
Endocrine therapy plays a key role in the treatment of breast cancer. Because of high efficacy and low toxicity, endocrine therapy is the first-line treatment of advanced pre- as well as post-menopausal breast cancer. In the adjuvant setting, endocrine therapy has a more profound effect on survival compared to chemotherapy in postmenopausal women harboring receptor positive tumors. The introduction of the novel third-generation aromatase inhibitors is the most important improvement in endocrine therapy since the introduction of tamoxifen 20 years ago. Thus, phase III studies have shown improved efficacy of these compounds compared to conventional therapy at relapse. Based on preliminary results from large phase III studies, aromfase inhibitors are now to be implemented as adjuvant therapy for postmenopausal women. The uncertainties relate to which drug should be used, regimen (monotherapy or sequential treatment with tamoxifen), and potential toxic effects related to long-term oestrogen deprivation.


Proventricular hyperplasia (malabsorption syndrome) in broiler chickens.
A syndrome has occurred in broilers over the past several years in widespread localities, including Georgia, Arkansas, and Texas. Poor feed conversion and delayed marketing are the principle clinical features. Lesions consist of enlargement of the proventriculus, gizzard erosion and dilatation, and decreased spleen and bursa size. Trichothecenes were demonstrated in the rations sampled at several broiler facilities. The clinical features and gross and microscopic changes observed in the field syndrome were duplicated by feeding chicks multiple combinations of a trichothecene mycotoxin (T-2 toxin) with histamines and diamines for 6 to 8 weeks.


Measurement scales in clinical research of the upper extremity, part 1: general principles, measures of general health, pain, and patient satisfaction.
Measurement is a fundamental cornerstone in all aspects of scientific discovery, including clinical research. To be useful, measurement instruments must meet several key criteria, the most important of which are satisfactory reliability, validity, and responsiveness. Part 1 of this article reviews the general concepts of measurement instruments and describes the measurement of general health, pain, and patient satisfaction.


A random-field model-based algorithm for anomalous complex image pixel detection.
Random-field model-based algorithms for the detection of anomalous pixels associated with complex valued imagery may be essential to robust focus of attention, target detection, and curing. The described algorithm includes the fitting of a specific class of causal, two-dimensional autoregressive random-field models to image data over specified estimation windows, and then subsequent construction of prediction error samples over specified detection windows. Statistical testing of the calculated prediction error samples is then used to localize anomalous image pixels. Experimental results obtained from running the described algorithm on SAR (synthetic aperture radar) imagery are included.


Facile fabrication of polydopamine nanotubes for combined chemo-photothermal therapy.
We report a novel synthesis scheme to produce polydopamine (PDA) nanotubes using halloysite clay nanotubes (HNT) as a sacrificial template. Polydopamine nanotubes were fabricated via the formation of a polydopamine coating on HNT from a dopamine solution followed by template removal. Michael Addition was used to decorate the outer surface with polyethylene glycol. Removal of the template material resulted in a bilayered organic nanotube consisting of an inner layer of polydopamine adjacent to the lumen and an outer polyethylene glycol surface. The tubes had an aspect ratio of 5.3 ± 0.6, a diameter on the order of 70 nm, and wall thicknesses on the order of 15 nm. The PDA nanotubes exhibited photothermal conversion upon irradiation at near infrared wavelengths; a temperature increase of 30 °C was observed when a 250 μg ml-1 sample was subjected to 1 W cm-2 density irradiation at 808 nm wavelength. Analysis indicated that the prepared tubes had slightly higher photothermal conversion efficiency than PDA nanospheres. An antitumor drug, doxorubicin, was used as a model to test the potential for drug delivery of the organic nanotubes. The nanotubes exhibited higher loading capacities than PDA nanospheres and were capable of controlled release at pHs relevant to human serum and tumors (pH 7.4 and 5.0 respectively). Drug release rates varied as a function of system pH and application of near infrared irradiation. Release of doxorubicin was enhanced at a pH of 5.0, and retarded at a pH of 7.4. Irradiation with 808 nm wavelength light also increased the release of doxorubicin.


Disposition, elimination, and metabolism of tri-o-cresyl phosphate following daily oral administration in Fischer 344 male rats.
The disposition, elimination, and metabolism of 50 mg/kg (1.36 muCi/animal) of tri-o-cresyl [phenyl-U-14C] phosphate after ten daily oral doses was investigated in adult male Fischer 344 rats. Groups of three treated animals were killed at intervals of 24, 48, 72, and 96 h after the last administrations. Generally, the highest concentrations of radioactive material were excreted via the gastrointestinal tract and the bladder, particularly at the earlier time points. Liver, adipose, epididymis, sciatic nerve tissues; plasma; and red blood cells also contained high concentrations of radioactivity. The lowest concentrations were found in brain, spleen, testes, and heart. Four days after the last dose, the rats had excreted approximately all of the cumulative dose in either urine (63.1%) or feces (36.1%). TOCP and its metabolites in urine, feces, plasma, brain, testes, kidneys, and liver were analyzed by high-performance liquid chromatography and liquid scintillation. Metabolism studies performed 24, 48, 72, and 96 h after administration of the last dose showed that TOCP was the major compound identified in brain, testes, kidneys, plasma, and liver. Liver, additionally, had high levels of di-o-cresyl hydrogen phosphate and o-cresol. TOCP and o-cresol were the predominant compounds in feces; only trace amounts of TOCP were detected in urine. The major metabolites in urine were di-o-cresyl hydrogen phosphate, o-cresol, and o-hydroxy benzoic acid. Testes in rats given ten doses had significantly more TOCP and saligenin cyclic-o-tolyl phosphate than those from rats given a single dose. These results may account for testicular toxicity in rats given daily oral administrations of TOCP but not following a single oral dose.


Independent activation of CREB3L2 by glucose fills a regulatory gap in mouse β-cells by co-ordinating insulin biosynthesis with secretory granule formation.
Although individual steps have been characterized, there is little understanding of the overall process whereby glucose co-ordinates the biosynthesis of insulin with its export out of the endoplasmic reticulum (ER) and incorporation into insulin secretory granules (ISGs). Here we investigate a role for the transcription factor CREB3L2 in this context. MIN6 cells and mouse islets were analysed by immunoblotting after treatment with glucose, fatty acids, thapsigargin and various inhibitors. Knockdown of CREB3L2 was achieved using si or sh constructs by transfection, or viral delivery. In vivo metabolic phenotyping was conducted after deletion of CREB3L2 in β-cells of adult mice using Ins1-CreER+. Islets were isolated for RNAseq and assays of glucose-stimulated insulin secretion (GSIS). Trafficking was monitored in islet monolayers using a GFP-tagged proinsulin construct that allows for synchronised release from the ER. With a Km ≈3.5 mM, glucose rapidly (T1/2 0.9 h) increased full length (FL) CREB3L2 followed by a slower rise (T1/2 2.5 h) in its transcriptionally-active cleavage product, P60 CREB3L2. Glucose stimulation repressed the ER stress marker, CHOP, and this was partially reverted by knockdown of CREB3L2. Activation of CREB3L2 by glucose was not due to ER stress, however, but a combination of O-GlcNAcylation, which impaired proteasomal degradation of FL-CREB3L2, and mTORC1 stimulation, which enhanced its conversion to P60. cAMP generation also activated CREB3L2, but independently of glucose. Deletion of CREB3L2 inhibited GSIS ex vivo and, following a high-fat diet (HFD), impaired glucose tolerance and insulin secretion in vivo. RNAseq revealed that CREB3L2 regulated genes controlling trafficking to-and-from the Golgi, as well as a broader cohort associated with β-cell compensation during a HFD. Although post-Golgi trafficking appeared intact, knockdown of CREB3L2 impaired the generation of both nascent ISGs and proinsulin condensates in the Golgi, implying a defect in ER export of proinsulin and/or its processing in the Golgi. The stimulation of CREB3L2 by glucose defines a novel, rapid and direct mechanism for co-ordinating the synthesis, packaging and storage of insulin, thereby minimizing ER overload and optimizing β-cell function under conditions of high secretory demand. Upregulation of CREB3L2 also potentially contributes to the benefits of GLP1 agonism and might in itself constitute a novel means of treating β-cell failure.


