Moderating Nutritious Habits in Psychiatric Patients Using Transtheoretical Model of Change and Counseling.
Motivational Interviewing provides the opportunity to health professionals to have an effective strategy to increase the level of readiness to change health behaviors. Along with the Transtheoretical Model (Stages of Change Model) compose the theoretical base of intervention in psychiatry settings. This study was aimed to change nutritious behavior of psychiatric patients using a specific Model of Change and Counseling implementing a health education program. A quasi-experimental design was adopted on a random sample of 60 psychiatric patients at Military Hospital of Athens. Patients were divided into two groups as follows; (a) Intervention Group (four sessions of counseling and encouraging motivation for modification of their nutritious habits), and (b) Control Group (simple information sessions about the principles of healthy alimentation). The mean age of Intervention Group (IG) was 43.9 ± 9.5 and Control Group (CG) 46.1 ± 9.1, ranging from 40 to 55 years old. Also, 26.7% of the participants were female, 23.3% were married and, 10% divorced. Our analyses showed that IG patients were significantly loss weight post-intervention compared to CG patients. Specifically, IG patients were significantly moderated the intake of starchy foods in every meal (p < 0.001) and the intake of fruits and vegetables (p < 0.001). Similarly, IG patients were moderated the intake of low fat dairy foods while they changed the full fat dairy foods with low fat (p < 0.001). Also important, IG patients showed significant enhance (80%) regarding drugs compliance, suggesting that 34% of the CG patients often forgot to take their medication. Finally, IG patients reported a positive attitude towards moderating unhealthy nutritious behaviors (p = 0.032). Our results confirms that health educational and promotional Interventions may change behavior of psychiatric patients and thus may positively influence their nutritious habits.


The role of myeloperoxidase and myeloperoxidase-antineutrophil cytoplasmic antibodies (MPO-ANCAs) in the pathogenesis of human MPO-ANCA-associated glomerulonephritis.
It is well known that antineutrophil cytoplasmic antibodies (ANCAs) are pathogenic and have a diagnostic value for ANCA-associated vasculitis. We demonstrated that a rise in myeloperoxidase (MPO)-ANCA titers during remission is often predictive of a future relapse in MPO-ANCA-associated vasculitis. Pathological examination of renal biopsies indicated that not only MPO-ANCAs, but also extracellular MPO, an in situ immune complex composed of MPO and MPO antibodies, may play important roles in the pathogenesis of glomerular capillary injury in MPO-ANCA-associated vasculitis.


Diffusion models of the flanker task: discrete versus gradual attentional selection.
The present study tested diffusion models of processing in the flanker task, in which participants identify a target that is flanked by items that indicate the same (congruent) or opposite response (incongruent). Single- and dual-process flanker models were implemented in a diffusion-model framework and tested against data from experiments that manipulated response bias, speed/accuracy tradeoffs, attentional focus, and stimulus configuration. There was strong mimcry among the models, and each captured the main trends in the data for the standard conditions. However, when more complex conditions were used, a single-process spotlight model captured qualitative and quantitative patterns that the dual-process models could not. Since the single-process model provided the best balance of fit quality and parsimony, the results indicate that processing in the simple versions of the flanker task is better described by gradual rather than discrete narrowing of attention.


Renal Artery Stenosis: When to Revascularize in 2017.
Atherosclerotic renal artery stenosis is the leading cause of secondary hypertension; it can also cause progressive renal insufficiency and cardiovascular complications such as refractory heart failure and flash pulmonary edema. Medical therapy including risk factor modification, renin-angiotensin-aldosterone system antagonists, lipid lowering agents, and antiplatelet therapy is the first line of treatment in all patients. Patients with uncontrolled renovascular hypertension despite optimal medical therapy, ischemic nephropathy, and cardiac destabilization syndromes who have severe renal artery stenosis are likely to benefit from renal artery revascularization. Screening for renal artery stenosis can be done with Doppler ultrasonography, computed tomographic angiography and magnetic resonance angiography. Invasive physiologic measurements are useful to confirm the severity of renal hypoperfusion and therefore improve the selection patients likely to respond to renal artery revascularization. Primary patency exceeds 80% at 5 years and surveillance for in-stent restenosis can be done with periodic clinical, laboratory, and imaging follow-up.


Breast cancer recurrence and survival rates in patients who underwent breast-conserving surgery under non-mechanically ventilated anesthesia.
Recurrence after primary treatment is an important obstacle to the curing of primary breast cancer. Less-immunosuppressive anesthetic techniques, such as local anesthesia with lidocaine, intravenous anesthesia (IVA) with propofol, and/or sedation with midazolam under spontaneous breathing may reduce breast cancer recurrence compared with standard general anesthesia techniques such as IVA and inhalation anesthesia with opioids under mechanical ventilation. The aim of this study was to analyze the factors involved in breast cancer recurrence in patients who underwent breast-conserving surgery (BCS) under non-mechanically ventilated anesthesia. The study included 491 consecutive patients with stages 0-III breast cancer who underwent BCS/axillary lymph-node management with local anesthesia and IVA and/or sedation under non-mechanical ventilation between May 2008 and September 2021. Survival and recurrence were assessed by retrospective cohort analysis. The median follow-up period was 2565 days (range, 28-4834 days). The overall and breast cancer-specific survival rates were 92.9% and 95.6%, respectively. Twenty-one deaths, of which 11 were breast cancer-related, occurred. Disease recurred in 29 (5.9%) patients, of whom 15 patients received neoadjuvant chemotherapy (NAC) and 14 patients received adjuvant therapy (chemotherapy in 12 cases). The surgical procedure performed, but not other clinicopathological factors [recurrence site, P stage, tumor subtype, and disease-free interval (DFI)], differed between the NAC and adjuvant therapy groups. The DFI tended to be shorter in the NAC group than in the adjuvant therapy group. The pathological therapeutic effect grade after NAC was 1 in 12 patients and ≥2 in 3 patients. More than 50% (15/29) of patients with recurrence who underwent BCS were given NAC, but most patients did not respond to it. Similarly, adjuvant chemotherapy may not have contributed to the eradication of residual tumor cells after BCS. To reduce breast cancer recurrence in patients undergoing BCS, treatment strategies, especially for patients who do not respond to NAC or adjuvant chemotherapy, need to be developed. Non-mechanical ventilation anesthesia may also affect the incidence of breast cancer recurrence.


Loss of Cell Differentiation in HPV-Associated Bladder Cancer.
Medical histories of 101 urothelial bladder cancer patients were compared with the results of morphological analysis and biomolecular detection of human papilloma viruses (HPV) in the tumor specimens. DNA of HPV16 (the major type of virus responsible for appearance of cervical carcinoma) was detected in 38 specimens, while mRNA of E6 and E7 oncogenes and E7 oncoprotein of HPV16 were observed in 13 specimens. HPV-positive bladder cancer was characterized by higher degree of cell anaplasia than HPV-negative cancer; in the primary bladder tumor, HPV was detected more often than in recurrent bladder cancer. These data attest to involvement of HPV16 in the genesis of bladder cancer. No correlations of HPV status of bladder tumor with patient's sex, age, and invasion into the muscle layer were revealed.


SPADE4: Sparsity and Delay Embedding Based Forecasting of Epidemics.
Predicting the evolution of diseases is challenging, especially when the data availability is scarce and incomplete. The most popular tools for modelling and predicting infectious disease epidemics are compartmental models. They stratify the population into compartments according to health status and model the dynamics of these compartments using dynamical systems. However, these predefined systems may not capture the true dynamics of the epidemic due to the complexity of the disease transmission and human interactions. In order to overcome this drawback, we propose Sparsity and Delay Embedding based Forecasting (SPADE4) for predicting epidemics. SPADE4 predicts the future trajectory of an observable variable without the knowledge of the other variables or the underlying system. We use random features model with sparse regression to handle the data scarcity issue and employ Takens' delay embedding theorem to capture the nature of the underlying system from the observed variable. We show that our approach outperforms compartmental models when applied to both simulated and real data.


A Fas agonist induces high levels of apoptosis in haematological malignancies.
We developed and tested a potent hexameric Fas agonist, termed MegaFasL, for its cytotoxic effects on a panel of human haematopoietic malignant cells and healthy human haematopoietic progenitor cells (CD34+CD38low). Results demonstrated that MegaFasL induced apoptosis in cell lines and primary cells representing multiple myeloma (MM), acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) and Burkitt's lymphoma. Cells from a chronic myeloid leukaemia (CML) line and from patients with chronic lymphocytic leukaemia (CLL) were resistant. Furthermore, CD34+CD38low progenitor cells were also resistant to MegaFasL. The data indicate that MegaFasL could be a highly efficient therapeutic agent ex vivo or potentially in vivo.


Smoking and risk of incident psoriasis among women and men in the United States: a combined analysis.
The authors evaluated the association between smoking and the incidence of psoriasis among 185,836 participants from a cohort of older women (the Nurses' Health Study, 1996-2008), a cohort of younger women (the Nurses' Health Study II, 1991-2005), and a cohort of men (Health Professionals' Follow-up Study, 1986-2006). Information on smoking was collected biennially during follow-up. The authors identified a total of 2,410 participants with incident psoriasis. Compared with never smokers, past smokers had a relative risk of incident psoriasis of 1.39 (95% confidence interval (CI): 1.27, 1.52) and current smokers had a relative risk of 1.94 (95% CI: 1.64, 2.28). For current smokers who smoked 1-14 cigarettes/day, the relative risk was 1.81 (95% CI: 1.38, 2.36); for those who smoked 15-24 cigarettes/day, the relative risk was 2.04 (95% CI: 1.68, 2.47); and for those who smoked 25 or more cigarettes/day, the relative risk was 2.29 (95% CI: 1.74, 3.01). There was a trend toward an increased risk of psoriasis with increasing pack-years or duration of smoking (P(trend) < 0.0001). The risk was highest among smokers who had 65 or more pack-years of smoking (relative risk = 2.72, 95% CI: 2.05, 3.60) and among those with a smoking duration of 30 or more years (relative risk = 1.99, 95% CI: 1.75, 2.25). The authors observed a graded reduction of risk with an increase in time since smoking cessation (P(trend) <0.0001). In this study, smoking was found to be an independent risk factor for psoriasis in both women and men. Psoriasis risk was particularly augmented for heavy smokers and persons with longer durations of smoking.


Corrigendum: Screening and identification of nucleocapsid protein-nanobodies that inhibited Newcastle disease virus replication in DF-1 cells.
[This corrects the article DOI: 10.3389/fmicb.2022.956561.].


