Predictors for restenosis after angioplasty of chronic coronary occlusions.
The Stenting In Chronic Coronary Occlusion (SICCO) study assessed the effects of additional intracoronary stenting (Palmaz-Schatz) after successful percutaneous transluminal coronary angioplasty (PTCA) of chronic coronary occlusions and showed a significant reduction of restenosis in stented patients. Univariate and logistic regression analyses were used to assess clinical, angiographic and procedure related predictors for restenosis (>50% diameter stenosis at follow-up) and Major Adverse Clinical Events (MACE=cardiac death, lesion-related acute myocardial infarction, repeat lesion-related angioplasty, bypass surgery involving the treated segment or angiographic documentation of reocclusion in non-revascularized patients) in the 114 SICCO patients with an angiographic end-point and 300 days clinical follow-up. By 6 months the restenosis rate was 53%, and after 300 days MACE had occurred in 39%. Both the rates of restenosis and MACE was significantly reduced by stenting. The restenosis rate was improved by stenting also in patients with a 'stentlike' result after the initial PTCA. In the multivariate model the risk of restenosis was increased by a history of unstable angina, a long lesion and a non-tapering occlusion stump. LAD location was associated with a threefold increased risk of MACE. Stent implantation should always be considered in successfully opened chronic occlusions.


Low serum levels of 25-hydroxyvitamin D (25-OHD) in children with autism.
To confirm previous evidence suggesting an association between autism and low vitamin D serum levels. This preliminary exploratory study assessed the circulating levels of 25-hydroxyvitamin D (25-OHD) in pediatric patients with autism and in typically developing controls from Juiz de Fora, Brazil. Serum levels of 25-OHD were lower in children with autism (26.48 ± 3.48 ng mL-1) when compared to typically developing subjects (40.52 ± 3.13 ng mL-1) (p < 0.001). Our findings attest to the importance of vitamin supplementation during pregnancy and in the treatment of children with autism, who tend to present low vitamin D consumption rates.


Which outcome measures are reported by clinical trials investigating OME treatment? A case for standardised reporting.
Many different OME treatment trials have been published using different outcomes measures to evaluate the success of particular interventions. We set out to identify the variation in reporting of outcome measures in OME trials that exists at present. This has been achieved by reviewing published trials to determine which outcome measures have been reported. The literature review was carried out using PUBMED database (1980 to 2013). Data were collected on the treatment outcomes reported, with particular focus on the methods of assessment and the number of treatment outcomes used in each study. The 171 studies identified used 12 broad treatment outcome measures. The most common outcome measure was OME resolution (48%) followed by hearing level (36%). Only 95 studies used a single outcome measure, with 76 studies using between 2 and 4 outcome measures. The method of assessment varied between studies that used the same treatment outcome measures. OME treatment trials report a wide range of measures and comparison across studies is thus difficult. Establishing a core set of outcome measures to be reported by all trials in the future could be useful, and would allow comprehensive comparison of different studies and minimise potential for reporting bias.


The HY2 gene as an efficient marker for transposon excision in Arabidopsis.
Transposable elements can generate germinal and somatic mutations, and hence represent a powerful tool for the analysis of gene function. Transposons from maize have been adapted to mutagenise the genomes of diverse species. The efficiency of these systems partly relies on the ease with which germinal (i.e. germinally transmitted) or somatic excisions can be detected. Here we describe the use of HY2, a gene that codes for an enzyme involved in the biosynthesis of the phytochrome chromophore, to monitor the excision of a Ds gene-trap element in Arabidopsis thaliana. Taking advantage of the altered germination and de-etiolation behaviour of a Ds -tagged hy2 mutant, we have designed an efficient protocol for the recovery of germinal revertants, making HY2 the most precocious excision marker available, to the best of our knowledge. In addition, HY2 is also useful for generating visible sectors in photosynthetic tissues, thanks to the somatic instability of this mutable hy2 allele.


Blocking anti-Trichinella spiralis antibodies in chronically infected rats.
Specific anti-newborn larva antibodies present in the serum of rats chronically infected with Trichinella spiralis were incapable of inducing killing of newborn larvae by activation of normal peritoneal cells. These late antibodies blocked the cytotoxic reaction induced by early antibodies produced a few weeks after infection. Passive transference of late serum to normal mice failed to induce protective immunity against infection by newborn T. spiralis larvae. When late immunoserum was fractionated by gel filtration, blocking activity was found only in the fraction containing IgG subclasses. By indirect immunofluorescence assay and cytotoxic reaction it was shown that blocking antibodies were specific for newborn larvae and could not be adsorbed with muscle larvae. It is concluded that the synthesis of anti-newborn larva antibodies is modulated in the course of a chronic infection: early antibodies developing shortly after infection are cytotoxic, whereas blocking antibodies predominate in the late population. Furthermore, the results suggest that during a chronic infection, resistance to reinfection may be modified.


Polypropylene pellets as an inexpensive reusable substitute for milk in the Morris milk maze.
A new inexpensive opaquing agent for the Morris milk maze is described. Small light-weight polypropylene pellets that float on the surface of the water were used to eliminate visual cues about the location of the hidden platform without impeding swimming or the use of distal spatial cues. Results obtained using the pellets are identical to those obtained with milk powder as an opaquing agent. An automatic tracking system works as well with the pellet as with the milk version of the maze.


A new method for inducing fatal, IgE-mediated, bronchial and cardiovascular anaphylaxis in the rat.
Brown-Norway rats, sensitized with trinitrophenyl (TNP) haptenized ovalbumin and AIPO4 as adjuvant 12 days before, were challenged with trinitrophenyl haptenized bovine serum albumin intravenously, while lung function (Vt, V, Ppl, Fres, Cdyn, and Rl) and cardiovascular function (BP and Fheart) were measured continuously. This resulted in a highly reproducible, plasma IgE-antiTNP related, immediate anaphylactic response characterized by a short-lasting (8-10 min) bronchoconstriction, together with a long-lasting fall in blood pressure. All rats died in shock within 21-150 min. This method is simple and appeared to be highly reproducible and therefore suitable to screen or study antiallergic drugs in vivo.