Differential sensitivity of various pediatric cancers and squamous cell carcinomas to lovastatin-induced apoptosis: therapeutic implications.
3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase is the rate-limiting enzyme of the mevalonate pathway, the diverse array of end products of which are vital for a variety of cellular functions, including cholesterol synthesis and cell cycle progression. We showed previously that this enzyme holds a critical role in regulating tumor cell fate, including cell death, as its expression is down-regulated in response to retinoic acid, a potent anticancer therapeutic. Indeed, direct inhibition of HMG-CoA reductase with lovastatin, a competitive inhibitor of this enzyme, induced a pronounced apoptotic response in neuroblastoma and acute myeloid leukemic cells. We have now extended this work and evaluated a wide variety and large number of tumor-derived cell lines for their sensitivity to lovastatin-induced apoptosis. These cell lines were exposed to a wide range (0-100 microM) of lovastatin for 2 days and assayed for cell viability using the 3,4,5-dimethyl thiazlyl-2,2,5-diphenyltetrazolium bromide assay and the induction of apoptosis by flow cytometric and ultrastructural analyses. Lovastatin induced a pronounced apoptotic response in cells derived from juvenile monomyelocytic leukemia, pediatric solid malignancies (rhabdomyosarcoma and medulloblastoma), and squamous cell carcinoma of the cervix and of the head and neck. Interestingly, the subset of malignancies that are particularly sensitive to lovastatin-induced apoptosis correspond to those tumor subtypes that are sensitive to the biological and antiproliferative effects of retinoids in vitro. The nature of the biologically active form of lovastatin has been challenged recently as the growth-inhibitory effects of this drug were attributed to its prodrug lactone form that does not inhibit HMG-CoA reductase function. In this report, we demonstrate that the apoptotic properties of lovastatin are triggered by the open ring acid form that is a potent inhibitor of HMG-CoA reductase activity. Thus, we have identified a subset of tumors that are sensitive to lovastatin-induced apoptosis and show HMG-CoA reductase as a potential therapeutic target of these cancers.


Delineating the effect of semantic congruency on episodic memory: the role of integration and relatedness.
A fundamental challenge in the study of learning and memory is to understand the role of existing knowledge in the encoding and retrieval of new episodic information. The importance of prior knowledge in memory is demonstrated in the congruency effect-the robust finding wherein participants display better memory for items that are compatible, rather than incompatible, with their pre-existing semantic knowledge. Despite its robustness, the mechanism underlying this effect is not well understood. In four studies, we provide evidence that demonstrates the privileged explanatory power of the elaboration-integration account over alternative hypotheses. Furthermore, we question the implicit assumption that the congruency effect pertains to the truthfulness/sensibility of a subject-predicate proposition, and show that congruency is a function of semantic relatedness between item and context words.


Visual outcome and ocular complications in patients with lacrimal gland carcinoma after eye-sparing surgery and adjuvant radiation therapy.
We report visual outcomes and ocular complications in patients with lacrimal gland carcinoma who had eye-sparing surgery followed by radiotherapy. This review included consecutive patients with lacrimal gland carcinoma who underwent eye-sparing surgery and adjuvant radiotherapy or concurrent chemoradiation therapy between 2007 and 2018. Clinical data, including details of ophthalmological examinations and radiation treatment were reviewed. The study included 23 patients, 15 males and 8 females, with median age 51 years. Twenty patients (87%) received intensity-modulated proton therapy; 3 (13%) received intensity-modulated radiotherapy. Nineteen patients (83%) received concurrent chemotherapy. After a median follow-up time of 37 months (range: 8-83), 13 patients (57%) had best-corrected visual acuity 20/40 or better, 3 (13%) had moderate vision loss (between 20/40 and 20/200) and 7 (30%) had severe vision loss (20/200 or worse). The most common ocular complications were dry eye disease (21 patients; 91%), radiation retinopathy (16; 70%) and cataract progression (11; 49%). Tumour crossing the orbital midline (p=0.014) and Hispanic ethnicity (p=0.014) were associated with increased risk of severe vision loss. The risk of radiation retinopathy was significantly different among the three racial groups; Hispanic patients (n=3) had the highest rate of retinopathy (p<0.001). Tumour size, initial T category and total prescribed radiation dose were not significantly associated with severe vision loss. Eye-sparing surgery followed by adjuvant radiotherapy in patients with lacrimal gland carcinoma has a reasonable overall visual prognosis. Patients with tumours crossing the orbital midline and Hispanic patients have a higher risk of severe vision loss.


Factors of delay in the diagnosis of melanoma.
Delay in the diagnosis of melanoma was defined as the interval in months from the patient's report of first noticing a suspected lesion to the date of the removal of a histologically confirmed melanoma. 216 patients were included in our study. Total delay was subdivided in three components: patient, medical and referral delay. The major component of delay is due to the patient and the most important cause of it was lack of concern. Lesions in men were detected more frequently by family members, while in women melanomas tended to be self-detected. Nodular melanoma had lower delay but higher thickness. Amelanotic melanomas had a higher delay principally due to the physicians. A significative positive correlation between Breslow thickness and patient delay was observed. The visibility of the tumor and the educational or socio-economic status did not seem to improve early diagnosis. The observation about the shorter delays in thicker tumors lead us to think that educational campaigns should be more focused on recognition of changing or growing lesions than other signs of the ABCD rule and that nodular melanomas are quite different from superficial spreading melanomas.