A tale of two waves: Delineating diverse genomic and transmission landscapes driving the COVID-19 pandemic in Pune, India.
Modern response to pandemics, critical for effective public health measures, is shaped by the availability and integration of diverse epidemiological outbreak data. Tracking variants of concern (VOC) is integral to understanding the evolution of SARS-CoV-2 in space and time, both at the local level and global context. This potentially generates actionable information when integrated with epidemiological outbreak data. A city-wide network of researchers, clinicians, and pathology diagnostic laboratories was formed for genome surveillance of COVID-19 in Pune, India. The genomic landscapes of 10,496 sequenced samples of SARS-CoV-2 driving peaks of infection in Pune between December-2020 to March-2022, were determined. As a modern response to the pandemic, a "band of five" outbreak data analytics approach was used. This integrated the genomic data (Band 1) of the virus through molecular phylogenetics with key outbreak data including sample collection dates and case numbers (Band 2), demographics like age and gender (Band 3-4), and geospatial mapping (Band 5). The transmission dynamics of VOCs in 10,496 sequenced samples identified B.1.617.2 (Delta) and BA(x) (Omicron formerly known as B.1.1.529) variants as drivers of the second and third peaks of infection in Pune. Spike Protein mutational profiling during pre and post-Omicron VOCs indicated differential rank ordering of high-frequency mutations in specific domains that increased the charge and binding properties of the protein. Time-resolved phylogenetic analysis of Omicron sub-lineages identified a highly divergent BA.1 from Pune in addition to recombinant X lineages, XZ, XQ, and XM. The band of five outbreak data analytics approach, which integrates five different types of data, highlights the importance of a strong surveillance system with high-quality meta-data for understanding the spatiotemporal evolution of the SARS-CoV-2 genome in Pune. These findings have important implications for pandemic preparedness and could be critical tools for understanding and responding to future outbreaks.


Mechanically flexible and optically transparent three-dimensional nanofibrous amorphous aerocellulose.
Aerocelluloses are considered as "third generation" aerogels after the silica and synthetic polymer-based ones. However, their brittleness and low optical translucency keep quite narrow their fields of applications. Here, both issues are addressed successfully through the fabrication of flexible and mechanically robust amorphous aerocellulose with high optical transparency, using trifluoroacetic acid as a solvent and ethanol as a non-solvent. The developed aerocellulose displays a meso-macroporous interconnected nanofibrous cellulose skeleton with low density and high specific surface area. We demonstrate its high efficiency as supporting matrix for nanoscale systems by incorporating a variety of colloidal quatum dots, that provide bright and stable photoluminescence to the flexible aerocellulose host.


Gender differences in management and clinical outcomes of atrial fibrillation patients.
Prior research has identified gender differences in the epidemiology and clinical management of atrial fibrillation (AF). The primary aim of this study is to systematically analyze a cohort of AF men and women and evaluate their baseline demographics, treatment, and clinical outcomes by gender. We examined the records of 5976 (42% women) consecutive AF patients who were prescribed at least one anti-arrhythmic drug between 2006 and 2013. From this cohort, 4311 (72%) patients had anticoagulation data available and were included in the final analysis. Time to clinical events was assessed using survival analysis and adjusted for covariates using Cox regression. Compared to men, women were older (73 years vs. 67 years, p<0.001), had higher CHADS2 scores (1.9 vs. 1.5, p<0.001), and fewer cardiac comorbidities. Compared to men, women were more often prescribed sotalol and less often dofetilide (p<0.001). Women were also less likely to be anticoagulated (76.8% vs. 82.5%, p<0.001). Over a mean follow-up of 40 months, women were more likely to die (HR 1.21, p=0.037) or to have an ischemic stroke (HR 1.35, p=0.058). Women also had higher rates of atrioventricular-nodal ablation (adjusted HR 2.11, p<0.001) and pacemaker implantation (adjusted HR 1.69, p<0.001) procedures, but lower rates of electrical cardioversions, AF ablations, and maze surgeries. There are significant gender differences in baseline demographics and clinical outcomes of AF patients. Women have higher mortality and ischemic strokes and are less often prescribed anticoagulation therapy despite higher CHADS2 scores. These data have important clinical implications.


Quantitative study of interactions between Saccharomyces cerevisiae and Oenococcus oeni strains.
This study examines the interactions that occur between Saccharomyces cerevisiae and Oenococcus oeni strains during the process of winemaking. Various yeast/bacteria pairs were studied by applying a sequential fermentation strategy which simulated the natural winemaking process. First, four yeast strains were tested in the presence of one bacterial strain leading to the inhibition of the bacterial component. The extent of inhibition varied widely from one pair to another and closely depended on the specific yeast strain chosen. Inhibition was correlated to weak bacterial growth rather than a reduction in the bacterial malolactic activity. Three of the four yeast strains were then grown with another bacteria strain. Contrary to the first results, this led to the bacterial stimulation, thus highlighting the importance of the bacteria strain. The biochemical profile of the four yeast fermented media exhibited slight variations in ethanol, SO(2) and fatty acids produced as well as assimilable consumed nitrogen. These parameters were not the only factors responsible for the malolactic fermentation inhibition observed with the first bacteria strain. The stimulation of the second has not been reported before in such conditions and remains unexplained.


Reviving virus based cancer vaccines by using cytomegalovirus vectors expressing modified tumor antigens.
Cancer vaccines that have utilized various immunization strategies to induce antitumor immunity have largely failed in clinical settings. We have recently developed a cancer vaccine using a cytomegalovirus (CMV) based vector that expressed a modified melanoma antigen that elicited a robust antitumor CD8+ T cell response and tumor rejection.


Pancreatic neuroendocrine tumor presenting in indolent systemic mastocytosis: A case report.
Systemic mastocystosis, a disorder of clonal mast cell expansion presents with symptoms of flushing, pruritus, musculoskeletal pain, gastrointestinal cramping and vascular instability. Patients with neuroendocrine tumors may present with similar symptoms due to the release of vasoactive mediators in both diseases. We report the co-occurrence of systemic mastocytosis and a neuroendocrine pancreatic tumor for which the patient received disease-specific treatment. A 58-year-old woman with a history of indolent systemic mastocytosis and a serum tryptase of 51 ng/mL was diagnosed with a solid pancreatic lesion on ultrasound when assessing for organomegaly. Lesional biopsy was consistent with a pancreatic neuroendocrine tumor which was successfully resected. Presenting symptoms such as skin rashes, flushing, fatigue and diarrhea, are similar for systemic mastocytosis and neuroendocrine tumors. The co-occurrence of both diseases has not been previously reported. Activating mutations in KIT, which are a hallmark of systemic mastocytosis, may drive neoplastic proliferation in neuroendocrine tumors. Furthermore, mast cells infiltrating pancreatic tissue may have a trophic effect on the development of pancreatic neuroendocrine tumors. While challenging to diagnose both diseases presenting with similar symptoms, recognition of these distinct diseases is necessary to ensure timely treatment.


FDG-PET/CT assessment of misty mesentery: feasibility for distinguishing viable mesenteric malignancy from stable conditions.
"Misty mesentery" is a CT appearance of mesenteric fat changes with increased attenuation often existing with swelled mesenteric lymph nodes. We evaluated diagnostic performance of FDG-PET/CT in distinguishing viable malignant disorders from benign conditions in misty mesentery. 4236 FDG-PET/CT images were reviewed to identify patients with appearances of misty mesentery. Only the initial examinations were evaluated. Patients undergoing chemotherapy and/or radiotherapy within 3 months, patients with bulky mesenteric mass, and patients without follow-up examinations were excluded. Maximum short-axis diameter of mesenteric nodules (Diam-max) and maximum standardized uptake value (SUVmax) for mesenteric abnormalities were measured, and the diagnostic performance to differentiate between viable malignancy and stable lesions was assessed by receiver-operating characteristic (ROC) analysis, based on final diagnoses obtained by histology or follow-up examinations. Their significance was assessed by multivariate logistic regression. 71 studies met the inclusion criteria with confirmed diagnoses (13 viable malignancies; 58 stable lesions). Of the 13 malignant cases, 12 were lymphoma. ROC curves indicated an optimal Diam-max cut-off value of >10mm and SUVmax cut-off of ≥3.0, with area under the curve of 0.961 and 0.926, respectively. Using the optimal Diam-max cut-off, sensitivity and specificity were 69% and 98%, respectively. Using the optimal SUVmax cut-off, they were 85% and 98%, respectively. The combination of either Diam-max>10mm or SUVmax≥3.0 had a sensitivity of 92%. Both Diam-max and SUVmax were significant independent factors for predicting malignancy. FDG-PET/CT is feasible for identifying viable malignancy in misty mesentery.


Gemcitabine in the treatment of advanced head and neck cancer.
Several new chemotherapy agents show varying degrees of activity in head and neck cancer. One of them is gemcitabine, which is a new nucleoside analogue with an innovative cytostatic mode of action. Gemcitabine has demonstrated a broad spectrum anti-tumoural effect and a favourable toxicity profile. These attributes prompted us to introduce gemcitabine into the treatment of head-and-neck tumours. Ten heavily pre-treated patients with recurrent and incurable squamous-cell carcinoma of the head and neck (SCCHN) were treated with Gem. The initial cycle consisted of six administrations of the drug (1250 mg/m2 once weekly intravenously over 30 min) followed by a week without cytotoxic treatment. All following cycles were composed of two infusions once weekly (d1, 8), followed by a week of rest. Toxic effects, length of survival and tumour response was assessable in eight patients owing to one suicide and loss of one patient for follow-up. One complete remission, two partial remissions and three 'no change' situations (stable disease) were observed, yielding a response rate of 37.5%. Median survival was 8 months (range 3-12). The incidence of haematological toxicity was low, with grade 3-4 neutropenia in less than 10%. Flu-like symptoms were reported by one-third of patients. In this small phase-II study, gemcitabine demonstrated a high anti-tumoural activity in SCCHN, with a favourable toxicity profile. Gemcitabine seems to be a promising new drug without severe burden even for patients who are refractory to other cytostatic drugs. Within recent years, the activity and tolerability of gemcitabine was documented in several phase I and phase II trials, especially in combination with cisplatin, and paclitaxel resp, carboplatin/paclitaxel, cisplatin/ifosfamide, and 5-fluorouracil/paclitaxel. The results of these trials will be outlined in the discussion.