Safety and efficacy of hyperthermic intraperitoneal chemoperfusion with high-dose oxaliplatin in patients with peritoneal carcinomatosis.
Cytoreduction with hyperthermic intraperitoneal chemoperfusion (HIPEC) has an established role in selected patients with peritoneal carcinomatosis (PC). We analyzed the safety and efficacy of HIPEC using high-dose oxaliplatin, a cytotoxic agent commonly used in metastatic colorectal cancer and showing promising activity in ovarian cancer and mesothelioma. Following complete cytoreduction, HIPEC was performed using 460 mg/m(2 )oxaliplatin in 5% dextrose for 30 min at a temperature of 41-42 degrees C. Open perfusion (coliseum technique) was performed in all patients. Metabolic, electrolyte, and hemodynamic changes were recorded during chemoperfusion as well as postoperative morbidity, mortality, late toxicity, and survival. From July 2005 to January 2007, 52 patients were treated. Chemoperfusion with 5% dextrose resulted in temporary significant hyperglycemia, hyponatremia, and metabolic acidosis. Major morbidity developed in 24% of patients, while 30-day mortality did not occur. One patient developed unexplained repeated episodes of hemoperitoneum. Chemoperfusion with oxaliplatin resulted in mild hepatic toxicity evidenced by persistent elevation of glutamyl transferase and alkaline phosphatase 1 month after surgery. After a mean follow-up time of 14.5 months, nine patients died from disease progression. In colorectal cancer patients, actuarial overall survival was 80% at 1 year. Cytoreduction with HIPEC using high-dose oxaliplatin leads to manageable metabolic and electrolyte disturbances and frequent mild hepatic toxicity without discernible impact on postoperative morbidity. Longer follow-up in a larger patient cohort will be required to assess the real risk of unexplained hemoperitoneum observed in one patient, and to establish the long-term effect on local relapse and survival.


Effect of xylene, toluene and methyl alcohol on liver collagenesis in rats.
Among the three important industrial solvents used, maximum stimulation of collagen formation in rat liver was caused by methyl alcohol followed by toluene and xylene. A combined treatment also promoted collagenesis suggesting a synergistic effect of these solvents.


Crowd and environmental management during mass gatherings.
Crowds are a feature of large cities, occurring not only at mass gatherings but also at routine events such as the journey to work. To address extreme crowding, various computer models for crowd movement have been developed in the past decade, and we review these and show how they can be used to identify health and safety issues. State-of-the-art models that simulate the spread of epidemics operate on a population level, but the collection of fine-scale data might enable the development of models for epidemics that operate on a microscopic scale, similar to models for crowd movement. We provide an example of such simulations, showing how an individual-based crowd model can mirror aggregate susceptible-infected-recovered models that have been the main models for epidemics so far.


Use of rivaroxaban attenuates renal function impairment in patients with atrial fibrillation: insights of the EMIR study.
In atrial fibrillation (AF) patients on vitamin K antagonists, a progressive deterioration of renal function is common but there is limited evidence with long-term use of rivaroxaban. Herein, we investigated the change in renal function in AF patients after 2 years of rivaroxaban treatment. The EMIR registry is an observational and multicentre study including AF patients treated with rivaroxaban for at least 6 months prior to inclusion. Changes in analytical parameters were recorded during 2 years of follow-up. Renal function was estimated using the Cockroft-Gault equation. 1433 patients (638, 44.5% women, mean age of 74.2 ± 9.7 years) were included. Creatinine clearance (CrCl) was available at baseline and at 2 years in 1085 patients. At inclusion, 33.2% of patients had impaired renal function (CrCl <60 ml/min). At 2 years, we were not able to find changes in the proportion of patients with impaired renal function, which increased to 34.6% (p = 0.290). However, the baseline mean CrCl was 76.0 ± 30.5 ml/min and slightly improved at 2 years (77.0 ± 31.8 ml/min; p = 0.014). Overall, the proportion of patients with CrCl <60 ml/min at baseline that had CrCl ≥60 ml/min at 2 years was significantly higher compared to that of patients with CrCl ≥60 ml/min at baseline and CrCl <60 ml/min after (22.2% vs. 13.1%; p < 0.001) CONCLUSIONS: In AF patients on long-term rivaroxaban therapy, a decrease in renal function was not observed. We even observed a slight improvement in the patients with renal impairment. These results reinforce the idea that rivaroxaban may be a safe option even in patients with renal impairment.


Silver stains and immunocytochemical analysis with monoclonal serotonin antibodies for liver metastases of endocrine tumors. A study on percutaneous biopsy specimens.
With the aid of ultrasonography, representative percutaneous biopsy specimens were obtained from 20 of 21 patients (95 percent) with liver metastases of carcinoids and endocrine pancreatic tumors. The specimens were examined with silver stains and immunocytochemically after the application of monoclonal serotonin antibodies. The Grimelius argyrophil silver nitrate stain was positive in all tumor metastases, demonstrating that they were of neurohormonal endocrine type. The argentaffin reaction stained 14 of 15 metastases of small intestinal carcinoids, whereas tumors with other primary sites were unreactive. Immunocytochemical analysis with monoclonal serotonin antibodies stained all metastases of small intestinal carcinoids, and the other endocrine tumor metastases were unreactive. With immunocytochemical analysis, optimal results were obtained in Bouin-fixed tumor specimens, whereas for the argentaffin reaction, formalin was preferable. The results show that silver stains and immunocytochemical analysis with monoclonal serotonin antibodies on small percutaneous biopsy specimens of liver metastases of endocrine tumors and carcinoids are valid for the prediction of the location of the primary tumors.


Detrusorrhaphy: extravesical ureteral advancement to correct vesicoureteral reflux in children.
We used a modified extravesical technique, coined detrusorrhaphy, to correct surgically vesicoureteral reflux. By detrusorrhaphy the submucosal ureteral tunnel is opened, the ureteral meatus is advanced and anchored onto the trigone, and the detrusor buttress of the ureter is closed (-rrhaphy). The operation is performed extravesically. The procedure was used in the last 5 years in 79 children, or 120 renal units. Reflux resolved in 93 per cent of the renal units. Postoperative morbidity related to bladder spasms and hematuria was minimal compared to conventional transvesical surgical procedures. Detrusorrhaphy is an effective method to correct vesicoureteral reflux and to minimize postoperative morbidity.


Plantmediated horizontal transmission of Wolbachia between whiteflies.
Maternal transmission is the main transmission pathway of facultative bacterial endosymbionts, but phylogenetically distant insect hosts harbor closely related endosymbionts, suggesting that horizontal transmission occurs in nature. Here we report the first case of plant-mediated horizontal transmission of Wolbachia between infected and uninfected Bemisia tabaci AsiaII7 whiteflies. After infected whiteflies fed on cotton leaves, Wolbachia was visualized, both in the phloem vessels and in some novel 'reservoir' spherules along the phloem by fluorescence in situ hybridization using Wolbachia-specific 16S rRNA probes and transmission electron microscopy. Wolbachia persisted in the plant leaves for at least 50 days. When the Wolbachia-free whiteflies fed on the infected plant leaves, the majority of them became infected with the symbiont and vertically transmitted it to their progeny. Multilocus sequence typing and sequencing of the wsp (Wolbachia surface protein) gene confirmed that the sequence type of Wolbachia in the donor whiteflies, cotton phloem and the recipient whiteflies are all identical (sequence type 388). These results were replicated using cowpea and cucumber plants, suggesting that horizontal transmission is also possible through other plant species. Our findings may help explain why Wolbachia bacteria are so abundant in arthropods, and suggest that in some species, Wolbachia may be maintained in populations by horizontal transmission.