Low-frequency transcranial magnetic stimulation over left dorsal premotor cortex improves the dynamic control of visuospatially cued actions.
Left rostral dorsal premotor cortex (rPMd) and supramarginal gyrus (SMG) have been implicated in the dynamic control of actions. In 12 right-handed healthy individuals, we applied 30 min of low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) over left rPMd to investigate the involvement of left rPMd and SMG in the rapid adjustment of actions guided by visuospatial cues. After rTMS, subjects underwent functional magnetic resonance imaging while making spatially congruent button presses with the right or left index finger in response to a left- or right-sided target. Subjects were asked to covertly prepare motor responses as indicated by a directional cue presented 1 s before the target. On 20% of trials, the cue was invalid, requiring subjects to readjust their motor plan according to the target location. Compared with sham rTMS, real rTMS increased the number of correct responses in invalidly cued trials. After real rTMS, task-related activity of the stimulated left rPMd showed increased task-related coupling with activity in ipsilateral SMG and the adjacent anterior intraparietal area (AIP). Individuals who showed a stronger increase in left-hemispheric premotor-parietal connectivity also made fewer errors on invalidly cued trials after rTMS. The results suggest that rTMS over left rPMd improved the ability to dynamically adjust visuospatial response mapping by strengthening left-hemispheric connectivity between rPMd and the SMG-AIP region. These results support the notion that left rPMd and SMG-AIP contribute toward dynamic control of actions and demonstrate that low-frequency rTMS can enhance functional coupling between task-relevant brain regions and improve some aspects of motor performance.


Direct activation of transient receptor potential vanilloid 1(TRPV1) by diacylglycerol (DAG).
The capsaicin receptor, known as transient receptor potential channel vanilloid subtype 1 (TRPV1), is activated by a wide range of noxious stimulants and putative ligands such as capsaicin, heat, pH, anandamide, and phosphorylation by protein kinase C (PKC). However, the identity of endogenous activators for TRPV1 under physiological condition is still debated. Here, we report that diacylglycerol (DAG) directly activates TRPV1 channel in a membrane-delimited manner in rat dorsal root ganglion (DRG) neurons. 1-oleoyl-2-acetyl-sn-glycerol (OAG), a membrane-permeable DAG analog, elicited intracellular Ca2+ transients, cationic currents and cobalt uptake that were blocked by TRPV1-selective antagonists, but not by inhibitors of PKC and DAG lipase in rat DRG neurons or HEK 293 cells heterologously expressing TRPV1. OAG induced responses were about one fifth of capsaicin induced signals, suggesting that OAG displays partial agonism. We also found that endogenously produced DAG can activate rat TRPV1 channels. Mutagenesis of rat TRPV1 revealed that DAG-binding site is at Y511, the same site for capsaicin binding, and PtdIns(4,5)P2binding site may not be critical for the activation of rat TRPV1 by DAG in heterologous system. We propose that DAG serves as an endogenous ligand for rat TRPV1, acting as an integrator of Gq/11-coupled receptors and receptor tyrosine kinases that are linked to phospholipase C.


Autologous B lymphoblastoid cell lines and long-term cultured T cells as stimulators in the mixed lymphocyte reaction: analysis of the role of HLA class II antigens as stimulatory molecules.
Human activated T cells, long-term cultured in the presence of interleukin 2 (IL 2), were compared with autologous Epstein Barr virus-transformed B lymphoblastoid cell lines for expression of human leukocyte (HLA)-HLA-DR and -DQ antigens and for ability to induce proliferative responses in autologous and allogeneic lymphocytes. Immunofluorescence analysis performed with a panel of monoclonal antibodies (mAb) specific for HLA-DR or -DQ antigens did not reveal any significant difference in the expression of HLA-DR antigens but revealed reduced expression of HLA-DQ antigens on two out of four T cell lines tested. No obvious difference could be detected in the two-dimensional gel electrophoretic profile of HLA-DR and -DQ beta-chains synthesized by the autologous pairs of B and T cell lines. In contrast with previous reports, the IL 2-dependent cell lines consistently induced alloproliferative responses in standard 6-day mixed lymphocyte cultures; however, these responses were severalfold lower than those elicited by the autologous B lymphoid lines. Both anti-HLA-DR and anti-HLA-DQ mAb blocked the proliferative responses induced by the B cell lines but did not affect those generated by the T cell lines, suggesting that the latter cells induce T lymphocyte activation via a mechanism independent of HLA-DR or -DQ antigen expression on their surface. Addition of IL 2 to the mixed cultures with B cell lines as stimulators did not affect the outcome of the proliferative responses but partially or completely reversed the blocking activity of the mAb. In contrast, IL 2 significantly enhanced the alloproliferation induced by the T lymphoblastoid cell lines, and the anti-HLA class II mAb partially antagonized this effect. Taken together, these data suggest that unlike the HLA-DR and -DQ gene products on B cells, those on IL 2-dependent long-term cultured T cells do not play a direct or primary stimulatory role in the mixed lymphocyte reaction; the reduced levels of alloproliferation induced by the T cell lines are, at least in part, due to a defective production of endogenous IL 2 by the responder lymphocytes rather than to a defective expression of IL 2 receptors by the alloproliferative T cell subset; and the anti-HLA class II mAb in these cultures act only at the responder cell level, since they can efficiently block the enhancement of T cell proliferation triggered by exogenous IL 2, but not the proliferative responses induced by T cell lines in standard conditions.


Risk factors for colorectal polyps in a Mexican population [Corrected and republished].
The prevalence of colorectal polyps and adenomas in the general population of Mexico is unknown. To determine the prevalence and risk factors for colorectal polyps detected during flexible sigmoidoscopy (FSIG) in asymptomatic patients. From 1995 to 2008, FSIG was performed as part of a complete check-up in patients who had lived in northeast Mexico for over 5 years. 946 (794 males/152 females) were included in the study. The mean age was 48.8 years (range 21-91). A family history of colorectal cancer (FHCRC) was present in 2.2 % of the cases. The adenoma prevalence found in patients with a BMI < 25, 26-30 or > 30 was 7.3%, 6.2% and 10.2% respectively. Independent risk factor for colorectal polyps and adenomas included a positive family history of colorectal cancer (OR 12.4, 95% CI 19.1-230, and OR 12.4, 95% CI 4.1-37.3, respectively) and a body mass index > 25 (OR 4.2, 95% CI 4.2-14.2 and OR 4.2, 95% CI 1.8-9.7, respectively). Seventy two patients had polyps (7.6%) and 29 patients had adenomas (3%). The prevalence of polyps and adenomas on FSIG in patients younger than 50 years was 5.8% and 1.9% respectively, and among those older than 50 years, it was 8.9% and 4.8% respectively. A positive family history of colorectal cancer and a body mass index > 25 are independent risk factors for colorectal polyps and adenomas. The adenoma prevalence found in our population was lower than the reported in developed countries.