Health-related needs reported by adolescents living with HIV and receiving antiretroviral therapy in sub-Saharan Africa: a systematic literature review.
Adolescents living with HIV (ALHIV) on antiretroviral therapy (ART) have specific health needs that can be challenging to deliver. Sub-Saharan Africa (SSA) is home to 84% of the global population of ALHIV, of whom about 59% receive ART. Several studies in SSA have demonstrated health service gaps due to lack of synchronized healthcare for ALHIV receiving ART. We conducted a systematic review of health-related needs among ALHIV on ART in SSA to inform decisions and policies on care. We searched MEDLINE, Web of Science, EMBASE, PsycINFO, Cochrane library and grey literature for studies reporting health-related needs among ALHIV receiving ART in SSA, between January 2003 and May 2020. Of the 2333 potentially eligible articles identified, 32 were eligible. Eligible studies were published between 2008 and 2019, in 11 countries: Zambia (7), Uganda (6), Tanzania (4), South Africa (4), Kenya (3), Ghana (2), Zimbabwe (2), Rwanda (1), Malawi (1), Botswana (1) and Democratic Republic of Congo (1). Seven categories of health needs among ALHIV were identified. In descending order of occurrence, these were: psychosocial needs (stigma reduction, disclosure and privacy support, and difficulty accepting diagnosis); dependency of care (need for family and provider support, and desire for autonomy); self-management needs (desire for better coping strategies, medication adherence support and reduced ART side effects); non-responsive health services (non-adolescent friendly facility services and non-compatible school system); need for food, financial and material support; inadequate information about HIV (desire for more knowledge to fight misinformation and misconception); and developmental and growth needs (desire to experience sex, parenthood and love). Ecological analysis identified different priority needs between ALHIV, their caregivers and healthcare providers, including psychosocial needs, financial challenges and non-responsive health services, respectively. To respond effectively to the health needs of ALHIV and improve ART adherence, interventions should focus on stigma reduction, disclosure challenges and innovative coping mechanisms for ART. Interventions that address the health needs of ALHIV from the perspective of carers and providers, such as financial support schemes and adolescent-friendly healthcare strategies, should supplement efforts to improve adolescent ART adherence outcomes.


A new D₂ dopamine receptor agonist allosterically modulates A(2A) adenosine receptor signalling by interacting with the A(2A)/D₂ receptor heteromer.
The structural and functional interaction between D₂ dopamine receptor (DR) and A(2A) adenosine receptor (AR) has suggested these two receptors as a pharmacological target in pathologies associated with dopamine dysfunction, such as Parkinson's disease. In transfected cell lines it has been demonstrated the activation of D₂DR induces a significant negative regulation of A(2A)AR-mediated responses, whereas few data are at now available about the regulation of A(2A)AR by D₂DR agonists at receptor recognition site. In this work we confirmed that in A(2A)AR/D₂DR co-transfected cells, these receptors exist as homo- and hetero-dimers. The classical D₂DR agonists were able to negatively modulate both A(2A)AR affinity and functionality. These effects occurred even if any significant changes in A(2A)AR/D₂DR energy transfer interaction could be detected in BRET experiments. Since the development of new molecules able to target A(2A)/D₂ dimers may represent an attractive tool for innovative pharmacological therapy, we also identified a new small molecule, 3-(3,4-dimethylphenyl)-1-(2-piperidin-1-yl)ethyl)piperidine (compound 1), full agonist of D₂DR and modulator of A(2A)-D₂ receptor dimer. This compound was able to negatively modulate A(2A)AR binding properties and functional responsiveness in a manner comparable to classical D₂R agonists. In contrast to classical agonists, compound 1 led to conformational changes in the quaternary structure in D₂DR homomers and heteromers and induced A(2A)AR/D₂DR co-internalization. These results suggest that compound 1 exerts a high control of the function of heteromers and could represent a starting point for the development of new drugs targeting A(2A)AR/D₂ DR heteromers.


A topographic approach to breast cancer: the relation of topographic and mammographic findings.
One hundred and twenty-eight patients with breast cancer who, on the basis of mammographic study, were treated by mastectomy were analyzed. The purpose of this endeavor was to correlate the roentgenologic features with the pathologic findings. The correlation between them was very good: the type of tumor opacity, the microcalcifications, and the various other radiologic patterns were compatible with both localized and extensive breast cancer. Mammography appears to be valuable in the selection of patients suitable for conservative treatment.


Passion in the performing arts: clarifying active occupational participation.
Active participation in daily occupations is a vital part of everyday life, social participation and healthy life long human development; however, enablers of active participation are not well understood. Passion, a strong tendency towards an activity that a person finds meaningful and spends a lot of time doing, is a potential enabler. Accordingly, it is important to understand how an individual's passion for a specific occupation plays out across the occupational life course. To explore the experience of passion across the life course of older adults involved in the performing arts. Seven older adults involved in, or retired from, the performing arts, who consider themselves passionate about their occupation. A constructivist grounded theory approach was used to explore, through interviews with older adults, passion for performing arts across the life course. Emerging themes supported development of an initial theoretical framework explicating active participation and passion. It centers on passion as an enabler of occupational participation through different modes, and suggests barriers to that enablement process. Findings suggest that passion has an important role in continued active participation in an occupation; however, barriers, such as social and financial, can derail the pursuit of a passionate occupation.


Reversed-phase capillary electrochromatography for the simultaneous determination of acetylsalicylic acid, paracetamol, and caffeine in analgesic tablets.
The separation and simultaneous determination of caffeine, paracetamol, and acetylsalicylic acid in two analgesic tablet formulations was investigated by capillary electrochromatography (CEC). The effect of mobile phase composition on the separation and peak efficiency of the three analytes was studied and evaluated; in particular, the influence of buffer type, buffer pH, and acetonitrile content of the mobile phase was investigated. The analyses were carried out under optimized separation conditions, using a full-packed silica capillary (75 microm ID; 30.0 cm and 21.5 cm total and effective lengths, respectively) with a 5 microm C8 stationary phase. A mixture of 25 mM ammonium formate at pH 3.0 and acetonitrile (30:70 v/v) was used as the mobile phase. UV detection was at 210 nm. Good linearity was found in the range of 50-200, 20-160, and 4-20 microg/mL for acetylsalicylic acid (r2=0.9988), paracetamol (r2=0.9990) and caffeine (r2=0.9990), respectively. Intermediate precision (RSD interday) as low as 0.1-0.8% was found for retention times, while the RSD values for the peak area ratios (Aanalyte/AIS) were in the range of 1.9-2.9%. The optimized CEC method was applied to the analysis of the studied compounds present in commercial tablets.


[Multicystic dysplastic kidney disease: update and information for parents at the time of prenatal diagnosis].
Multicystic kidney disease (MCKD) is the most common form of Congenital Abnormality of Kidney and Urinary Tract (CAKUT). This anomaly of renal development is characterized by unilateral enlarged cystic formations and fibrous dysplastic parenchyma. The long-term prognosis is usually good; however because of reduced nephron mass, an early prevention of cardiovascular risk and nephrotoxicity is recommended. A lifelong follow-up of blood pressure, serum creatinine and microalbuminuria seems logical as well as in other patients with a single kidney. MCKD is usually diagnosed during pregnancy so that parents often question about long-term prognosis and follow-up. Therefore, we propose an information sheet for parents.


Transcriptome profiling reveals the occurrence mechanism of bisexual flowers in melon (Cucumis melo L.).
Most cultivated melons are andromonoecies in which male flowers arose both in main stem and lateral branches but bisexual flowers only emerged from the leaf axils of lateral branches. However, bisexual flowers emerged in leaf axils of main stem after ethephon treatment. Therefore, the mechanism regulating the occurrence of bisexual flowers were investigated by performing transcriptome analysis in two comparison sets: shoot apex of main stem (MA) versus that of lateral branches (LA), and shoot apex of main stem after ethephon treatment (Eth) versus control (Cont). KEGG results showed that genes involved in "plant hormone signal transduction", "MAPK signaling pathway" and "carbon metabolism" were significantly upregulated both in LA and Eth. Further, details of DEGs involved in ethylene signaling pathway were surveyed and six genes were co-upregulated in two comparison sets. Among these, CmERF1, downstream in ethylene signaling pathway, showed the most significantly difference and expressed higher in bisexual buds than that in male buds. Furthermore, fifteen DEGs were found to contain GCC box or CRT/DRE cis-element for CmERF1 in their putative promoter region, and these DEGs involved in several plant hormones signaling pathway, camalexin synthesis, carbon metabolism and plant pathogen interaction.


Matrix metalloprotease-mediated cleavage of neural glial-related cell adhesion molecules activates quiescent olfactory stem cells via EGFR.
Quiescent stem cells have been found in multiple adult organs, and activation of these stem cells is critical to the restoration of damaged tissues in response to injury or stress. Existing evidence suggests that extrinsic cues from the extracellular matrix or supporting cells of various stem cell niches may interact with intrinsic components to initiate stem cell differentiation, but the molecular and cellular mechanisms regulating their activation are not fully understood. In the present study, we find that olfactory horizontal basal cells (HBCs) are stimulated by neural glial-related cell adhesion molecules (NrCAMs). NrCAM activation requires matrix metalloproteases (MMPs) and epidermal growth factor receptors (EGFRs). Inhibiting MMP activity or EGFR activation not only blocks HBC proliferation in the cultured olfactory organoids, but also severely suppresses HBC proliferation in the olfactory epithelium following methimazole-induced injury, resulting in a delay of olfactory mucosa reconstitution and functional recovery of the injured mice. Both NrCAMs and EGFR are expressed by the HBCs and their expression increases upon injury. Our data indicate that MMP-mediated cleavage of NrCAMs serves as an autocrine or paracrine signal that activates EGFRs on HBCs to trigger HBC proliferation and differentiation to reconstruct the entire olfactory epithelium following injury.


Application of probabilistic and fuzzy cognitive approaches in semantic web framework for medical decision support.
This study aimed to focus on medical knowledge representation and reasoning using the probabilistic and fuzzy influence processes, implemented in the semantic web, for decision support tasks. Bayesian belief networks (BBNs) and fuzzy cognitive maps (FCMs), as dynamic influence graphs, were applied to handle the task of medical knowledge formalization for decision support. In order to perform reasoning on these knowledge models, a general purpose reasoning engine, EYE, with the necessary plug-ins was developed in the semantic web. The two formal approaches constitute the proposed decision support system (DSS) aiming to recognize the appropriate guidelines of a medical problem, and to propose easily understandable course of actions to guide the practitioners. The urinary tract infection (UTI) problem was selected as the proof-of-concept example to examine the proposed formalization techniques implemented in the semantic web. The medical guidelines for UTI treatment were formalized into BBN and FCM knowledge models. To assess the formal models' performance, 55 patient cases were extracted from a database and analyzed. The results showed that the suggested approaches formalized medical knowledge efficiently in the semantic web, and gave a front-end decision on antibiotics' suggestion for UTI.