Protective effect of baicalin on the small intestine in rats with food allergy.
The therapeutic effect of baicalin and its mechanism were explored. A total of 30 Sprague Dawley (SD) rats were randomly divided into 3 groups of 10: ovalbumin group (OVA group), baicalin intervention group (HQ group), and saline-group (NC group). Serum OVA-IgE antibody levels were detected by enzyme-linked immunosorbent assay (ELISA); and diarrhea in rats was observed. Animals were sacrificed at week seven. Then, a 5-cm long duodenum beneath the Treitz ligament was collected from each rat, and was fixed, embedded, sliced and stained with toluidine blue to evaluate the integrity of mast cells. Next, pathological changes of the intestine were observed by hematoxylin and eosin (H&E) staining, and the ultrastructure of the intestinal mucosa was observed under a transmission electron microscope. Serum OVA-sIgE level were significantly lower (at sixth week, OVA group: 12.86±1.35, HQ group: 3.47±0.51, F=117.05, P<0.01), the number of eosinophils significantly decreased (HQ group: 2.73±1.02, OVA group: 16.48±2.32, P<0.01), mast cell integrated rate was significantly increased (HQ group: 89.90±4.43, OVA group: 35.30±9.78, P<0.01) uniform small intestinal villi were observed, the organelles were basically normal, and lesions were significantly fewer in the HQ group, compared with the OVA group. Baicalin can effectively reduce serum OVA-sIgE in rats with food allergy, increase mast cell integrated rate and alleviate intestinal pathological changes. Hence, baicalin has a good therapeutic effect on food allergy.


PET imaging of PARP expression using 68Ga-labelled inhibitors.
Imaging the PARP expression using 18F probes has been approved in clinical trials. Nevertheless, hepatobiliary clearance of both 18F probes hindered their application in monitoring abdominal lesions. Our novel 68Ga-labelled probes aim for fewer abdominal signals while ensuring PARP targeting by optimizing the pharmacokinetic properties of radioactive probes. Three radioactive probes targeted PARP were designed, synthesized, and evaluated based on the PARP inhibitor Olaparib. These 68Ga-labelled radiotracers were assessed in vitro and in vivo. Precursors that did not lose binding affinity for PARP were designed, synthesized, and then labelled with 68Ga in high radiochemical purity (> 97%). The 68Ga-labelled radiotracers were stable. Due to the increased expression of PARP-1 in SK-OV-3 cells, the uptake of the three radiotracers by SK-OV-3 cells was significantly greater than that by A549 cells. PET/CT imaging of the SK-OV-3 models indicated that the tumor uptake of 68Ga-DOTA-Olaparib (0.5 h: 2.83 ± 0.55%ID/g; 1 h: 2.37 ± 0.64%ID/g) was significantly higher than that of the other 68Ga-labelled radiotracers. There was a significant difference in the T/M (tumor-to-muscle) ratios between the unblocked and blocked groups as calculated from the PET/CT images (4.07 ± 1.01 vs. 1.79 ± 0.45, P = 0.0238 < 0.05). Tumor autoradiography revealed high accumulation in tumor tissues, further confirming the above data. PARP-1 expression in the tumor was confirmed by immunochemistry. As the first 68Ga-labelled PARP inhibitor, 68Ga-DOTA-Olaparib displayed high stability and quick PARP imaging in a tumor model. This compound is thus a promising imaging agent that can be used in a personalized PARP inhibitor treatment regimen.


The sum of many small changes: microRNAs are specifically and potentially globally altered by vitamin D3 metabolites.
Vitamin D3 deficiency is rampant which may contribute to increased risk of many diseases including cancer, cardiovascular disease and autoimmune disorders. Genomic activity of the active metabolite 1,25-dihydroxyvitamin D (1,25D) mediates most vitamin D3's actions and many gene targets of 1,25D have been characterized. As the importance of non-coding RNAs has emerged, the ability of vitamin D3via 1,25D to regulate microRNAs (miRNAs) has been demonstrated in several cancer cell lines, patient tissue and sera. In vitamin D3 intervention patient trials, significant differences in miRNAs are observed between treatment groups and/or between baseline and followup. In patient sera from population studies, specific miRNA differences associate with serum levels of 25D. The findings thus far indicate that dietary vitamin D3 in patients and 1,25D in vitro not only regulate specific miRNA(s), but may also globally upregulate miRNA levels. This article is part of a Special Issue entitled 'Vitamin D Workshop'.


Endogenous thrombin potential (ETP) in plasma from patients with AMI during antithrombotic treatment.
The beneficial impact of warfarin in preventing new events after AMI is well established. Decrease in thrombin generation seems to be the key element in anticoagulant treatment. The aims were to investigate the effect of warfarin and platelet inhibition on thrombin generation, assessed by the endogenous thrombin potential (ETP), and study the relation between coagulation parameters and ETP in patients with AMI. In the present sub-study of the WARIS II trial, patients with AMI were randomly assigned to treatment with aspirin 160 mg/d (n=57), aspirin 75 mg/d and warfarin (INR 2.0-2.5) (n=68) or warfarin (INR 2.8-4.2) (n=61). Fasting blood samples were collected from patients at discharge from hospital and after 6 weeks treatment. Correlation analyses showed that both ETP and peak thrombin levels were significantly correlated with Factor VII Ag (r=0.38 and 0.36 respectively, p<0.01 for both) and with F1+2 (r=0.26 and 0.23 respectively, p=0.01 for both) at baseline. Antithrombotic treatment for 6 weeks caused a highly significant inhibition of ETP in patients treated with warfarin (-28%+/-5%, p<0.001), and patients treated with aspirin/warfarin (-24%+/-8%, p=0.04). Similarly, peak thrombin levels were reduced in patients treated with warfarin (-18%+/-7%, p=0.049) and aspirin/warfarin (-19%+/-5%, p=0.029), whereas an increase (12%+/-4%, p=0.029) occurred during aspirin treatment alone. F1+2 levels decreased by 64% and 58% in the warfarin and aspirin/warfarin groups, respectively (p=0.001 for both). In patients with AMI, warfarin significantly reduced the endogenous thrombin generation and the potential to generate thrombin in plasma ex vivo, whereas aspirin alone had no effect on thrombin generation in vivo or ex vivo, assessed by ETP.