Apigenin attenuates edifenphos-induced toxicity by modulating ROS-mediated oxidative stress, mitochondrial dysfunction and caspase signal pathway in rat liver and kidney.
Edifenphos (EDF) (O-ethyl-S, S-diphenyldithiophosphate) is an organophosphate pesticide that is extensively used as a fungicide in agricultural rice fields. However, EDF accumulated in various agricultural products and caused potential health hazards to human and other living organisms. Therefore, the present study was investigated to evaluate the ameliorative role of apigenin (APG); a natural antioxidant against EDF-induced hepato-renal toxicity in rats. Six groups with five male Wistar rats each, were used for this purpose; these groups included the control group (A) that received corn oil; (B) 10 mg/kg APG; (C) 10 mg/kg EDF; (D) 25 mg/kg EDF; (E) 10 mg/kg APG pretreatment for 1 h then 10 mg/kg EDF; (F) 10 mg/kg APG pretreatment for 1 h then 25 mg/kg EDF for 14 consecutive days. Oral administration of EDF led to disruption of the intracellular antioxidant machinery which cause the generation of intracellular reactive oxygen species (ROS). However, EDF promotes deleterious effects like oxidative stress, DNA damage, reduced mitochondrial membrane potential, generation of ROS production, activation of caspase 3/9 activities and causing hepato-renal histopathological changes. However, the pretreatment of APG ameliorated the EDF-induced oxidative damage and apoptosis, through their antioxidant activity or by directly scavenging free radical property. Overall, these results suggest that EDF exerts oxidative stress, and APG could be a potent dietary anti-oxidant regimen against EDF-induced toxicity.


Utility of trichoscopy to diagnose early female pattern hair loss in resource-poor setting: A cross-sectional study.
Trichoscopy is a reliable instrument for diagnosis and for tracking therapy-related changes in female pattern hair loss (FPHL). Videodermoscopic diagnosis of FPHL has been established, which requires fine measurements of hair-related parameters; the method requires an expensive equipment/digital program. To determine whether a low-cost, simple USB dermoscope can ascertain the hair-related changes in early FPHL. An age-matched, cross-sectional study was performed over 3 years on subjects with less than 6-month history of hair loss and without an obvious broadening of midline hair parting. Trichoscopic analysis of the frontal and occipital scalp of the study subjects were performed, using a USB-connected dermoscope. The subjects were analyzed for the presence of microscopic hair changes in the form of anisotrichosis, vellus-like hair, single hair follicle unit, peri-pilar sign and yellow dots. A total of 230 cases and 230 controls were analyzed. The dermoscopic hair changes were found to be significantly associated with the frontal scalp zone of cases. Histopathological evaluation of the cases was not done. Microscopic changes recorded with the help of a simple USB dermoscope are helpful in establishing a diagnosis of FPHL even in early disease.


Analysis of tidal breathing flow volume loops for automated lung-function diagnosis in infants.
Lung-function analysis in the age group below 5 years has not yet found its way into clinical routine. One possible candidate for routine lung testing in this age group is the analysis of tidal breathing flow-volume (TBFV) loops, a technique that has not yet proven to be capable of detecting obstructive and other lung disorders at an early stage. We present a new set of mathematical features useful to analyze TBFV loops. These new features attempt to describe more complex properties of the loops, thus imitating medical judgment of the curves (e.g., "round," "triangular," etc.) in a "linguistic" manner. Furthermore, we introduce support vector machines (SVMs) as a method for automated classification of diseases. In a retrospective clinical trial on 195 spontaneously breathing infants aged 3 to 24 months, the discriminant power of individual features and the overall diagnostic performance of SVMs is investigated and compared with the results obtained with traditional Bayes' classifiers. We demonstrate that the proposed new features perform better in all examined disease groups and that depending on the disease, the classification error can be reduced by up to 50%. We conclude that TBFV loops may have a much stronger discriminant power than previously thought.


Excess floppy modes and multibranched mechanisms in metamaterials with symmetries.
Floppy modes-deformations that cost zero energy-are central to the mechanics of a wide class of systems. For disordered systems, such as random networks and particle packings, it is well-understood how the number of floppy modes is controlled by the topology of the connections. Here we uncover that symmetric geometries, present in, e.g., mechanical metamaterials, can feature an unlimited number of excess floppy modes that are absent in generic geometries, and in addition can support floppy modes that are multibranched. We study the number Δ of excess floppy modes by comparing generic and symmetric geometries with identical topologies, and show that Δ is extensive, peaks at intermediate connection densities, and exhibits mean-field scaling. We then develop an approximate yet accurate cluster counting algorithm that captures these findings. Finally, we leverage our insights to design metamaterials with multiple folding mechanisms.


Anti-inflammatory activity and molecular mechanism of Oolong tea theasinensin.
Oolong tea theasinensins are a group of tea polyphenols different from green tea catechins and black tea theaflavins, and they are considered as bioactive compounds in Oolong tea. In the present study, based on the properties of theasinensin and information about inflammatory processes, we investigated the anti-inflammatory activity and molecular mechanisms of theasinensin A (TSA) in both cell and animal models. In the cell model, TSA reduced the levels of pro-inflammatory mediators including inducible nitric oxide synthase (iNOS), nitric oxide (NO), interleukin-12 (IL-12) (p70), tumor necrosis factor alpha (TNF-α), and monocyte chemotactic protein-1 (MCP-1) induced by lipopolysaccharide (LPS). Cellular signaling analysis revealed that TSA downregulated MAPK/ERK kinase (MEK)-extracellular signal-regulated kinase (ERK) signaling. Pull-down assay and affinity data revealed that TSA might directly bind to MEK-ERK for the inhibitory action. In the animal model, TSA suppressed the production of IL-12 (p70), TNF-α, and MCP-1 and attenuated mouse paw edema induced by LPS.


Asthma is associated with increased mortality in individuals with sickle cell anemia.
An analysis of a prospective cohort of individuals with sickle cell anemia (SCA), enrolled from birth through adulthood, was conducted to determine if asthma is a risk factor for death in SCA. All-cause mortality was determined for participants after adjusting for known risk factors for death in SCA. The study included 1,963 individuals who were followed for 18,495 patient-years. After controlling for established risk factors, individuals with SCA and asthma had a more than two-fold higher risk of mortality (hazard ratio 2.36, 95% CI 1.21 to 4.62, p=0.01). To summarize, asthma is a risk factor for death in SCA.