A novel homozygous SYNJ1 mutation in two siblings with typical Parkinson's disease.
Mutations in the SYNJ1 have been associated with early onset of atypical Parkinson's disease (PARK20). Patients with PARK20 exhibit a wide phenotypic variability. Here, we report the clinical and genetic findings in two affected siblings with a novel homozygous SYNJ1 mutation. A consanguineous family with two affected siblings with Parkinson's disease was recruited. Both siblings underwent detailed neurological examinations. Whole genome sequencing was performed in the proband. Both affected siblings presented with pure parkinsonism with no other atypical symptoms and a slow disease progression. The proband had an excellent response to levodopa. Performing the levodopa challenge test in the proband's older brother resulted in improvements in the parkinsonism signs. Genetic analysis identified a homozygous missense mutation in SYNJ1 (c.2495A > G, p.Y832C) in both of siblings. In silico analyses revealed that the mutation was deleterious. Screening for SNYJ1 should be considered in patients with typical levodopa-responsive Parkinson's disease.


A new pancreatic lipase inhibitor isolated from the roots of Actinidia arguta.
A new coumaroyl triterpene, 3-O-trans-p-coumaroyl actinidic acid (1), as well as five known triterpenes, ursolic acid (2), 23-hydroxyursolic acid (3), corosolic acid (4), asiatic acid (5) and betulinic acid (6) were isolated from an EtOAc-soluble extract of the roots of Actinidia arguta. The structure of compound 1 was elucidated from interpretation of the spectroscopic data, particularly by extensive 1D and 2D NMR studies. All the isolates (1-6) were evaluated in vitro for their inhibitory activities on pancreatic lipase (PL). Of the isolates, the new compound 1 possessed the highest inhibitory activity on PL, with an IC(50) of 14.95 microM, followed by ursolic acid (2, IC(50) = 15.83 microM). The other four triterpenes (3-6) also showed significant PL inhibitory activity, with IC(50) values ranging from 20.42 to 76.45 microM.


Intraobserver agreement in interpretation of digital epiluminescence microscopy.
Although a major problem with the classification of epiluminescence microscopy (ELM) findings is the lack of standard definitions, reproducibility of the criteria proposed has never been investigated. Our purposes were (1) to perform a review of four major published classifications to obtain a set of apparently well-defined ELM variables and descriptors and (2) to evaluate the ability of one of us to report consistently ELM findings in melanocytic lesions according to these criteria. Intraobserver agreement (with a set of 44 selected descriptors) between two readings of 150 digital ELM images was evaluated with the kappa (kappa) statistic. Subgroups of descriptors were compared for kappa value distribution. The median kappa value for the whole series of descriptors was 0.66. Median kappa did not vary significantly among the four classification systems (kappa = 0.61 to 0.67). Agreement was significantly better as to the presence or absence of ELM findings (kappa range, 0.39 to 1.00; median kappa, 0.77) compared with agreement as to their distribution (kappa range, 0.10 to 0.79; median kappa, 0.47; p = 0.0007) and their width, thickness, and size (kappa range, 0.06 to 0.83; median kappa, 0.39; p = 0.0075). Although nothing can be inferred from a single study, descriptors associated with low intraobserver agreement are likely to be inadequately defined.


Chemotherapeutic efficacy of Nocodazole encapsulated in liposomes on L1210 murine leukemia.
The use of sonicated phospholipid vesicles (liposomes) as carriers of methyl [5-(2-thienylcarbonyl)-1H-benzimidazol-2-yl] carbamate (Nocodazole), a water insoluble antimitotic compound active on mouse L1210 leukemia was investigated. Nocodazole was incorporated in dipalmitoyl-phosphatidylcholine: cholesterol: stearylamine (4:3:1) liposomes that were stable at room temperature for at least 48 hr. No drug leakage nor lipid exchange occurred after a 4 hr incubation at 37 degrees C with RPMI 1640 medium supplemented with 10% fetal calf serum. L1210 cells preincubated (2 x 10(6) cells/ml) at 37 degrees C for 3 hr with various concentrations of micronized Nocodazole or liposome-entrapped Nocodazole were injected i.p. into normal CDF1 mice (10(5) cells/mouse). Longest mean survival times and long-time survivors were observed in the group inoculated with L1210 cells preincubated with liposomes containing Nocodazole. CDF1 mice bearing i.p. or i.v. L1210 leukemia were treated i.p. on days 1, 5 and 9 with micronized or liposome-entrapped Nocodazole. Administration of this latter preparation induced a 50% increase in animal life span at the dosage (25 mg/kg/day) half the one required with the free compound (50 mg/kg/day). The present data indicate that enclosing Nocodazole, a water insoluble antimitotic compound, in liposomes results in an enhanced therapeutic activity against L1210 murine leukemia.


Publisher's Note: Continued Publication of Nursing Reports by MDPI.
Nursing Reports was launched in 2011 and published over the past nine years by PAGEPress Publications [...].


Testicular adrenal rest tumors in patients with congenital adrenal hyperplasia: prevalence and sonographic, hormonal, and seminal characteristics.
Testicular adrenal rest tumors have been described in patients with congenital adrenal hyperplasia (CAH). The aim of this work was to (1) evaluate the prevalence of testicular adrenal rest tumors in patients with CAH; (2) study the hormonal profile; (3) define the sonographic features; (4) assess the seminal profile; and (5) initiate a longitudinal study on the possible role of corticotropin (ACTH) plasma levels in the induction and persistence of testicular adrenal rest tumors. Eighteen patients affected by CAH, aged 21 to 41 years, were studied. These were all patients referred to our endocrinology unit for the first time to undergo a clinical evaluation. All of the patients were taking long-term cortisone acetate and fludrocortisone replacement therapy. The study included (1) a physical examination, (2) testis sonography, (3) a hormonal profile, (4) semen analysis. Sonography showed testicular adrenal rest tumors in 11 patients (61.1%); of these, 9 cases (50.0%) were bilateral, and 2 (11.1%) were unilateral. The diameter ranged from 4 to 38 mm. In 9 patients, the lesions were hypoechoic, whereas in 2, they were hyperechoic. High plasma ACTH levels were detected in all of the patients with tumors despite long-term therapy. Semen analysis found 2 cases of azoospermia and 6 cases of oligoasthenoteratozoospermia; the 3 remaining patients were normospermic. The preliminary longitudinal study has shown 3 patients with a disappearance or reduction of the tumors after 6 months of modified treatment. This study confirms the high prevalence of testicular adrenal rest tumors in patients with CAH and the major role played in its pathogenesis by high plasma ACTH levels.


Indications for seminal vesicle biopsy and laparoscopic pelvic lymph node dissection in men with localized carcinoma of the prostate.
The ability of seminal vesicle biopsy and laparoscopic pelvic lymph node dissection to identify patients with stage T3 or N+ disease before undergoing treatment for localized carcinoma of the prostate was investigated. A total of 157 patients with clinical stages T1a to T2c prostate cancer underwent ultrasound guided seminal vesicle biopsy (3 on each side) and 130 underwent subsequent laparoscopic pelvic lymph node dissection. Of 157 patients 23 (14.6%) had a positive seminal vesicle biopsy. Predictors of a positive seminal vesicle biopsy were stages T2b to T2c versus T1a to T2a disease (20% versus 4%, respectively, p = 0.005), Gleason score 7 or more versus less than 7 (34% versus 9%, respectively, p < 0.0001) and prostate specific antigen (PSA) 4 to 10 ng./ml., 10 to 20 ng./ml. or more than 20 ng./ml. (9%, 14% and 27%, respectively, p = 0.03). Of 130 patients 14 (10.7%) had a positive laparoscopic pelvic lymph node dissection. Predictors for a positive laparoscopic pelvic lymph node dissection were Gleason score 7 or more versus less than 7 (32% versus 2%, respectively, p < 0.0001), PSA more than 20 ng./ml. or less than 20 ng./ml. (24% versus 4.5%, respectively, p = 0.009) and stage T2b or T2c (15% and 24%, respectively, p = 0.056). Of the patients with a positive seminal vesicle biopsy 48% had a positive laparoscopic pelvic lymph node dissection (p < 0.0001). All patients with a Gleason score more than 4, PSA more than 10 ng./ml. or clinical stage T2b or more should undergo seminal vesicle biopsy, and those with a positive seminal vesicle biopsy or Gleason score 7 or greater should undergo laparoscopic pelvic lymph node dissection before initiating therapy for localized carcinoma of the prostate.


Pronephric tubule formation in zebrafish: morphogenesis and migration.
The nephron is the functional subunit of the vertebrate kidney and plays important osmoregulatory and excretory roles during embryonic development and in adulthood. Despite its central role in kidney function, surprisingly little is known about the molecular and cellular processes that control nephrogenesis. The zebrafish pronephric kidney, comprising two nephrons, provides a visually accessible and genetically tractable model system for a better understanding of nephron formation. Using this system, various developmental processes, including the commitment of mesoderm to a kidney fate, renal tubule proliferation, and migration, can be studied during nephrogenesis. Here, we discuss some of these processes in zebrafish with a focus on the pathways that influence renal tubule cell morphogenesis.


Neutrophil to lymphocyte ratio and cancer prognosis: an umbrella review of systematic reviews and meta-analyses of observational studies.
Although neutrophils have been linked to the progression of cancer, uncertainty exists around their association with cancer outcomes, depending on the site, outcome and treatments considered. We aimed to evaluate the strength and validity of evidence on the association between either the neutrophil to lymphocyte ratio (NLR) or tumour-associated neutrophils (TAN) and cancer prognosis. We searched MEDLINE, Embase and Cochrane Database of Systematic Reviews from inception to 29 May 2020 for systematic reviews and meta-analyses of observational studies on neutrophil counts (here NLR or TAN) and specific cancer outcomes related to disease progression or survival. The available evidence was graded as strong, highly suggestive, suggestive, weak or uncertain through the application of pre-set GRADE criteria. A total of 204 meta-analyses from 86 studies investigating the association between either NLR or TAN and cancer outcomes met the criteria for inclusion. All but one meta-analyses found a hazard ratio (HR) which increased risk (HR > 1). We did not find sufficient meta-analyses to evaluate TAN and cancer outcomes (N = 9). When assessed for magnitude of effect, significance and bias related to heterogeneity and small study effects, 18 (9%) associations between NLR and outcomes in composite cancer endpoints (combined analysis), cancers treated with immunotherapy and some site specific cancers (urinary, nasopharyngeal, gastric, breast, endometrial, soft tissue sarcoma and hepatocellular cancers) were supported by strong evidence. In total, 60 (29%) meta-analyses presented strong or highly suggestive evidence. Although the NLR and TAN hold clinical promise in their association with poor cancer prognosis, further research is required to provide robust evidence, assess causality and test clinical utility. PROSPERO CRD42017069131 .