Immune responses after immunization with plasmid DNA encoding Bet v 1, the major allergen of birch pollen.
Immunization with plasmid DNA encoding various antigens is a promising method in vaccine research. Recent studies also indicate that DNA-based immunization might represent a potential approach in allergen-specific immunotherapy. In this study we have characterized the immune responses induced by recombinant Bet v 1a and plasmid DNA encoding for Bet v 1a, the major allergen of birch pollen in a mouse system. Balb/c mice were injected intraperitoneally with recombinant Bet v 1a and intradermally with plasmid DNA encoding for the gene of Bet v 1a (pCMV-Bet). In addition, the effect of immunostimulatory DNA sequences was investigated by appending CpG motifs to the gene of Bet v 1a, coinjecting CpG-oligodeoxynucleotides together with the pCMV-Bet construct, or both. IgE and IgG antibody responses, as well as IgG subclasses, were measured by ELISA in sera after each immunization. IFN-gamma and IL-4 levels were also measured by ELISA in sera and supernatants of allergen-stimulated spleen cells. The primary humoral response to a single treatment with pCMV-Bet was very weak, but the reaction could be boosted to higher levels by 2 additional injections. On the other hand, proliferation assays of spleen cells and measurements of cytokine levels already indicated a cellular response after the first injection of plasmid DNA. After 2 immunizations with pCMV-Bet, the ratio of IgG1 to IgG2a pointed to a TH1 subclass profile. IgE was not detectable in any group at any time during the immune reaction. Accordingly, IL-4 levels were markedly reduced in the serum, as well as in the supernatants, of stimulated spleen cells. Animals immunized with pCMV-Bet containing appended CpG motifs at the 3' end of the Bet v 1a gene and/or with the CpG-ODN GCTAGACGTTAGCGT plus pCMV-Bet displayed reduced humoral responses against Bet v 1a when compared with animals injected with pCMV-Bet alone. The levels of IFN-gamma measured after allergen stimulation of isolated spleen cells were significantly higher in animals immunized with pCMV-Bet plus CpG motifs than with pCMV-Bet alone. Immunization with recombinant Bet v 1a protein elicited a strong TH2 -type response, including IgE production, a high titer of IgG1, and IL-4 production in both serum and supernatants of proliferation cultures. In contrast to immunization with protein, DNA immunization induces a strong TH1 -type response against a relevant inhalant allergen. Our data support the concept of developing a novel type of allergen immunotherapy based on plasmid DNA immunization.


Foraging time and spatial patterns of predation in experimental populations : A comparative study of three mite predator-prey systems (Acari: Phytoseiidae, Tetranychidae).
Responses of the predaceous mites Phytoseiulus persimilis, Typhlodromus (=Metaseiulus) occidentalis, and Amblyseius andersoni to spatial variation in egg density of the phytophagous mite, Tetranychus urticae, were studied in the laboratory.The oligophagous predator P. persimilis showed initially a direct density dependent foraging time allocation and variation in foraging time increased with prey density. With changes in prey density due to predation, predator foraging rates (per hour) decreased with time and density dependent foraging gradually became density independence, because P. persimilis continued to respond to initial prey density, instead of the changing prey density and distribution. The consequent spatial pattern of predation by P. persimilis was density independent, although slopes of predation rate-prey density regressions increased with time.Compared with P. persimilis, the narrowly polyphagous predator T. occidentalis responded relatively slowly to the the presence or absence of prey eggs but not to prey density: the mean and variation of foraging time spent in patches with prey did not differ with prey density, but was significantly greater in patches with prey eggs than in patches without eggs. Prey density and distribution changed only slightly due to predation and overall foraging rates remained more or less constant. The consequent spatial pattern of predation by T. occidentalis was inversely density dependent. As with P. persimilis, slopes of predation rate-prey density regressions increased with time (i.e. the inverse density dependence in T. occidentalis became weaker through time).The broadly polyphagous predator A. andersoni showed density independent foraging time allocation with variation independent of prey density. With changes in prey density over time due to prey depletion, overall foraging rates decreased. The consequent spatial pattern of predation by A. andersoni also changed through time; it initially was inversely density dependent, but soon became density independent.Overall, P. persimilis and T. occidentalis spent more time in prey patches than A. andersoni, suggesting that A. andersoni tended to spend more time moving outside patches. The overall predation rates and searching efficiency were higher in P. persimilis than in A. andersoni and T. occidentalis. Predator reproduction was highest in P. persimilis, lower in T. occidentalis and the lowest A. andersoni.The differences in response to prey distribution among the three predaceous species probably reflect the evolution of these species in environments with different patterns of prey distribution. The degree of polyphagy is a major determinant of the aggregative response, but other attributes such as handling time are also important in other aspects of phytoseiid foraging behavior (e.g. searching efficiency or predation rate).


[PEDIATRIC NEPHROLOGY - CLINICAL MEDICINE, GENETIC AND REGENERATIVE MEDICINE…TOGETHER].
This special issue of the "Harefuah" journal is dedicated to pediatric nephrology. Four review articles and nine original articles will present acute and chronic clinical cases in daily nephrology medicine in order to inform the medical community about the risk of development of kidney injury and of acute and chronic renal insufficiency in children. The scientific articles will expand the knowledge on recent and future trends in research in nephrogenetics and regenerative nephrology.