[Investigation of hepatitis C virus genotype distribution in patients with chronic hepatitis C infections in Antalya Training and Research Hospital, Turkey].
Hepatitis C virus (HCV) infection is a major global health problem due to high chronicity rates, occurrence of severe hepatic diseases, and absence of an accurate therapy and effective vaccine. It is well known that viral genome is highly variable and HCV has at least six genotypes, each of them containing a series of subtypes. HCV genotypes exhibit geographical and epidemiological distribution. Genotype identification is clinically important to decide the dosage and duration of treatment since different genotypes exhibit variable response to treatment. The aim of this study was to determine the HCV genotypes in chronic HCV patients who were followed-up in Antalya Research and Training Hospital, Turkey. Anti-HCV and HCV-RNA positive blood samples obtained from 148 chronic hepatitis C patients (67 female, 81 male; mean age: 50.5 ± 10.8, age range: 17-73 years) who were admitted to Antalya Research and Training Hospital Microbiology Laboratory during January 2011-June 2013, were included in the study. Epidemiological data of the patients and HCV genotype results were evaluated retrospectively. Viral genotypes were determined by real-time (Rt) PCR assay (Abbott Molecular Diagnostic, USA). HCV genotype (Gt)-1 was detected in 119 (80.4%) of the patients, of them 15.9% (19/119) were identified as subtype 1a and 75.6% (90/119) were subtype 1b. The prevalence rates of Gt-2, -3, and -4 were found as 3.4% (n= 5), 11.5% (n= 17), and 2% (n= 3), respectively. Gt-6 was not detected in our patients. Mixed infection with HCV types was detected in four patients (2.7%) by Rt-PCR; of these three were detected as Gt-1 and one was Gt-2 by RFLP (Restriction Fragment Length Polymorphism) and sequencing. The high prevalence of Gt-3 (11.5%) obtained in this study was attributed to the determination of Gt-3 in seven of 13 foreign national subjects. Rt-PCR method used in this study is user independent, standardized, automated, rapid and reliable method, however in case of detection of mixed types, the samples should be confirmed by other methods. In conclusion, we reported that the majority of the chronic hepatitis C infected patients had Gt-1b, and Gt-3 exhibited the highest rate ever reported by other studies from Turkey.


Spectroscopy detects skeletal muscle microvascular dysfunction during onset of sepsis in a rat fecal peritonitis model.
Sepsis is a dysregulated host inflammatory response to infection potentially leading to life-threatening organ dysfunction. The objectives of this study were to determine whether early microvascular dysfunction (MVD) in skeletal muscle can be detected as dynamic changes in microvascular hemoglobin (MVHb) levels using spectroscopy and whether MVD precedes organ histopathology in septic peritonitis. Skeletal muscle of male Sprague-Dawley rats was prepared for intravital microscopy. After intraperitoneal injection of fecal slurry or saline, microscopy and spectroscopy recordings were taken for 6 h. Capillary red blood cell (RBC) dynamics and SO2 were quantified from digitized microscopy frames and MVHb levels were derived from spectroscopy data. Capillary RBC dynamics were significantly decreased by 4 h after peritoneal infection and preceded macrohemodynamic changes. At the same time, low-frequency oscillations in MVHb levels exhibited a significant increase in Power in parts of the muscle and resembled oscillations in RBC dynamics and SO2. After completion of microscopy, tissues were collected. Histopathological alterations were not observed in livers, kidneys, brains, or muscles 6 h after induction of peritonitis. The findings of this study show that, in our rat model of sepsis, MVD occurs before detectable organ histopathology and includes ~ 30-s oscillations in MVHb. Our work highlights MVHb oscillations as one of the indicators of MVD onset and provides a foundation for the use of non-invasive spectroscopy to continuously monitor MVD in septic patients.


Impaired fasting glucose and the metabolic syndrome in an indigenous Siberian population.
This study investigated the lifestyle and anthropometric correlates of impaired fasting glucose and the presence of metabolic syndrome (MetS) among an Indigenous high-latitude herding population from north-eastern Siberia. Cross-sectional study of Yakut (Sakha) adult volunteers. We collected health, lifestyle and anthropometric data among 166 Yakut adults (>or=18 years old; 101 females, 65 males) from the rural village of Tyungyulyu (62 degrees N, 130 degrees E; population 2,500), Sakha Republic (Yakutia), Russia. Measurements of fasting glucose, triglycerides, HDL cholesterol, blood pressure and waist circumference were used to document the presence of MetS based on the updated Adult Treatment Panel (ATP) III definition. Metabolic syndrome was relatively uncommon among study participants, with only 10% of participants classified as having MetS, including 8% of females and 12% of males. Elevated blood pressure and low HDL cholesterol were the most common features of MetS in Yakut men and women, while elevated fasting glucose and high triglycerides were uncommon in both sexes. Relatively low mean fasting glucose concentrations were documented among Yakut women (4.46+/-0.65 mmol/L) and men (4.41+/-0.76 mmol/L); no participants were classified as diabetic. Fasting glucose and MetS are at relatively low levels in this population; however, rising rates of obesity are likely to lead to future increases in MetS and impaired fasting glucose in this population. Further, increasing consumption of market foods, many high in refined sugars, is likely to contribute to an increased presence of impaired fasting glucose and MetS.


Effect of a selective thromboxane synthase inhibitor on arterial graft patency and platelet deposition in dogs.
This study examined the effect of selective thromboxane synthase inhibition and nonselective cyclooxygenase inhibition on vascular graft patency and indium 111-labeled platelet deposition in 35 mongrel dogs undergoing carotid artery replacement with 4 mm X 4 cm polytetrafluoroethylene (PTFE) (one side) and Dacron (opposite side) end-to-end grafts. Aspirin-dipyridamole therapy improved one-week graft patency, from 46% in untreated dogs to 93% in treated dogs. Thromboxane synthase inhibition (U-63557A) improved graft patency in these dogs to 81%. Both drug treatments reduced platelet deposition on Dacron and PTFE grafts by 48% to 68% compared with control dogs. Dacron grafts accumulated significantly more platelets than PTFE grafts but had comparable patency rates. Low-dose aspirin therapy had no significant effect on either graft patency or platelet deposition. All treatment groups showed a 60% to 76% reduction in serum thromboxane B2, but only thromboxane synthase inhibitor treatment increased plasma 6-keto-prostaglandin F1 alpha by 100%. Selective thromboxane synthase inhibition improved small-caliber prosthetic graft patency to the same extent as did conventional cyclooxygenase inhibition in this preliminary study.


Economic evaluation of micafungin vs. liposomal amphotericin B (LAmB) for the treatment of candidaemia and invasive candidiasis (IC).
Micafungin was non-inferior to liposomal amphotericin B (LAmB) for the treatment of candidaemia and invasive candidiasis (IC) in a major clinical trial. The present study investigated the economic impact of micafungin vs. LAmB in treating candidaemia and IC. A decision analytical model was constructed to capture downstream consequences of using micafungin or LAmB as primary definitive therapy. The main outcomes were treatment success and treatment failure due to mycological persistence, or death. Outcome probabilities were derived from key published sources. Resource used was estimated by an expert panel and cost inputs were from the latest Australian resources. The analysis was from an Australian hospital perspective. Sensitivity analyses using Monte Carlo simulation were conducted. Micafungin (AU$61 426) had a lower total cost than LAmB (AU$72 382), with a total net cost-saving of AU$10 957 per patient. This was primarily due to the lower cost associated with initial antifungal treatment and shorter length of stay for patients in the micafungin arm. Hospitalisation was the main cost driver for both arms. Results were robust over a wide range of variables. The uncertainty analysis demonstrated that micafungin had a 99.9% chance of being cost-saving compared with LAmB. Micafungin was associated with cost-saving relative to LAmB in the treatment of candidaemia and IC in Australia.