A descriptive evaluation of unfractionated heparin use during pregnancy.
The mainstay of oral anticoagulant therapy, warfarin sodium, crosses the placenta during pregnancy and may cause fetal complications. Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) do not cross the placenta and have demonstrated utility in the prevention and treatment of thrombosis during pregnancy. The purpose of this study was to review treatment strategy, indication, and maternal and fetal outcomes in anticoagulated pregnancies at Kaiser Permanente Colorado. We identified 103 pregnancies in 93 mothers prescribed an anticoagulant during a pregnancy occurring between January 1, 1998 and March 31, 2005. The majority of patients were treated with UFH (89.3%). Indications for anticoagulation included venous thromboembolism (VTE) prophylaxis (53.4%), history of pregnancy loss (29.1%), acute VTE (16.5%), and history of cerebral vascular accident (CVA) (1.0%). There were no maternal deaths. Fetal demise occurred in 8 pregnancies (7.8%) at a median 14 weeks gestation (range 7-22 weeks). No fetal demise occurred in pregnancies treated for acute VTE or history of CVA. There were two occurrences of pulmonary embolism (1.9%) and two hemorrhagic events requiring transfusion (1.9%). Maternal and fetal adverse events were infrequent in our population of anticoagulated pregnancies. UFH remains a viable option among more expensive LMWH products.


All hands on deck! Guiding rural hospitals takes a team effort.
It takes incredible teamwork to guide a rural hospital in today's challenging environment. Leaders need to be well-informed, innovative, inspiring and compassionate.


Preparation and novel photoluminescence properties of the self-supporting nanoporous InP thin films.
Self-supporting nanoporous InP membranes are prepared by electrochemical etching, and are then first transferred to highly reflective (> 96%) mesoporous GaN (MP-GaN) distributed Bragg reflector (DBR) or quartz substrate. By the modulation of bandgap, the nanoporous InP samples show a strong photoluminescence (PL) peak at 541.2 nm due to the quantum size effect of the nanoporous InP structure. Compared to the nanoporous InP membrane with quartz substrate, the nanoporous membrane transferred to DBR shows a twofold enhancement in PL intensity owing to the high light reflection effect of bottom DBR.


In vitro formation of a complex between cytoskeletal proteins of the human erythrocyte.
The formation of a high-molecular weight complex between spectrin and F-actin depends on the presence of a third cytoskeletal constituent, protein 4.1. Electron microscopy shows that in this ternary complex the actin filaments are linked by bridges, which have the appearance of spectrin. The spectrin must be in the tetrameric state for such bridges to form: the dimer is evidently univalent, for it binds but forms no cross-links. G-actin also fails to form extended complexes. It is inferred that in the native cytoskeleton the spectrin is tetrameric and associated with 4.1 and probably oligomers of actin.


Differential in vitro effects of targeted therapeutics in primary human liver cancer: importance for combined liver cancer.
The incidence of primary liver tumors, hepatocellular carcinoma (HCC), intrahepatic cholangiocellular carcinoma (ICC), and combined HCC/ICC (cHCC/CC) is increasing. For ICC, targeted therapy exists only for a small subpopulation of patients, while for HCC, Sorafenib and Lenvatinib are in use. Diagnosis of cHCC/CC is a great challenge and its incidence is underestimated, bearing the risk of unintended non-treatment of ICC. Here, we investigated effects of targeted inhibitors on human ICC cell lines (HUH28, RBE, SSP25), in comparison to extrahepatic (E)CC lines (EGI1, CCC5, TFK1), and HCC/hepatoblastoma cell lines (HEP3B, HUH7, HEPG2). Cells were challenged with: AKT inhibitor MK-2206; multikinase inhibitors Sorafenib, Lenvatinib and Dasatinib; PI3-kinase inhibitors BKM-120, Wortmannin, LY294002, and CAL-101; and mTOR inhibitor Rapamycin. Dosage of the substances was based on the large number of published data of recent years. Proliferation was analyzed daily for four days. All cell lines were highly responsive to MK-2206. Thereby, MK-2206 reduced expression of phospho(p)-AKT in all ICC, ECC, and HCC lines, which mostly corresponded to reduction of p-mTOR, whereas p-ERK1/2 was upregulated in many cases. Lenvatinib showed inhibitory effects on the two HCC cell lines, but not on HEPG2, ICCs and ECCs. Sorafenib inhibited proliferation of all cells, except the ECC line CCC5. However, at reduced dosage, we observed increased cell numbers in some ICC experiments. Dasatinib was highly effective especially in ICC cell lines. Inhibitory effects were observed with all four PI3-kinase inhibitors. However, cell type-specific differences were also evident here. Rapamycin was most effective in the two HCC cell lines. Our studies show that the nine inhibitors differentially target ICC, ECC, and HCC/hepatoblastoma lines. Caution should be taken with Lenvatinib and Sorafenib administration in patients with cHCC/CC as the drugs may have no effects on, or might even stimulate, ICC.


Outcomes of Venoplasty-Assisted, Peripherally Inserted Central Catheter Placement in Patients with Upper-Arm Venous Stenosis: Comparison with Midlines and Contralateral Placement.
To compare the effectiveness and safety of percutaneous transluminal angioplasty and peripherally inserted central catheter (PTA + PICC), contralateral PICC, and midline catheterization (MC) in patients with venous stenosis. A total of 7,327 PICC procedures were performed in 5,421 patients at a single institution between 2013 and 2019. Among them, 87 patients had upper-arm venous stenoses and were managed with PTA + PICC, contralateral PICC, or MC. Data on catheter-dwell time, clinical success rate, and adverse events were recorded. The procedure was considered to have clinically succeeded when a PICC was removed from the patient just before discharge or after the completion of therapy. Catheter survival time and the chance of adverse events were compared among the groups using the Kaplan-Meier method and log-rank test. PTA + PICC, contralateral PICC, and MC procedures were performed for 57 (65.5%, 57/87), 10 (11.5%, 10/87), and 20 (23.0%, 23/87) patients, respectively. The mean catheter-dwell time in the PTA + PICC, contralateral PICC, and MC groups was 49.7, 28.7, and 15.1 days, respectively, and the clinical success rate of each group was 86.0% (49/57), 80.0% (8/10), and 50.0% (10/20). The PTA + PICC group had a significantly longer catheter survival time than the MC group (P < .001). The chance of a catheter-related infection (P = .008) was significantly lower in the PTA + PICC group than in the MC group. PTA + PICC or contralateral PICC should be considered prior to ipsilateral MC when venous stenosis is encountered during PICC procedures.


Bone-conduction electrocochleography: clinical applications.
Cases are presented which show the clinical utility of recording an electrocochleographic response to bone-conducted stimuli. The procedure is fraught with problems of acoustic control and artifact generation, but has distinct although limited values in clarifying masking dilemmas in patients with bilateral hearing loss.


Epidemiology of schizophrenia: review of findings and myths.
By describing patterns of disease distribution within populations, identifying risk factors, and finding associations, epidemiologic studies have contributed to the current understanding of schizophrenia. Advanced paternal age and the association with autoimmune diseases are some of the newly described epidemiologic findings shaping the current definition of schizophrenia. Although early intervention strategies have gained momentum, primary prevention of schizophrenia still seems a very distant aspiration. This article reviews the major epidemiological features of schizophrenia, with particular attention to the recent advances using population-based data. It also discusses some pervasive misconceptions about schizophrenia epidemiology, such as universal distribution and gender equality.


Effect of Light Intensity under Different Photoperiods on Expression Level of Carbonic Anhydrase Genes of the α- and β-Families in Arabidopsis thaliana Leaves.
Changes in expression levels of genes encoding carbonic anhydrases α-CA1, α-CA2, α-CA4, β-CA1, β-CA2, β-CA3, β-CA4, β-CA5, and β-CA6 in Arabidopsis thaliana leaves after light increase from 80 to 400 µmol PAR quanta·m-2·s-1 were investigated under short day (8 h) and long day (16 h) photoperiods. The expression of two forms of the gene, At3g01500.2 and At3g01500.3, encoding the most abundant carbonic anhydrase of leaves, β-CA1, situated in chloroplast stroma, was found. The content of At3g01500.3 transcripts was higher by approximately an order of magnitude compared to the content of At3g01500.2 transcripts. When plants were adapted to high light intensity under short day photoperiod, the expression level of both forms increased, whereas under long day photoperiod, the content of At3g01500.3 transcripts increased, and the content of transcripts of At3g01500.2 decreased. The expression levels of the At3g01500.3 gene and of genes encoding chloroplast carbonic anhydrases α-CA1, α-CA4, α-CA2 and cytoplasmic carbonic anhydrase β-CA2 increased significantly in response to increase in light intensity under short day, and these of the first three genes increased under long day as well. The expression level of the gene encoding α-CA2 under long day photoperiod as well as of genes of chloroplast β-CA5 and β-CA4 from plasma membranes and mitochondrial β-CA6 under both photoperiods depended insignificantly on light intensity. Hypotheses about the roles in higher plant metabolism of the studied carbonic anhydrases are discussed considering the effects of light intensity on expression levels of the correspondent genes.