Housing and health outcomes: evidence on child morbidities from six Sub-Saharan African countries.
The connection between healthy housing status and health is well established. The quality of housing plays a significant role in infectious and non-communicable as well as vector-borne diseases. The global burden of disease attributable to housing is considerable with millions of deaths arising from diarrheal and respiratory diseases annually. In sub-Saharan Africa (SSA), the quality of housing remains poor although improvements have been documented. There is a general dearth of comparative analysis across several countries in the sub-region. We assess in this study, the association between healthy housing and child morbidity across six countries in SSA. We use the Demographic and Health Survey (DHS) data for six countries where the most recent survey collected health outcome data on child diarrhoea, acute respiratory illness, and fever. The total sample size of 91,096 is used in the analysis (representing 15, 044 for Burkina Faso, 11, 732 for Cameroon, 5, 884 for Ghana, 20, 964 for Kenya, 33, 924 for Nigeria, and 3,548 for South Africa). The key exposure variable is healthy housing status. We control for various factors associated with the three childhood health outcomes. These include quality housing status, residency (rural/urban), age of the head of the household, mother's education, mother's BMI status, marital status, mother's age, and religious status. Others include the child's gender, age, whether the child is from multiple or single births, and breastfeeding status. Inferential analysis using survey-weighted logistic regression is employed. Our findings indicate that housing is an important determinant of the three outcomes investigated. Compared to unhealthier housing, healthy housing status was found to be associated with reduced odds of diarrhoea in Cameroon [Healthiest: aOR = 0.48, 95% CI, (0.32,0.71), healthier: aOR = 0.50, 95% CI,(0.35,0.70), Healthy: aOR = 0.60, 95% CI, (0.44,0.83), Unhealthy: aOR = 0.60, 95% CI, (0.44,0.81)], Kenya [Healthiest: aOR = 0.68, 95% CI, (0.52,0.87), Healtheir: aOR = 0.79, 95% CI, (0.63,0.98), Healthy: aOR = 0.76, 95% CI, (0.62,0.91)], South Africa[Healthy: aOR = 0.41, 95% CI, (0.18, 0.97)], and Nigeria [Healthiest: aOR = 0.48, 95% CI,(0.37,0.62), Healthier: aOR = 0.61, 95% CI,(0.50,0.74), Healthy: aOR = 0.71, 95%CI, (0.59,0.86), Unhealthy: aOR = 0.78, 95% CI, (0.67,0.91)], and reduced odds of Acute Respiratory Infection in Cameroon [Healthy: aOR = 0.72, 95% CI,(0.54,0.96)], Kenya [Healthiest: aOR = 0.66, 95% CI, (0.54,0.81), Healthier: aOR = 0.81, 95% CI, (0.69,0.95)], and Nigeria [Healthiest: aOR = 0.69, 95% CI, (0.56,0.85), Healthier: aOR = 0.72, 95% CI, (0.60,0.87), Healthy: aOR = 0.78, 95% CI, (0.66,0.92), Unhealthy: aOR = 0.80, 95% CI, (0.69,0.93)] while it was associated with increased odds in Burkina Faso [Healthiest: aOR = 2.45, 95% CI, (1.39,4.34), Healthy: aOR = 1.55, 95% CI, (1.09,2.20)] and South Africa [Healthy: aOR = 2.36 95% CI, (1.31, 4.25)]. In addition, healthy housing was significantly associated with reduced odds of fever among children in all countries except South Africa [Healthiest: aOR = 2.09, 95% CI, (1.02, 4.29)] where children living in the healthiest homes had more than double the odds of having fever. In addition, household-level factors such as the age of the household head, and place of residence were associated with the outcomes. Child-level factors such as breastfeeding status, age, and sex, and maternal-level factors such as education, age, marital status, body mass index (BMI), and religion were also associated with the outcomes. The dissimilarity of findings across similar covariates and the multiple relations between healthy housing and under 5 morbidity patterns show unequivocally the heterogeneity that exists across African countries and the need to account for different contexts in efforts to seek an understanding of the role of healthy housing in child morbidity and general health outcomes.


Attitudes towards poverty, organizations, ethics and morals: Israeli social workers' shared decision making.
Partnerships between service users and social workers are complex in nature and can be driven by both personal and contextual circumstances. This study sought to explore the relationship between social workers' involvement in shared decision making with service users, their attitudes towards service users in poverty, moral standards and health and social care organizations' policies towards shared decision making. Based on the responses of 225 licensed social workers from health and social care agencies in the public, private and third sectors in Israel, path analysis was used to test a hypothesized model. Structural attributions for poverty contributed to attitudes towards people who live in poverty, which led to shared decision making. Also, organizational support in shared decision making, and professional moral identity, contributed to ethical behaviour which led to shared decision making. The results of this analysis revealed that shared decision making may be a scion of branched roots planted in the relationship between ethics, organizations and Stigma.


Distinct degree of radiculopathy at different levels of peripheral nerve injury.
Lumbar radiculopathy is a common clinical problem, characterized by dorsal root ganglion (DRG) injury and neural hyperactivity causing intense pain. However, the mechanisms involved in DRG injury have not been fully elucidated. Furthermore, little is known about the degree of radiculopathy at the various levels of nerve injury. The purpose of this study is to compare the degree of radiculopathy injury at the DRG and radiculopathy injury proximal or distal to the DRG. The lumbar radiculopathy rat model was created by ligating the L5 nerve root 2 mm proximal to the DRG or 2 mm distal to the DRG with 6.0 silk. We examined the degree of the radiculopathy using different points of mechanical sensitivity, immunohistochemistry and in vivo patch-clamp recordings, 7 days after surgery. The rats injured distal to the DRG were more sensitive than those rats injured proximal to the DRG in the behavioral study. The number of activated microglia in laminas I-II of the L5 segmental level was significantly increased in rats injured distal to the DRG when compared with rats injured proximal to the DRG. The amplitudes and frequencies of EPSC in the rats injured distal to the DRG were higher than those injured proximal to the DRG. The results indicated that there is a different degree of radiculopathy at the distal level of nerve injury. Our study examined the degree of radiculopathy at different levels of nerve injury. Severe radiculopathy occurred in rats injured distal to the DRG when compared with rats injured proximal to the DRG. This finding helps to correctly diagnose a radiculopathy.


Direct segment aperture and weight optimization for intensity-modulated radiotherapy of prostate cancer.
To describe the implementation and to evaluate the results of direct segment aperture optimization using the segment outline and weight adapting tool (SOWAT) in intensity-modulated radiotherapy (IMRT) for prostate cancer. 14 consecutive, unselected patients with localized prostate cancer were entered in a planning study comparing IMRT without and with the use of SOWAT. The clinical target volume (CTV) consisted of the prostate and seminal vesicles in all cases. To create the planning target volume (PTV), a three-dimensional anisotropic margin (10 mm in craniocaudal direction, 7 mm in both other directions) was used. To compare both plans, physical as well as biological endpoints were considered. Considering the CTV, SOWAT resulted in a significantly higher minimal dose together with a higher dose to 95% (D(95)) and 90% (D(90)) of the CTV volume (p < 0.05; Figure 2). Target dose homogeneity was significantly improved (p < 0.001). Tumor control probability (TCP) was significantly increased (p < 0.05). Considering the PTV, D(90) was significantly increased (p < 0.05). Target dose homogeneity was significantly improved (p < 0.05; Figure 1). For rectum, the volumes receiving 50 Gy (R(vol50)), 60 Gy (R(vol60)), or 65 Gy (R(vol65)) as well as the mean dose were significantly lowered after SOWAT (p = 0.0001; Figure 3). Rectal normal tissue complication probability (NTCP) was significantly lower after SOWAT (p = 0.005). Probability of uncomplicated local control (P+) was significantly higher after SOWAT (p < 0.0001). SOWAT is a powerful planning tool to increase the therapeutic ratio of IMRT for prostate cancer. It leaves the delivery time unchanged, so that treatments can still be delivered within a time slot of 8 min.