Arterial spin labeling magnetic resonance imaging: toward noninvasive diagnosis and follow-up of pediatric brain arteriovenous malformations.
OBJECT Arterial spin labeling (ASL)-MRI is becoming a routinely used sequence for ischemic strokes, as it quantifies cerebral blood flow (CBF) without the need for contrast injection. As brain arteriovenous malformations (AVMs) are highflow vascular abnormalities, increased CBF can be identified inside the nidus or draining veins. The authors aimed to analyze the relevance of ASL-MRI in the diagnosis and follow-up of children with brain AVM. METHODS The authors performed a retrospective analysis of 21 patients who had undergone digital subtraction angiography (DSA) and pseudo-continuous ASL-MRI for the diagnosis or follow-up of brain AVM after radiosurgery or embolization. They compared the AVM nidus location between ASL-MRI and 3D contrast-enhanced T1 MRI, as well as the CBF values obtained in the nidus (CBFnidus) and the normal cortex (CBFcortex) before and after treatment. RESULTS The ASL-MRI correctly demonstrated the nidus location in all cases. Nidal perfusion (mean CBFnidus 137.7 ml/100 mg/min) was significantly higher than perfusion in the contralateral normal cortex (mean CBFcortex 58.6 ml/100 mg/min; p < 0.0001, Mann-Whitney test). Among 3 patients followed up after embolization, a reduction in both AVM size and CBF values was noted. Among 5 patients followed up after radiosurgery, a reduction in the nidus size was observed, whereas CBFnidus remained higher than CBFcortex. CONCLUSIONS In this study, ASL-MRI revealed nidus location and patency after treatment thanks to its ability to demonstrate focal increased CBF values. Absolute quantification of CBF values could be relevant in the follow-up of pediatric brain AVM after partial treatment, although this must be confirmed in larger prospective trials.


Prognostic value of vascular endothelial growth factor expression in colorectal cancer patients.
Solid tumours require neovascularisation for growth and metastasis. Vascular endothelial growth factor (VEGF) has been shown to be an important regulator of tumour angiogenesis. To examine the relevance of VEGF in the neoplastic transformation of human colon, we analysed protein expression in a total 30 polyps and 145 colorectal carcinomas by immunohistochemistry. All adenoma specimens, regardless of histological differentiation, and normal colonic mucosa did not express VEGF. Amongst 90 patients with non-metastatic colorectal cancer, VEGF expression was observed in 43 (48%) cases, whilst 29 of the 55 patients (53%) with metastases expressed the angiogenic factor. Both the proportion and intensity of VEGF expression were positively associated with the progression of colon carcinogenesis. Tumours with the highest VEGF expression tended to correlate with patients' survival, although VEGF expression did not emerge as an independent risk factor in a multivariate analysis. After exclusion of the patients with distant metastases, both univariate and multivariate analysis did not indicate any prognostic value for the tissues with the highest VEGF expression. Our results suggest that VEGF may play a role in the progression of colon cancer, although evaluation of this angiogenic phenotype did not provide additional prognostic information compared with that obtained from Dukes' staging of the tumours.


Comparison of the hemagglutination-inhibition test with the constant-virus diluting-serum microneutralization test for detecting antibody to avian infectious bronchitis virus.
An evaluation was made of the hemagglutination-inhibition test and the constant-virus diluting-serum microneutralization test, two serological techniques that are used in detecting antibodies to avian infectious bronchitis. The repeatabilities and sensitivities of both tests were similar. Both tests compared favorably when testing high-titered antisera, but antibody titers detected varied when low-titered sera were used.


Interferon-induced protein 10 and interleukin 8. C-X-C chemokines present in proliferative diabetic retinopathy.
To determine vitreous levels of interleukin 8 (IL-8) and interferon-induced protein 10 (IP-10), which are members of the C-X-C chemokine family that promote and inhibit neovascularization, respectively. We measured the levels of IL-8 and IP-10 by specific enzyme-linked immunosorbent assays in the vitreous from 30 patients with proliferative diabetic retinopathy (PDR) and 10 control patients undergoing vitrectomy for idiopathic macular holes or idiopathic macular puckers. Detectable levels of IL-8 were found in 23 of 24 patients with active PDR, 4 of 6 patients with inactive PDR, and 6 of 10 controls. Levels of IL-8 were significantly increased in vitreous samples from the patients with active PDR (P = .02) when compared with vitreous samples from the controls. The IL-8 levels detected in vitreous samples from patients with inactive PDR were not significantly elevated over those found in the control samples. Interferon-induced protein 10 was detected in the vitreous samples from 23 of 24 patients with active PDR, all patients with inactive PDR, and 9 of 10 controls. Significant elevations of IP-10 were measured in samples from patients with active PDR (P = .004) and in those with inactive PDR (P = .00) over those from controls. In addition, levels of IP-10 were significantly elevated in vitreous samples from patients with inactive PDR compared with vitreous samples from patients with active PDR (P = .02). Both IL-8 and IP-10 participate in the pathogenesis of PDR.


Th2 immune response plays a critical role in the development of nickel-induced allergic contact dermatitis.
The precise roles of T helper (Th)1-type and Th2-type cytokine responses in nickel (Ni)-induced allergic contact dermatitis have not yet been clearly defined. We investigated the involvement of Th2 cytokines in Ni-induced contact hypersensitivity reaction using GATA-3 transgenic (Tg) mice. A Ni-titanium (Ti) alloy was implanted under the skin of GATA-3 Tg mice. A Ni solution was then injected 1 month after sensitization. The ear swelling response was measured at several time points after the injection; the cytokine levels in the skin were measured at 48 h after injection, and the serum levels of IgE were measured 1 month after injection. In addition, purified CD4+ splenic cells obtained from the GATA-3 Tg mice sensitized with the Ni-Ti alloy were infused into Rag-2(-/-) mice, and the ear swelling response of these mice after a further challenge with Ni solution was also measured. Marked ear swelling and elevated serum IgE levels and skin tissue levels of IL-4 were observed in Ni-Ti-sensitized GATA-3 Tg mice. The Rag-2(-/-) mice transfused with the CD4+ splenic cells from the Ni-Ti alloy sensitized GATA-3 Tg mice showed a significantly more pronounced ear swelling response than the control mice. We confirmed the participation of Th2-type immune reactions in Ni-induced allergy using GATA-3 Tg mice.