Prevalence of human papillomavirus infections among heterosexual men and women with multiple sexual partners.
A prospective study of 65 men and 111 women with multiple heterosexual partners was designed to assess the prevalence and potential risk factors of genital human papillomavirus (HPV) infections. In addition, the HPV reservoir in genital, rectal, and oral mucosa was examined. The specimens for the detection of HPV DNA were taken from different sites such as the urethra and coronal sulcus (men), cervix and labia minora (women), anus, rectum, tongue, and buccal mucosa (both men and women). Women underwent speculum examination and colposcopic evaluation of the anogenital region, and a smear for routine cytological classification was also taken. In men, the anogenital region was examined clinically and colposcopically. The polymerase chain reaction (PCR) was used for the detection of HPV types 6/11, 16, 18, and 33. A high prevalence of HPV infection at one or more sites was detected, in 32% of the male and in 23% of the female participants. Seventeen percent of the male distal urethral specimens were positive for HPV DNA. From the female cervical specimens 14% were found positive. Ten proctal specimens (five men and five women) were positive for HPV DNA without any discernible lesion. The persons from whom these samples were taken denied anal insertive intercourse. No oral manifestation of HPV infection was detected. In both men and women a difference between HPV DNA-positive and -negative persons was not found in relation to known risk factors associated HPV infection.(ABSTRACT TRUNCATED AT 250 WORDS)


Low oxygen concentration improves yak oocyte maturation and inhibits apoptosis through HIF-1 and VEGF.
The gas-phase environment of in vitro culture system plays an important role in the development of oocytes, and oxygen concentration is one of the important factors. In the present study, we aimed to explore the effect of different oxygen concentrations (20%, 10%, 5% or 1% O2 ) in yak oocyte maturation and to detect the expression of hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF) and cell apoptosis in yak COCs. First, the maturation rate of oocytes, cleavage rate and blastocysts rate following parthenogenetic activation in the group with 5% oxygen concentration were significantly higher (p < .05) than the other groups. Then, TUNEL analysis showed that the 5% oxygen concentration group significantly inhibited apoptosis of cumulus-oocyte complexes (COCs) compared to the other group, and the transcription and protein levels of pro-apoptotic factor Bax, HIF-1α and VEGF in yak COCs significantly reduced, while anti-apoptotic factor Bcl-2 significantly increased. Furthermore, immunohistochemical staining results indicated that HIF-1α protein was mainly located in theca follicle interna, mural follicular stratum granulosum, corona radiata and ovarian stroma in the follicular ovarian tissue, while VEGF protein was mainly located in the granulosa and theca cell layers. In summary, our findings demonstrate that 5% oxygen concentration may promote maturation and inhibit apoptosis of oocytes through HIF-1α-mediated VEGF expression.


Overproduction of the membrane-bound components of the histidine permease from Salmonella typhimurium: identification of the M protein.
The periplasmic histidine permease of Salmonella typhimurium is composed of a soluble histidine-binding protein and three membrane-bound components. These latter are produced in very small amounts and only two, the Q and the P protein, have been previously identified. This paper describes the construction of a plasmid carrying the hisQ, hisM, and hisP genes under the control of the lambda PL promoter, thus allowing great overproduction of those gene products. The M protein has been identified in such overproducing strains and its nature confirmed by constructing in vitro hisM deletions within the plasmid. With these results the identification of all components of the histidine permease has been completed.


Pancreatic volume does not correlate with histologic fibrosis in adult patients with recurrent acute and chronic pancreatitis.
Reduced pancreatic volume, often referred to as atrophy, is a commonly reported imaging feature of chronic pancreatitis (CP). This study evaluated whether there is an association between pancreatic volume and fibrosis, the criterion standard of CP, in patients undergoing total pancreatectomy with islet autotransplantation (TPIAT) for recurrent acute pancreatitis (RAP) and CP. All adult patients who underwent TPIAT between 2010 and 2019 were categorized into 3 groups: RAP, definite CP and indeterminate CP. Pancreatic volume was calculated by summing up the areas from each thin section of the pancreas on 3D CT imaging. Excisional biopsies of the pancreatic head as well as body/tail region were obtained at the time of TPIAT. Two different fibrosis scores were used for histologic assessment. A total of 16, 29 and 15 patients underwent TPIAT for RAP, definite CP and indeterminate CP, respectively. The mean pancreatic volumes for patients with RAP, definite CP and indeterminate CP were 65.7 ± 28.5 cc, 54.9 ± 22.9 cc and 61.8 ± 23.6 cc, respectively (p = 0.3). The mean fibrosis scores were significantly higher in patients with definite CP compared to RAP (p < 0.001) and indeterminate CP (p < 0.001). Pancreatic volume was not associated with either fibrosis score after adjusting for age, gender, duration of disease, BMI and diabetes in the multivariable analysis. While the fibrosis scores were higher in definite CP compared to both RAP and indeterminate CP, there was no correlation between pancreatic volume and fibrosis. This suggests that atrophy alone cannot be used to diagnose CP.


Blastocystis surface antigen is stable in chemically preserved stool samples for at least 1 year.
Blastocystis spp. refer to a group of prevalent enteric protists found in humans and animals. Detection of Blastocystis spp. in fecal samples is often performed by clinicians with direct microscopy, which provides low sensitivity, or with culture and polymerase chain reaction testing, a method which is problematic when used with formalin-preserved stool samples. Prior study of Blastocystis and other enteric protists suggests that immunofluorescence antibody (IFA) stain could provide sensitivity and compatibility with formalin, but no information is available on the longevity of Blastocystis sp.'s surface antigens in formalin. We collected fecal samples from animals at a country fair held in the summer of 2009 in Oregon, USA. Samples were tested for the presence of Blastocystis infection using an IFA stain shortly after collection, and again after 1 year, with samples stored refrigerated at 4-8 °C. Most samples collected from steer, pigs, and goats were found to be Blastocystis positive. All fecal samples that were Blastocystis positive initially remained positive after 1 year. Blastocystis-negative samples remained negative. Minimal degradation was observed in stained slides. Blastocystis surface antigens detected by a polyclonal stain remained stable in formalin for a period of at least 1 year.


Predator avoidance by the freshwater snailPhysella virgata in response to the crayfishProcambarus simulans.
We examined predator avoidance behavior of the freshwater snailPhysella (=Physa) virgata in response to the crayfishProcambarus simulans. In both laboratory and field enclosure experiments snails crawled above the waterline for 2 h or longer, then returned to the water.Physella virgata react to chemical signals given off by crayfish actively foraging on conspecific snails; they do not react to inactive crayfish. Low dissolved oxygen, crowding, and disturbance of the sediments did not elicit "crawlout" behavior. Crawling above the waterline, by reducing the probability of encounter between vulnerable, thin-shelled snails and crayfish, is an adaptive response to predation.


Investigation of Doppler waveforms in porcine renal allografts: Doppler-pathologic correlation.
A porcine model was devised to investigate Doppler waveforms in dysfunctional renal allografts. NIH miniature pigs served as allografts donors and recipients. Renal transplantation was effected into the recipient pelvis while the left normotopic kidney was subjected to warm ischemia in order to induce acute tubular necrosis (ATN). Doppler demonstration of allograft arterial occlusion in six animals was confirmed at surgery. Increased pulsatility of intrarenal arterial signals constituted evidence of vascular rejection in two animals. Biopsies confirmed the diagnosis in both cases. Histologic changes of ATN were identified in two native kidneys subjected to ischemia. No waveform or pulsatility alterations were observed in these animals. The porcine model provides for the investigation of allograft Doppler waveforms in a controlled setting with free access to biopsy and operative pathologic correlation.


Prospective assessment of the effectiveness of autonomous emergency braking in car-to-cyclist accidents in France.
Objective: This study aimed to assess the effectiveness of autonomous emergency braking (AEB) systems in car-to-cyclist frontal collisions by simulating their effects, in terms of crash avoidance and injury mitigation, on a representative target population of real-world accidents. Identifying effectiveness-critical AEB-cyclist design parameters through a sensitivity analysis was also targeted.Methods: The analysis is based on a representative set of real-world car-to-cyclist frontal collisions gathered from French police reports. AEB-cyclist-relevant accident cases were first selected and used to build injury risk curves for fatal, severe, and slight cyclist injuries. The effect of AEB-cyclist on these cases was then simulated by means of a car kinematic model involving sensor detection strategies and actuator actions. Combining the resulting simulated impact speed distributions with the injury risk curves allowed to assess AEB-cyclist's effectiveness in terms of lives saved and mitigated injuries. Using design of experiments methods, the sensitivity of this effectiveness with regards to AEB-cyclist design parameters could be assessed.Results: Cyclist injury risks curves were built, along with their confidence intervals, for fatal, severe, and slight injuries using a polytomous complementary log-log regression model, with squared impact speed as an independent variable. A sensitivity analysis on an ideal bisensor AEB-cyclist setting highlighted influential design parameters such as maximal braking intensity or crucial decision algorithm parameters such as maximal time and distance to collision thresholds. AEB-cyclist effectiveness was nevertheless shown to range from 35% to 59% in fatalities, 14% to 54% in severe injuries, and 11% to 42% in slight injuries, depending on field of view parameters alone, once reference values of decision algorithm parameters had been set.Conclusions: This study illustrates the potential benefits and limits of AEB-cyclist systems. High-end systems show acceptable effectiveness rates, but road safety performance strongly depends on external factors such as road surface conditions or has to be tuned in order to avoid unnecessary activations and driver discomfort. Limits of the system's everyday use (lack of maintenance, driver reaction time to collision warnings, etc.) were not taken into account, thus resulting in optimistic evaluations of AEB-cyclist effectiveness.


Serum IgD levels in mice: effect of strain, age and autoimmune disease.
Serum IgD levels were studied in mice. Strain-related variability of serum IgD levels was noted, and advanced age was associated with markedly increased IgD levels in a large percentage of mice from all strains. Strains prone to spontaneously arising autoimmune disease had elevated IgD levels; in NZB mice this was already present very early after birth (one week), whereas in MRL mice the elevated serum IgD levels were first seen somewhat later (3 months). In contrast, mice with collagen type II (CII)-induced autoimmune arthritis had no increase in serum IgD. Injection of the immunomodulating agents LPS and complete Freund's adjuvant (CFA) did not have a significant effect on serum IgD levels, but IL-1 induced a significant decrease in IgD.


Response to neonatal anesthesia: effect of sex on anatomical and behavioral outcome.
Numerous studies have documented the consequences of exposure to anesthesia in models of term and post-term infants, evaluating the incidence of cell loss, physiological alterations and cognitive dysfunction. However, surprisingly few studies have investigated the effect of anesthetic exposure on outcomes in newborn rodents, the developmental equivalent of premature human infants. This is critical given that one out of every eight babies born in the United States is premature, with an increased prevalence of surgical procedures required in these individuals. Also, no studies have investigated if the genetic sex of the individual influences the response to neonatal anesthesia. Using the newborn rat as the developmental equivalent of the premature human, we documented the effect of a single bout of exposure to either the inhalant isoflurane or the injectable barbiturate phenobarbital on hippocampal anatomy, hippocampal dependent behavioral performance and normal developmental endpoints in male and female rats. While both forms of anesthesia led to significant decrements in cognitive abilities, along with a significant reduction in volume and neuron number in the hippocampus in adulthood, the decrements were significantly greater in males than in females. Interestingly, the deleterious effects of anesthesia were manifest on developmental measures including surface righting and forelimb grasp, but were not evident on basic physiological parameters including body weight or suckling. These findings point to the hazardous effects of exposure to anesthesia on the developing CNS and the particular sensitivity of males to deficits.