Predicting performance in primary school subjects.
Correlations among letter naming, word reading, letter writing, and visual-motor integration scores at school start in Grade 1 and reading, spelling, and handwriting scores at the end of Grades 2 and 5 obtained in a longitudinal design for 217 boys and 190 girls entering Grade 1 at the age of 7 years are reported. The correlations between letter naming, word reading, and letter writing and reading and spelling in Grades 2 and 5 fall in the ranges .51 < or = r < or = .62 and .43 < or = r < or = .50, respectively (alpha = .01). For all other correlations (r < .40) alpha = .01.


Understanding ozone pollution in the Yangtze River Delta of eastern China from the perspective of diurnal cycles.
Ozone (O3) pollution has aroused increasing attention in China in past years, especially in the Yangtze River Delta (YRD), eastern China. Ozone and its precursors generally feature different diurnal patterns, which is closely related to atmospheric physical and chemical processes. This work aims to shed more light on the causes of ozone pollution from the perspective of the diurnal patterns. Hundreds of ozone pollution days (with maximum hourly O3 concentration over 100 ppb) during 2013-2017 were identified and then clustered into 4 typical types according to the diurnal variation patterns. We found that ozone pollution in Shanghai was particularly severe when anthropogenic pollutant mixed with biogenic volatile organic compounds (BVOCs) under the prevailing southwesterly wind in summer. The reason could be attributed to the spatial disparities of ozone sensitivity regime in YRD: VOC-limited regime around in the urban area and NOx-limited regime in the rural forest regions in the southern and southwest. The transition of sensitivity regimes along south/southwest wind tended to promote the photochemical production of ozone, making daily O3 pollution time exceeding 6 h of the day. In addition, ozone peak concentration in Shanghai was highly dependent on the evolution of sea-land breezes (SLBs). Earlier sea breeze associated with approaching typhoon in the West Pacific caused less cloud (-25%) and more solar radiation (11%) in YRD, which subsequently led to a rapid increase of O3 concentration in the morning and a deteriorated ozone pollution during noon and the afternoon. This study highlights the importance of observation-based processes understanding in air quality studies.


Microbial functional changes mark irreversible course of Tibetan grassland degradation.
The Tibetan Plateau's Kobresia pastures store 2.5% of the world's soil organic carbon (SOC). Climate change and overgrazing render their topsoils vulnerable to degradation, with SOC stocks declining by 42% and nitrogen (N) by 33% at severely degraded sites. We resolved these losses into erosion accounting for two-thirds, and decreased carbon (C) input and increased SOC mineralization accounting for the other third, and confirmed these results by comparison with a meta-analysis of 594 observations. The microbial community responded to the degradation through altered taxonomic composition and enzymatic activities. Hydrolytic enzyme activities were reduced, while degradation of the remaining recalcitrant soil organic matter by oxidative enzymes was accelerated, demonstrating a severe shift in microbial functioning. This may irreversibly alter the world´s largest alpine pastoral ecosystem by diminishing its C sink function and nutrient cycling dynamics, negatively impacting local food security, regional water quality and climate.


Brain activation of SIRT1: role in neuropathology.
Sirtuins (SIRTs) are a family of regulatory proteins of genetic information with a high degree of conservation among species. The SIRTs are heavily involved in several physiological functions including control of gene expression, metabolism, and aging. SIRT1 has been the most studied sirtuin and plays important role in the prevention and progression of neurodegenerative diseases acting in different pathways of proteins involved in brain function. SIRT1 activation regulates important genes that also exert neuroprotective actions such as p53, nuclear factor kappa B, peroxisome proliferator-activated receptor-gamma (PPARγ), PPARγ coactivator-1α, liver X receptor, and forkhead box O. It is well established in literature that growing population aging, oxidative stress, inflammation, and genetic factors are important conditions to development of neurodegenerative disorders. However, the exact pathophysiological mechanisms leading to these diseases remain obscure. The sirtuins show strong potential to become valuable predictive and prognostic markers for diseases and as therapeutic targets for the treatment of a variety of neurodegenerative disorders. In this context, the aim of the current review is to present an actual view of the potential role of SIRT1 in modulating the interaction between target genes and neurodegenerative diseases on the brain.


A novel CS-NET architecture based on the unification of CNN, SVM and super-resolution spectrogram to monitor and classify blood pressure using photoplethysmography.
Continuous blood pressure (BP) monitoring plays an important role while treating various cardiovascular diseases and hypertension. A high correlation between arterial blood pressure (ABP) and Photoplethysmogram (PPG) signal enables using a PPG signal to monitor and classify BP continuously. Control of BP in realtime is the basis for the prevention of hypertension. This work proposes a CS-NET architecture by unifying CNN and SVM approaches to classify BP using PPG signals. The main objective of the CS-NET method is to establish an accurate and reliable algorithm for the ABP classification. ABP signals are labeled normal and abnormal using the hypertension criteria the American College of Cardiology (ACC)/American Heart Association (AHA) laid down. The proposed CS-NET model incorporates three critical steps in three successive stages. The first stage includes converting a preprocessed PPG signal into a time-frequency (TF) representation called a super-resolution spectrogram by superlet transform. The second stage uses a convolutional neural network (CNN) model with several hidden layers to extract morphological features from every PPG super-resolution spectrogram. The third stage uses a support vector machine (SVM) classifier to classify the PPG signal. PPG signals are used to train and test the proposed model. The performance of the proposed CS-NET method is tested using MIMIC-II, MIMIC-III, and PPG-BP-figshare database in terms of accuracy and F1 score. Moreover, the CS-NET method achieves better results with high accuracy when compared with other benchmark approaches that require an electrocardiogram signal for reference. The proposed model achieved an aggregate classification accuracy of 98.21% across a five-fold cross-validation technique, making it a reliable approach for BP classification in clinical settings and realtime monitoring.


Hippocampal convergence during anticipatory midbrain activation promotes subsequent memory formation.
The hippocampus has been a focus of memory research since H.M's surgery abolished his ability to form new memories, yet its mechanistic role in memory remains debated. Here, we identify a candidate memory mechanism: an anticipatory hippocampal "convergence state", observed while awaiting valuable information, and which predicts subsequent learning. During fMRI, participants viewed trivia questions eliciting high or low curiosity, followed seconds later by its answer. We reasoned that encoding success requires a confluence of conditions, so that hippocampal states more conducive to memory formation should converge in state space. To operationalize convergence of neural states, we quantified the typicality of multivoxel patterns in the medial temporal lobes during anticipation and encoding of trivia answers. We found that the typicality of anticipatory hippocampal patterns increased during high curiosity. Crucially, anticipatory hippocampal pattern typicality increased with dopaminergic midbrain activation and uniquely accounted for the association between midbrain activation and subsequent recall. We propose that hippocampal convergence states may complete a cascade from motivation and midbrain activation to memory enhancement, and may be a general predictor of memory formation.