Effects of Renin-Angiotensin system blockers on outcomes from COVID-19: A systematic review and meta-analysis of randomised controlled trials.
Randomised controlled trials (RCTs) have assessed the effects of renin-angiotensin system (RAS) blockers in adults with COVID-19. This meta-analysis provides estimates of the safety and efficacy of treatment with (versus without) RAS blockers from these trials. PubMed, Web of Science, and ClinicalTrials.gov were searched (March 1-April 12, 2023). Event/patient numbers were extracted, comparing ACE inhibitor/ARB treatment, to no treatment, for the outcomes: intensive care unit (ICU) admission, mechanical ventilation, vasopressor use, acute kidney injury (AKI), renal replacement therapy (RRT), acute myocardial infarction, stroke/transient ischaemic attack, heart failure, thromboembolic events, and all-cause death. Fixed-effects meta-analysis estimates were pooled. Sixteen RCTs including 3492 patients were analysed. Compared with discontinuation of RAS blockers, continuation was not associated with increased risk of ICU (RR 0.96, 0.66-1.41), ventilation (RR 0.77, 0.55-1.09), vasopressors (RR 0.92, 0.58-1.44), AKI (RR 1.01, 0.40-2.56), RRT (RR 1.01, 0.46-2.21), or thromboembolic events (RR 1.07, 0.36-3.19). RAS blocker initiation was not associated with increased risk of ICU (RR 0.71, 0.47-1.08), ventilation (RR 1.12, 0.91-1.38), AKI (RR 1.28, 0.89-1.86), RRT (RR 1.66, 0.89-3.12), or thromboembolic events (RR 1.20, 0.06-23.70), although vasopressor use increased (RR 1.27, 1.02-1.57). The RR for all-cause death in the continuation/discontinuation trials was 1.24 (0.80-1.92), and 1.22 (0.96-1.55) in the initiation trials. In patients with severe/critical COVID-19, RAS blocker initiation increased the risk of all-cause death (RR 1.31, 1.01-1.72). ACE inhibitors and ARBs may be continued in non-severe COVID-19 infection, where indicated. Conversely, initiation of RAS blockers may be harmful in critically ill patients. PROSPERO registration number: CRD42023408926.


Development of a highly sensitive and specific immunoassay for determining chrysoidine, a banned dye, in soybean milk film.
A highly specific and sensitive indirect competitive enzyme-linked immunosorbent assay (icELISA)was developed for the first time for the detection of chrysoidine, a dye banned in soybean milk film. Two haptens with different spacer arms were synthesized to produce antibodies. Both homologous and heterologous immunoassay formats were compared to enhance the icELISA sensitivity. The heterologous icELISA exhibited better performance, with an IC(50) (50% inhibitory concentration) of 0.33 ng/mL, a limit of detection (LOD, 10% inhibitory concentration) of 0.04 ng/mL, and a limit of quantitation (LOQ, 20%-80% inhibitory concentration) from 0.09 to 4.9 ng/mL. The developed icELISA was high sensitive and specific, and was applied to determine chrysoidine in fortified soybean milk film samples. The results were in good agreement with that obtained by high-performance liquid chromatography (HPLC) analyses.


Therapeutic inhibition of Mcl-1 blocks cell survival in estrogen receptor-positive breast cancers.
Cancers often overexpress anti-apoptotic Bcl-2 proteins for cell death evasion, a recognized hallmark of cancer progression. While estrogen receptor (ER)-α+ breast cancers express high levels of three anti-apoptotic Bcl-2 family members (Bcl-2, Bcl-xL, and Mcl-1), pharmacological inhibition of Bcl-2 and/or Bcl-xL fails to induce cell death in ERα+ breast cancer cell lines, due to rapid and robust Mcl-1 upregulation. The mechanisms of acute Mcl-1 upregulation in response to Bcl-2/Bcl-xL inhibition remain undefined in in ERα+ breast cancers. We report here that blockade of Bcl-2 or Bcl-xL, alone or together, rapidly induced mTOR signaling in ERα+ breast cancer cells, rapidly increasing cap-dependent Mcl-1 translation. Cells treated with a pharmacological inhibitor of cap-dependent translation, or with the mTORC1 inhibitor RAD001/everolimus, displayed reduced protein levels of Mcl-1 under basal conditions, and failed to upregulate Mcl-1 protein expression following treatment with ABT-263, a pharmacological inhibitor of Bcl-2 and Bcl-xL. Although treatment with ABT-263 alone did not sustain apoptosis in tumor cells in culture or in vivo, ABT-263 plus RAD001 increased apoptosis to a greater extent than either agent used alone. Similarly, combined use of the selective Mcl-1 inhibitor VU661013 with ABT-263 resulted in tumor cell apoptosis and diminished tumor growth in vivo. These findings suggest that rapid Mcl-1 translation drives ABT-263 resistance, but can be combated directly using emerging Mcl-1 inhibitors, or indirectly through existing and approved mTOR inhibitors.


Effect of cadmium on the regulatory mechanism of steroidogenic pathway of Leydig cells during spermatogenesis.
Cadmium is a male reproductive toxicant that interacts with a variety of pathogenetic mechanisms. However, the effect of cadmium on the regulatory mechanism of the steroidogenic pathway of Leydig cells during spermatogenesis is still ambiguous. Light microscopy, Western blot, immunohistochemistry, immunofluorescence, and quantitative polymerase chain reaction were performed to study the regulatory mechanism of the steroidogenic pathway of Leydig cells during spermatogenesis. The results indicated that in the control group, Leydig cells showed dynamic immunoreactivity and immunosignaling action with a strong positive significant secretion of 3β-hydroxysteroid hydrogenase (3β-HSD) in the interstitial compartment of the testis. Leydig cells showed a high active regulator mechanism of the steroidogenic pathway with increased the proteins and genes expression level of steroidogenic acute regulatory protein (STAR), cytochrome P450 cholesterol (CYP11A1), cytochrome P450 cholesterol (CYP17A1), 3β-hydroxysteroid hydrogenase (3β-HSD) 17β-hydroxysteroid hydrogenase (17β-HSD), and androgen receptor (AR) that maintained the healthy and vigorous progressive motile spermatozoa. However, on treatment with cadmium, Leydig cells were irregularly dispersed in the interstitial compartment of the testis. Leydig cells showed reduced immunoreactivity and immunosignaling of 3β-HSD protein. Meanwhile, cadmium impaired the regulatory mechanism of the steroidogenic process of the Leydig cells with reduced protein and gene expression levels of STAR, CYP11A1, CYP17A1, 3β-HSD, 17β-HSD, and AR in the testis. Additionally, treatment with cadmium impaired the serum LH, FSH, and testosterone levels in blood as compared to control. This study explores the hazardous effect of cadmium on the regulatory mechanism of the steroidogenic pathway of Leydig cells during spermatogenesis.


Cost-effectiveness of individualized nutrition and exercise therapy for rehabilitation following hip fracture.
To undertake a cost-utility analysis of the Individual Nutrition Therapy and Exercise Regime: A Controlled Trial of Injured, Vulnerable Elderly (INTERACTIVE) trial. Cost-utility analysis of a randomized controlled trial. A total of 175 patients following a hip fracture were allocated to receive either alternate weekly visits from a physical therapist and dietitian (intervention group), or social visits for 6 months (control group). Costs for utilization of hospitals, health and community services were compared with quality-adjusted life years gained, calculated from responses to the Assessment of Quality of Life instrument. There were minimal differences in mean costs between the intervention ($AUD 45,331 standard deviation (SD): $AUD 23,012) and the control group ($AUD 44,764 SD: $AUD 20,712, p = 0.868), but a slightly higher mean gain in quality-adjusted life years in the intervention group (0.155, SD: 0.132) compared with the control group (0.139, SD: 0.149, p = 0.470). The incremental cost-effectiveness ratio was $AUD 28,350 per quality-adjusted life year gained, which is below the implied cost-effectiveness threshold utilized by regulatory authorities in Australia. A comprehensive 6-month programme of therapy from dietitians and physical therapists could be provided at a relatively low additional cost in this group of frail older adults, and the incremental cost-effectiveness ratio indicates likely cost-effectiveness, although there was a very high level of uncertainty in the findings.