Brain functional connectivity dynamics at rest in the aftermath of affective and cognitive challenges.
Carry-over effects on brain states have been reported following emotional and cognitive events, persisting even during subsequent rest. Here, we investigated such effects by identifying recurring co-activation patterns (CAPs) in neural networks at rest with functional magnetic resonance imaging (fMRI). We compared carry-over effects on brain-wide CAPs at rest and their modulation after both affective and cognitive challenges. Healthy participants underwent fMRI scanning during emotional induction with negative valence and performed cognitive control tasks, each followed by resting periods. Several CAPs, overlapping with the default-mode (DMN), salience, dorsal attention, and social cognition networks were impacted by both the preceding events (movie or task) and the emotional valence of the experimental contexts (neutral or negative), with differential dynamic fluctuations over time. Temporal metrics of DMN-related CAPs were altered after exposure to negative emotional content (compared to neutral) and predicted changes in subjective affect on self-reported scores. In parallel, duration rates of another attention-related CAP increased with greater task difficulty during the preceding cognitive control condition, specifically in the negative context. These findings provide new insights on the anatomical organization and temporal inertia of functional brain networks, whose expression is differentially shaped by emotional states, presumably mediating adaptive homeostatic processes subsequent to behaviorally challenging events.


A highly facile and selective Chemo-Paper-Sensor (CPS) for detection of strontium.
Chemosensors have attracted increasing attention for their usefulness on-site detection and monitoring. In this study, we elucidated a novel, facile, and highly selective Chemo-Paper-Sensor (CPS) for detection and monitoring of strontium (Sr(2+)) ions, which means a potent colorimetric sensor based on a Chrysoidine G (CG)-coated paper strip. The CPS for highly selective colorimetric detection of strontium ion was handily analyzed to determine the red-green-blue (RGB) value using portable devices such as desktop digital scanner and mobile phone camera, quantitatively. Interestingly, an orange to dark orange color transition was observed when the aqueous and solid paper colorimetric sensor was introduced to Sr(2+) ion, respectively. It was demonstrated that the value of the signal has a linear relationship with concentrations of the strontium in the 500 ppm to 100 ppb range with a detection limit of 200 ppb. We believe that a newly developed Chemo-Paper-Sensor will be useful in a wide range of sensing applications.


Can Straw Phonation Be Considered As Vocal Warm Up Among Speech Language Pathologists?
Straw phonation exercises have been proved to be effective in improving voice quality among persons with voice pathology. The aim of the study was to investigate the effects of straw phonation as a warm-up exercise on maximum phonation duration, acoustic, and perceptual parameters of voice among Speech Language Pathologists. The study adopted a pretest-posttest design. Twenty-five females with the mean age range of 20.87 ± 1.15 years participated in the study and completed a series of straw phonation exercises for three cycles. Maximum phonation duration, acoustic, and self-perceptual measures were assessed before and after the straw phonation exercises. F0, jitter, shimmer, nose to harmonic ratio, intensity, F1, F2, F3, F4, Maximum phonation duration, and the post self-perceptual measures were analyzed. The results indicated a significant improvement in the F0, intensity, F1, F2, F4, Maximum phonation duration, and self-perceptual measures. Straw phonation exercises provides an easy and effective warm up technique to improve the voice quality among Speech Language Pathologists and can be considered before conducting therapy sessions.


Fusion between myogenic cells in vivo: an ultrastructural study in regenerating murine skeletal muscle.
Fusion of myogenic cells in adult murine skeletal muscle regenerating in vivo was examined at the ultrastructural level. Fusion of myoblast to myoblast, myoblast to myotube, and myotube to myotube was observed by 4 to 5 days after injury. Fusion between myogenic cells (myoblasts or myotubes) lacking a definitive glycocalyx or external lamina (basal lamina) occurred at multiple sites. It was defined by zones of cytoplasmic confluence between apposed cells at sites where contiguous segments of the cell membranes were interrupted while their edges had united resulting in linear continuity; vesicles of varying dimensions were frequent in these areas of fusion. Myoblasts were seen invaginating the surface of myofibres and again vesicles were seen in abundance in such regions. Cilia were often observed at this junctional zone suggesting that they might play a role in fusion. In the one example of probable fusion between a myotube and a myofibre, only a single area of cytoplasmic continuity was apparent.


Comparing Laparoscopic to Endoscopic Resections for Early Gastric Cancer in a High Volume North American Center.
Endoscopic submucosal dissection as an organ sparing option for early gastric cancer is becoming increasingly accepted as an alternative to laparoscopic gastrectomy. Given the very limited North American data, we sought to compare outcomes between endoscopic and laparoscopic resection of gastric malignant and premalignant tumors. Patients undergoing laparoscopic gastrectomy or endoscopic submucosal dissection from 2007 to 2014 for adenocarcinoma or dysplasia at the McGill University Health Center were identified from a prospectively collected database and dichotomized according to the surgical approach. Patient demographics, tumor characteristics, stage, oncologic outcome, length of stay, and postoperative complications were recorded. Of 155 patients with gastric cancer identified, 67 were treated by laparoscopic gastrectomy (n = 37) or endoscopic submucosal dissection (ESD) (n = 30). There were significantly more invasive lesions in the laparoscopic group and patients subject to ESD harbored more T1 lesions. No significant difference in the rate of R0 resection or overall complications was observed between the groups. Accordingly, length of stay was significantly shorter in the ESD group. There were no significant differences in terms of overall and disease-free survival. In selected patients, ESD is associated with improved short-term outcomes and provides an appropriate oncologic resection option in a North American patient cohort.


MR-safety in clinical practice at 7T: Evaluation of a multistep screening process in 1819 subjects.
MR facilities must implement and maintain adequate screening and safety procedures to ensure safety during MR examinations. The aim of this study was to evaluate a multi-step MR safety screening process used at a 7T facility regarding incidence of different types of safety risks detected during the safety procedure. Subjects scheduled for an MR examination and having entered the 7T facility during 2016-2019 underwent a pre-defined multi-step MR safety screening process. Screening documentation of 1819 included subjects was reviewed, and risks identified during the different screening steps were compiled. These data were also related to documented decisions made by a 7T MR safety committee and reported MR safety incidents. Passive or active implants (n = 315) were identified in a screening form and/or an additional documented interview in 305 subjects. Additional information not previously self-reported by the subject, regarding implants necessitating safety decisions performed by the staff was revealed in the documented interview in 102 subjects (106 items). In total, the 7T MR safety committee documented a decision in 36 (2%) of the included subjects. All of these subjects were finally cleared for scanning. A multi-step screening process allows a thorough MR screening of subjects, avoiding safety incidents. Different steps in the process allow awareness to rise and items to be detected that were missed in earlier steps. Safety questions posed at a single timepoint during an MR screening process might not reveal all safety risks. Repetition and rephrasing of screening questions leads to increased detection of safety risks. This could be effectively mitigated by a multi-step screening process. A multi-disciplinary safety committee is efficient at short notice responding to unexpected safety issues.


Effective use of rabbit gastric antral mucosal slices in prostaglandin synthesis and metabolism studies.
Intact slice preparations of rabbit stomach (antral mucosa, corporal mucosa, antral muscle and corporal muscle) were incubated and the released prostaglandins (PGs) were measured by reverse-phase high-performance liquid chromatography using 9-anthryldiazomethane for derivatization. With respect to total PG production, the highest amounts were generated by antral mucosal slices. Antral mucosal slices produced PGE2, 6-keto PGF1 alpha, thromboxane B2, PGF2 alpha and PGD2 (in descending order of magnitude) and possessed a high capacity for producing 13,14-dihydro-15-keto derivatives of both PGE2 and PGF2 alpha. Studies utilizing aspirin, EGTA or Ca2+ revealed that PG release by antral mucosal slices in the present in vitro system reflects a composite of the activities of phospholipase A3, PG cyclooxygenase and PG-metabolizing enzymes. These results show that antral mucosal slices will be useful in physiological and pharmacological studies on PG synthesis and metabolism of the stomach.


Changes in Hypothesized Mechanisms of Change Before and After Initiating Abstinence in Cognitive-Behavioral Therapy for Women With Alcohol Use Disorder.
Abstinence self-efficacy, coping skills, and therapeutic alliance are hypothesized mechanisms of behavioral change (MOBCs) in cognitive-behavioral therapy (CBT) for alcohol use disorder (AUD). However, little is known about when these hypothesized MOBCs change during treatment or in relation to the initiation of abstinence from alcohol, which the current study investigated. Patient-reported abstinence self-efficacy, drinking-related coping skills, and therapeutic alliance were measured at every session throughout a 12-session clinical trial that previously showed equivalent drinking reductions in female-specific individual- and group-based CBT for AUD. Participants (N = 121 women) were classified into subgroups based on whether and when they first initiated 14 days of continuous abstinence from alcohol during treatment. Interrupted time-series analyses evaluated the magnitude and timing of change in MOBC variables in relation to the initiation of abstinence. All three MOBC measures showed gradual improvements throughout treatment (within-subjects d = 0.03 to 0.09 change per week). Participants who initiated abstinence during treatment experienced additional sudden improvements in abstinence self-efficacy (d = 0.47) and coping skills (d = 0.27), but not therapeutic alliance (d = -0.02), the same week they initiated abstinence. Participants who were already abstinent when treatment started maintained higher abstinence self-efficacy and coping skills, but not therapeutic alliance, throughout treatment compared to participants who never initiated abstinence. Initiating abstinence may help facilitate improvements in abstinence self-efficacy and drinking-related coping skills. Clinicians may help patients anticipate when and how much these variables are expected to improve during treatment and encourage initiation of abstinence to potentially help facilitate improvements in abstinence self-efficacy and coping skills.


Normoxic and anoxic heat output of the freshwater bivalves Pisidium and Sphaerium : I. Rhythms of spontaneous quiescence and behaviour.
In fasting Pisidium amnicum and Sphaerium corneum, regular periods of behavioural and metabolic quiescence were shown to occur in the normoxic, constant environment of the flow-through chamber of a heat-flow microcalorimeter. The metabolic rate was suppressed to 7.5% of normal at 10° C and to 8.5-9.7% at 20° C for periods exceeding the period of active metabolism by a factor of 3.5 at 10° C and 8.3 at 20° C. The rate of heat output during normoxic quiescence was equal to that during environmental anoxia, suggesting spontaneous achievement of body anoxia by complete shell closure. The mass-specific integrated heat output during closure periods was independent of size. Parallel observations on clam behaviour suggested that metabolic quiescence coincided with shell closure, and bursts of heat flow with active ventilation. Shell closure was accompanied by pronounced bradycardia, down to 20% of the active rate. In a constant environment, the rhythmic quiescence is regulated by shell closure which is probably triggered by lack of food. Regular quiescence of fasting bivalves may conserve energy reserves considerably, the amount depending on the possible excretion rate of the end products, and the post-quiescence recovery costs, which were not measured. Heat output during the active period was close to the average metabolic rate found earlier for Sphaeriidae. However, all the values determined so far are likely to be underestimates of the natural metabolism because the effects of digestion and growth are not included.