Neurocognitive and behavioral functioning in frontal lobe epilepsy: a review.
Frontal lobe epilepsy (FLE) is a seizure disorder with a lower prevalence than temporal lobe epilepsy (TLE). Despite its consequences on cognitive and emotional well-being, the neuropsychology of FLE has not been well studied. By contrast, TLE has been studied meticulously, leading to a relevant understanding of memory and the functional characteristics of the temporal and limbic circuits. The neuropsychological studies on FLE report deficits in motor coordination and planning, reduced attention span, and difficulties in response inhibition in complex cognitive tasks. This review aims to illustrate the most relevant neurocognitive dimensions, psychiatric comorbidity, and postoperative neuropsychological outcome of FLE. Methodological suggestions for future research are also included by critically reviewing the existing literature.


Analysis of Ascorbate Metabolism in Arabidopsis Under High-Light Stress.
Ascorbate is the most abundant soluble antioxidant in plants, and its concentration is enhanced under high-light and other abiotic stresses. One of the main functions of ascorbate is the detoxification of reactive oxygen species, as ascorbate-deficient plants are highly sensitive to high-light-induced photooxidative stress. Its antioxidative role in plants is further complemented by the presence of ascorbate peroxidases, as well as enzymes that recycle ascorbate from its oxidized forms. In parallel with ascorbate biosynthesis, the expression and activity of these enzymes are enhanced by photooxidative stress. Thus, ascorbate metabolism plays a key role in photooxidative stress acclimation. Herein, the present authors' preferred protocols for the application of high-light stress and the measurement of ascorbate and the activity of related enzymes are described.


Crystal structure and Hirshfeld surface analysis of bis-(μ-4-tert-but-oxy-4-oxobut-2-en-2-olato)bis-[(4-tert-but-oxy-4-oxobut-2-en-2-olato)ethano-lzinc(II)].
The mol-ecular and crystal structure of the title binuclear Zn2+ complex, [Zn2(C8H13O3)4(C2H5OH)2], with enolated anionic tert-butyl-aceto-acetate and ethanol was analysed. The coordination polyhedra of the Zn atoms are distorted octa-hedra formed by six oxygen atoms that belong to three ligand mol-ecules and a coordinated ethanol mol-ecule. In the crystal phase, alternating layers can be distinguished parallel to the ac plane. A Hirshfeld surface analysis showed that there are no strong inter-molecular inter-actions in the structure. The most significant contributions to the overall crystal packing are from H⋯H inter-molecular contacts.


Structural dissection of the DNA-binding domain of the yeast transcriptional activator GAL4 reveals an alpha-helical region responsible for dimerization.
Limited proteolysis of the DNA-binding domain (residues 1-147) of the yeast transcriptional activator GAL4 has been used to define more precisely the subdomain structure required for DNA binding and dimerization. Two regions of the protein were found to be resistant to proteolysis: the cysteine-rich, zinc-binding region (residues 6-43) and a hydrophobic sequence between residues 52 and 97. Carboxy-terminal deletion fragments of the DNA-binding domain were generated and assayed by DNase 1 footprinting. This showed that the affinity of DNA binding depends on the sequence between residues 65 and 94. Structural comparisons by UV circular dichroism (CD) were made and the difference CD spectra indicate that strong alpha-helical content is found specifically in the region between residues 65 and 94, which previous studies have shown to enable dimerization and in this study the formation of a stable protein-DNA complex.


Intravascular NK/T-cell lymphoma: a report of five cases with cutaneous manifestation from China.
Intravascular lymphoma is a rare type of lymphoma that frequently affects the skin and is usually of B-cell origin. This lymphoma type is very rare and not recognized as a separate entity in the 2008 World Health Organization classification of hematopoietic and lymphoid tissue tumors. We reported five cases of intravascular NK/T cell lymphoma with cutaneous manifestation and reviewed 12 published cases involving Chinese patients with similar characteristics. All five patients were adults who exhibited red or brown patches or plaques on the lower extremities or trunk; four cases were associated with B symptoms; one case developed subsequent to a lymphoma on the face (possibly extranodal NK/T cell lymphoma, nasal type). Histopathologically, all patients exhibited abnormal, medium-sized intravascular lymphocytes in the dermis and subcutaneous tissues. All patients were positive for CD2, CD3ϵ, CD56 and cytotoxic proteins. All cases were Epstein-Barr virus (EBV) positive. Four of FIVE patients died of lymphoma within a few months of diagnosis. Intravascular NK/T-cell lymphoma is a rare highly aggressive and EBV-associated lymphoma that is prone to develop in Chinese patients. The relationship between intravascular NK/T-cell lymphoma and extranodal NK/T-cell lymphoma, nasal type, requires clarification.


Immobilisation of metals from bottom sediments using two additives and thermal treatment.
A major problem associated with the land-based management of bottom sediments is their contamination with metals. The aims of the study were: 1) to use two additives for the immobilisation of metals; and 2) to evaluate the effect of three combustion temperatures on metal content and bottom sediment properties. The mixtures were prepared using contaminated bottom sediment and the following waste materials: cellulosic waste and biomass ash. In the second experiment, the bottom sediment samples were subjected to a thermal process, and three temperatures were chosen 500/800/950 °C. Overall, the addition of cellulosic waste and biomass ash to acidic, metal-contaminated bottom sediments significantly improved the properties of the resulting mixtures, including an increase in the pH value, sorption capacity, macronutrient content, and a decrease in the content and mobility of metals (Cd, Zn, Pb, Cr). The study confirmed the effectiveness of the thermal process on a significant reduction in the ecotoxicity of the sediments, a reduction in total content of elements, and a decrease in their leachability, and thus mobility, with increasing process temperature. The study results revealed that the converted contaminated bottom sediments can be effectively managed, provided that further studies on their technical application are carried out.