The sigmaE regulon and the identification of additional sporulation genes in Bacillus subtilis.
We report the identification and characterization on a genome-wide basis of genes under the control of the developmental transcription factor sigma(E) in Bacillus subtilis. The sigma(E) factor governs gene expression in the larger of the two cellular compartments (the mother cell) created by polar division during the developmental process of sporulation. Using transcriptional profiling and bioinformatics we show that 253 genes (organized in 157 operons) appear to be controlled by sigma(E). Among these, 181 genes (organized in 121 operons) had not been previously described as members of this regulon. Promoters for many of the newly identified genes were located by transcription start site mapping. To assess the role of these genes in sporulation, we created null mutations in 98 of the newly identified genes and operons. Of the resulting mutants, 12 (in prkA, ybaN, yhbH, ykvV, ylbJ, ypjB, yqfC, yqfD, ytrH, ytrI, ytvI and yunB) exhibited defects in spore formation. In addition, subcellular localization studies were carried out using in-frame fusions of several of the genes to the coding sequence for GFP. A majority of the fusion proteins localized either to the membrane surrounding the developing spore or to specific layers of the spore coat, although some fusions showed a uniform distribution in the mother cell cytoplasm. Finally, we used comparative genomics to determine that 46 of the sigma(E)-controlled genes in B.subtilis were present in all of the Gram-positive endospore-forming bacteria whose genome has been sequenced, but absent from the genome of the closely related but not endospore-forming bacterium Listeria monocytogenes, thereby defining a core of conserved sporulation genes of probable common ancestral origin. Our findings set the stage for a comprehensive understanding of the contribution of a cell-specific transcription factor to development and morphogenesis.


Combined strategies for optimal detection of the contact point in AFM force-indentation curves obtained on thin samples and adherent cells.
Atomic Force Microscopy (AFM) is a widely used tool to study cell mechanics. Current AFM setups perform high-throughput probing of living cells, generating large amounts of force-indentations curves that are subsequently analysed using a contact-mechanics model. Here we present several algorithms to detect the contact point in force-indentation curves, a crucial step to achieve fully-automated analysis of AFM-generated data. We quantify and rank the performance of our algorithms by analysing a thousand force-indentation curves obtained on thin soft homogeneous hydrogels, which mimic the stiffness and topographical profile of adherent cells. We take advantage of the fact that all the proposed algorithms are based on sequential search strategies, and show that a combination of them yields the most accurate and unbiased results. Finally, we also observe improved performance when force-indentation curves obtained on adherent cells are analysed using our combined strategy, as compared to the classical algorithm used in the majority of previous cell mechanics studies.


CRISPR/Cas9-mediated knockout of c-REL in HeLa cells results in profound defects of the cell cycle.
Cervical cancer is the fourth common cancer in women resulting worldwide in 266,000 deaths per year. Belonging to the carcinomas, new insights into cervical cancer biology may also have great implications for finding new treatment strategies for other kinds of epithelial cancers. Although the transcription factor NF-κB is known as a key player in tumor formation, the relevance of its particular subunits is still underestimated. Here, we applied CRISPR/Cas9n-mediated genome editing to successfully knockout the NF-κB subunit c-REL in HeLa Kyoto cells as a model system for cervical cancers. We successfully generated a homozygous deletion in the c-REL gene, which we validated using sequencing, qPCR, immunocytochemistry, western blot analysis, EMSA and analysis of off-target effects. On the functional level, we observed the deletion of c-REL to result in a significantly decreased cell proliferation in comparison to wildtype (wt) without affecting apoptosis. The impaired proliferative behavior of c-REL-/- cells was accompanied by a strongly decreased amount of the H2B protein as well as a significant delay in the prometaphase of mitosis compared to c-REL+/+ HeLa Kyoto cells. c-REL-/- cells further showed significantly decreased expression levels of c-REL target genes in comparison to wt. In accordance to our proliferation data, we observed the c-REL knockout to result in a significantly increased resistance against the chemotherapeutic agents 5-Fluoro-2'-deoxyuridine (5-FUDR) and cisplatin. In summary, our findings emphasize the importance of c-REL signaling in a cellular model of cervical cancer with direct clinical implications for the development of new treatment strategies.


Exercise on prescription: trial protocol and evaluation of outcomes.
In many countries exercise prescriptions are used in an attempt to initiate a physically active lifestyle in sedentary populations. Previous studies have primarily evaluated low intensive exercise prescription interventions and found moderately positive effects on physical activity and aerobic fitness. In a highly intensive Danish exercise prescription scheme called 'Exercise on Prescription' (EoP) the general practitioners can prescribe EoP to sedentary patients with lifestyle diseases. The aim of this randomized trial is to assess the short- and long-term effects of the EoP scheme. Thus, the aim of this paper is to describe the randomized controlled trial designed for evaluating effectiveness of EoP, and to present results from validations of outcome measures. EoP involves a 16-week supervised training intervention and five counselling sessions (health profiles). All patients referred to EoP were eligible for the trial and were offered participation during the baseline health profile. Comparisons between the EoP group and the control group were made at baseline, and after four and ten months. Physiological measures used were maximal oxygen uptake (VO2max), glycosylated haemoglobin (HbA1c), bodyweight, and BMI. Patient-reported measures used were physical activity, health-related quality of life, amount and intensity of exercise, compliance with national guidelines for physical activity, and physical fitness. The validation of the cycle ergometer test found a strong correlation between maximal work capacity and VO2max, and acceptable test-retest reliability at group level. Calibration of the HbA1c apparatus was stable over ten weeks with minimal use, and test-retest reliability was good. High agreement percents were found for test-retest reliability for the self-administered questionnaire. The trial is designed to provide information about the effectiveness of the EoP scheme. The trial is part of a health technology assessment of EoP, which besides the effectiveness covers the patient perspective, the organization, and the health economy. All three methods validated were found useful for the EoP trial.


The MID1 protein is a central player during development and in disease.
Loss-of-function mutations in the MID1 gene cause a rare monogenic disorder, Opitz BBB/G syndrome (OS), which is characterized by malformations of the ventral midline. The MID1 gene encodes the MID1 protein, which assembles a large microtubule-associated protein complex. Intensive research over the past several years has shed light on the function of the MID1 protein as a ubiquitin ligase and regulator of mTOR signalling and translational activator. As a central player in the cell MID1 has been implicated in the pathogenesis of various other disorders in addition to OS including cancer and neurodegenerative diseases. Influencing the activity of the MID1 protein complex is a promising new strategy for the treatment of these diseases. In this review we will summarize the current knowledge about MID1, its involvement in the pathogenesis of OS and other diseases and possible strategies for therapy development.