Inherited disorders of calcium homeostasis.
In mammals a complicated homeostatic mechanism has evolved to maintain near consistency of extracellular calcium ion levels. The homeostatic mechanism involves several hormones, which comprise among others, parathyroid hormone and vitamin D. The recent resurge in vitamin D deficiency, as a global health issue, has increased interest in the hormone. In addition to vitamin D deficiency, other causes of rickets are calcium deficiency and inherited disorders of vitamin D and phosphorus metabolism. Vitamin D-resistant syndromes are caused by hereditary defects in metabolic activation of the hormone or by mutations in the vitamin D receptor, which binds the hormone with high affinity and regulates the expression of genes through zinc finger mediated DNA binding and protein-protein interaction. Current interest is to correlate the type/position of mutations that result in disorders of vitamin D metabolism or in vitamin D receptor function with the variable phenotypic features and clinical presentation. The calcium sensing receptor plays a key role in calcium homeostasis. Loss of function mutations in the calcium sensing receptor can cause familial benign hypocalciuric hypercalcemia in heterozygotes and neonatal severe hyperparathyroidism when homozygous mutations occur in the calcium sensing receptor. Gain of function mutation can cause the opposite effect causing autosomal dominant hypocalcemia. Mouse models using targeted gene disruption strategies have been valuable tools to study the effect of mutations on the calcium sensing receptor or in the vitamin D activation pathway. Dysfunctional calcium sensing receptors with function altering mutations may be responsive to treatment with allosteric modulators of the calcium sensing receptor. Vitamin D analogs which induce unusual structural conformations on the vitamin D receptor may have a variety of therapeutic indications. This review summarises recent advances in knowledge of the molecular pathology of inherited disorders of calcium homeostasis.


Increased suicide attempt rate among patients interrupting use of atypical antipsychotics.
The aim of the study is to investigate whether patients at risk to commit suicide could be identified based on their drug refill patterns. Data for this study were obtained from the PHARMO system comprising drug-dispensing data linked to hospital discharge records. All patients aged 15-45 years, suspected to suffer from schizophrenia and exclusive users of olanzapine or risperidone were selected. The use of antipsychotics was converted into treatment episodes of uninterrupted use. Therapy non-compliance was defined as a drug holiday of at least 30 days. The follow-up started with a treatment episode of at least 90 days. Relative risks for suicide attempts and 95% confidence limits due to drug holidays were estimated using Poisson regression analyses. Of 603 patients, 33% interrupted treatment for at least 30 days. An increased suicide attempt rate was observed when comparing uninterrupted and interrupted drug use (20.0/1000 person years vs 72.1/1000 person years, respectively). A four-fold increased risk for attempting suicide among patients with drug holidays was found (RR adjusted for age and gender 4.2, 95% CI: 1.7-10.1) compared to patients without drug holidays. Patients who do not refill atypical antipsychotics in time can be identified in the pharmacy and are most likely those with an increased risk to commit suicide.


Effect of heart ischemia and administration route on biodistribution and transduction efficiency of AAV9 vectors.
Adeno-associated viruses (AAV) have become one of the most promising tools for gene transfer in clinics. Among all the serotypes, AAV9 has been described as the most efficient for cardiac transduction. In order to achieve optimal therapeutic delivery in heart disease, we have explored AAV9 transduction efficiency in an infarcted heart using different routes of administration and promoters, including a cardiac-specific one. AAV9 vectors carrying luciferase or green fluorescence protein under the control of the ubiquitous elongation-factor-1-alpha or the cardiac-specific troponin-T (TnT) promoters were administered by intramyocardial or intravenous injection, either in healthy or myocardial-infarcted mice. The transduction efficacy and specificity, the time-course expression, and the safety of each vector were tested. High transgene expression levels were found in the heart, but not in the liver, of mice receiving AAV-TnT, which was significantly higher after intramyocardial injection regardless of ischemia-induction. On the contrary, high hepatic transgene expression levels were detected with the elongation-factor-1-alpha-promoter, independently of the administration route and heart damage. Moreover, tissue-specific green fluorescence protein expression was found in cardiomyocytes with the TnT vector, whereas minimal cardiac expression was detected with the ubiquitous one. Interestingly, we found that myocardial infarction greatly increased the transcriptional activity of AAV genomes. Our findings show that the use of cardiac promoters allows for specific and stable cardiac gene expression, which is optimal and robust when intramyocardially injected. Furthermore, our data indicate that the pathological status of the tissue can alter the transcriptional activity of AAV genomes, an aspect that should be carefully evaluated for clinical applications.


The 9p21.3 risk of childhood acute lymphoblastic leukaemia is explained by a rare high-impact variant in CDKN2A.
Genome-wide association studies (GWAS) have provided strong evidence for inherited predisposition to childhood acute lymphoblastic leukaemia (ALL) identifying a number of risk loci. We have previously shown common SNPs at 9p21.3 influence ALL risk. These SNP associations are generally not themselves candidates for causality, but simply act as markers for functional variants. By means of imputation of GWAS data and subsequent validation SNP genotyping totalling 2,177 ALL cases and 8,240 controls, we have shown that the 9p21.3 association can be ascribed to the rare high-impact CDKN2A p.Ala148Thr variant (rs3731249; Odds ratio = 2.42, P = 3.45 × 10(-19)). The association between rs3731249 genotype and risk was not specific to particular subtype of B-cell ALL. The rs3731249 variant is associated with predominant nuclear localisation of the CDKN2A transcript suggesting the functional effect of p.Ala148Thr on ALL risk may be through compromised ability to inhibit cyclin D within the cytoplasm.


Cancer modeling in the modern era: progress and challenges.
Genetically engineered mouse models have contributed extensively to the field of cancer research. The ability to manipulate the mouse germline affords numerous approaches toward understanding the complexities of this disease, possibly providing accurate preclinical models for therapeutic and diagnostic advances. This review highlights some of the current strategies for modeling cancer in the mouse, recent accomplishments, and key remaining challenges.


Honeycomb-like structure in spontaneous recanalized coronary thrombus demonstrated by serial angiograms: a case report.
The honeycomb-like structure (HLS) is a rare cause of myocardial ischaemia characterized by multiple communicating channels divided by thin septa. The aetiology of this specific structure remains speculative. A 55-year-old man was admitted due to worsening effort angina during the previous 2 months. Diagnostic coronary angiography revealed occlusion of the distal right coronary artery (RCA) with good collateral flow from the left coronary artery. We considered this lesion as a recent total occlusion, and planned a percutaneous coronary intervention (PCI). At the time of PCI, 7 days after admission, an angiogram showed a spontaneous recanalization of the occlusive RCA. Intravascular ultrasound (IVUS) depicted a HLS at the recanalized lesion, including atherosclerotic stenosis. We managed these lesions with drug-eluting stents. A recanalized thrombus may manifest as a HLS. In this case, the patient suffered from worsening effort angina during the previous 2 months, we confirmed a spontaneous recanalization of the occluded coronary lesion by serial angiographic images, and observed HLS adjacent to the atherosclerotic attenuated plaque by using high-resolution IVUS. Recanalized organizing thrombus is considered an entity of HLS. However, all previous studies on the HLS in vivo have detected the structure in an already recanalized state. Therefore, the aetiology remained speculative and evidence has been indirect. This present case demonstrates that recanalized atherosclerotic thrombosis might be one of the causes of HLS.


Substance P: depletion in the dorsal horn of rat spinal cord after section of the peripheral processes of primary sensory neurons.
The substance P content, glutamic acid decarboxylase and choline acetyltransferase activities and the level of [3H]diprenorphine binding were measured in various regions of the lumbar spinal cord of rats after unilateral section of the sciatic nerve or after dorsal rhizotomy. Sciatic nerve section produced a 75--80% depletion of substance P in the dorsal horn but did not change the substance P content of the ventral horn. The onset of substance P depletion occurred within 7 days and was maintained for 2 months. The substance P content of the dorsal root ganglia and both the peripheral and central branches of primary sensory neurons was also reduced after sciatic nerve section. Glutamic acid decarboxylase and choline acetyltransferase activity were unchanged; however, a small decrease in opiate receptor binding occurred 1 month after nerve section. Dorsal rhizotomy produced an 80% depletion of substance P in the dorsal horn. In addition, the substance P content of the ventral horn was significantly reduced. Glutamic acid decarboxylase activity in the dorsal horn was unaffected by dorsal rhizotomy whereas opiate receptor binding was reduced by 40%. From these studies it appears that peripheral nerve injury results in the degeneration of primary sensory neurons which contain and release substance P as neurotransmitter.


The satiety signaling neuropeptide perisulfakinin inhibits the activity of central neurons promoting general activity.
The metabolic state is one of the determinants of the general activity level. Satiety is related to resting or sleep whereas hunger correlates to wakefulness and activity. The counterpart to the mammalian satiety signal cholecystokinin (CCK) in insects are the sulfakinins. The aim of this study was to resolve the mechanism by which the antifeedant activity of perisulfakinin (PSK) in Periplaneta americana is mediated. We identified the sources of PSK which is used both as hormone and as paracrine messenger. PSK is found in the neurohemal organ of the brain and in nerve endings throughout the central nervous system. To correlate the distributions of PSK and its receptor (PSKR), we cloned the gene coding for PSKR and provide evidence for its expression within the nervous system. It occurs only in a few neurons, among them are the dorsal unpaired median (DUM) neurons which release octopamine thereby regulating the general level of activity. Application of PSK to DUM neurons attenuated the spiking frequency (EC(50)=11pM) due to reduction of a pacemaker Ca(2+) current through cAMP-inhibited pTRPgamma channels. PSK increased the intracellular cAMP level while decreasing the intracellular Ca(2+) concentration in DUM neurons. Thus, the satiety signal conferred by PSK acts antagonistically to the hunger signal, provided by the adipokinetic hormone (AKH): PSK depresses the electrical activity of DUM neurons by inhibiting the pTRPgamma channel that is activated by AKH under conditions of food shortage.