A study of autoimmune gastritis in the postpartum period and at a 5-year follow-up.
The presence of autoimmune gastritis was investigated in 54 women with postpartum thyroiditis. Parietal cell antibodies (PCA) specific against H+, K(+)-adenosine triphosphatase (EC 188.8.131.52) were found in 18 women during pregnancy; in 10 of them, a 2-9-fold increase in the PCA level was observed in the postpartum period. At a 5-year follow-up, the initially PCA-positive women still had elevated antibody levels. Hypergastrinemia and low pepsinogen levels were noted in 4 women. In 2 of these women low serum vitamin B12 levels had developed. In 6 of 9 PCA-positive women examined by gastroscopy, biopsy specimens from the gastric body mucosa contained mononuclear cells, mainly T lymphocytes (CD3+) and macrophages (Leu-M3+) combined with an aberrant epithelial expression of HLA-DR. In four patients with chronic gastritis, all parietal cells, as defined by a specific monoclonal antibody, were found to have immunoglobulin G (IgG) deposits by a double-immunostaining method. Three of them had microscopic evidence of atrophy, whereas in 1 patient the body mucosa was intact. In 1 further patient with intact glands at histological examination, the basolateral membrane of some oxyntic glands was coated with IgG. The selective in situ deposition of antibodies associated with histologically intact parietal cells may support the concept that specific autoantibodies participate in the early pathogenesis of parietal cell destruction.


New insights into spotty calcification and plaque rupture in acute coronary syndrome: an optical coherence tomography study.
Although recent optical coherence tomography (OCT) studies have focused on spotty calcification, whether there were any characteristics in the concomitant existence of calcification and plaque rupture remains unknown. The aim of the present study was to investigate the characteristics of spotty calcification in acute coronary syndrome (ACS) patients with or without plaque rupture, using OCT. This study enrolled 98 consecutive patients with ACS. OCT image acquisitions were performed in the culprit lesions, and patients were divided into the plaque rupture group (n = 38) and the non-rupture group (n = 60). The frequency of spotty calcification (p = 0.006), thin-capped fibroatheroma (p = 0.012), macrophage infiltration (p = 0.022), and the number of spotty calcification per patient (p < 0.001) were significantly higher and the largest arc and the minimum depth of spotty calcification from the luminal surface were significantly smaller in the rupture group. Moreover, in the rupture group, most of the spotty calcifications in the site nearest to the minimum lumen area were observed in the proximal portion of that site, and tended to be located near the plaque rupture. Multivariate analysis revealed that the presence of spotty calcification (OR 3.19, 95 % CI 1.12-9.76, p = 0.030) and age (OR 1.08, 95 % CI 1.02-1.14, p = 0.008) were independent predictive factors for plaque rupture. This study demonstrates the characteristics of spotty calcification in ACS patients with plaque rupture and the positional relationship between spotty calcification and plaque rupture. These detailed observations could impact on treatment strategies for the prevention of ACS.


[The radioecology of the grapevine. 1. The transfer of nuclear weapons fallout from the soil into wine].
In a field investigation (1983-1985) comprising eight places of the most important viticultural regions in the Federal Republic of Germany, the contents of the radionuclides tritium (3H), carbon-14 (14C), strontium-90 (90Sr), and cesium-137 (137Cs) in air, soils, leaves of the vine, grapes and wine were measured and site-specific transfer factors were calculated. Data concerning soil parameters, climatic conditions, cultivation and vinification were collected. The tritium content of all samples was 10 Bq/l water of combustion, independent of location and year. The specific activity of 14C in the atmosphere and in biological material was 0.22 Bq/g carbon, independent of site and year. 90Sr contents of soils fluctuated between 0.7 and 3.5 Bq/kg dry matter. The mean content of leaves was 2 Bq/kg fresh material, of grapes 0.035 Bq/kg and of wine 0.008 Bq/l. 137Cs content of soils fluctuated between 1.3 and 7.9 Bq/kg dry matter. The mean content of leaves was 0.098 Bq/kg fresh material, of grapes 0.021 Bq/kg and of wine 0.0085 Bq/l. A relation between transfer of radionuclides and soil parameters and between the contents of grapes and wine was not recognizable. While cultivar-specific differences were not observed in grapes, red wines contained somewhat more 137Cs than white wines. Transfer factors soil grapes were 0.027 for 90Sr and 0.0057 for 137Cs. Site-specific influences such as soil parameters, climate, cultivation, vinification and differences between years led to a relatively small fluctuation of values. An influence of the nuclear power station Neckarwestheim has not been found in any of the radionuclides.


Changes in volemia and natremia and onset of sodium appetite in sodium depleted rats.
Rats depleted of sodium by the IP injection of 10% b.w. of isotonic glucose for 30 min, developed a specific sodium appetite. The blood volume decreased 16% of the control value immediately after the treatment, returning to normal levels 2 to 4 hr later. The plasma sodium concentration showed a sudden and significant decrease, returning to control value 10-12 hr after the dialysis. In contrast, the sodium appetite became evident 10-12 hr after dialysis and reached the highest volume of ingestion at the sixteenth hr when both volemia and natremia had returned to normal. Since the appearance of the sodium appetite was not initiated during the state of hypovolemia and hyponatremia, the results show that the decrease in plasma volume and sodium concentration of the intravascular fluid that occurs after acute sodium depletion by IPD does not initiate an immediate onset of the sodium appetite.


Isovolaemic haemodilution decreases the shivering threshold in rabbits.
The inhibition of thermoregulatory control by anaesthesia is manifested by reduced vasoconstriction and shivering thresholds. As intraoperative bleeding can result in haemodynamic changes, including vasoconstriction, we investigated the effect of experimental bleeding on the shivering threshold in rabbits. Twenty-four rabbits were randomly assigned to one of three treatment strategies: (1) no blood removal (control), (2) 5 mL kg(-1) isovolaemic blood removal and (3) 10 mL kg(-1) isovolaemic blood removal. After tracheal intubation under isoflurane anaesthesia, anaesthesia was maintained with 50% nitrous oxide in oxygen. The removed blood volume was replaced with the same volume of warm hydroxyethyl starch colloid solution. Oesophageal temperature was measured as a core temperature at 1-min intervals. After blood removal, the animal's body was cooled at a rate of 2-3 degrees C h(-1) by perfusing water at 10 degrees C through a U-shaped thermode positioned in the colon. Hypothermic shivering was evaluated by visual inspection, and the core temperature at which shivering was triggered was identified as the thermoregulatory threshold for this response. Just before the cooling, the body temperature of the animals was around 38.6 degrees C in all of the three groups. The shivering threshold in the control group was 37.2 +/- 0.2 degrees C (mean +/- SD). The shivering thresholds in the 5 mL kg(-1) (36.9 degrees +/- 0.3 degrees C) and 10 mL kg(-1) (36.5 degrees +/- 0.5 degrees C) blood removal groups were significantly lower and in proportion with the volume of blood removed than that in the control group. Isovolaemic haemodilution decreased the shivering threshold in rabbits in proportion with the volume of blood removed.


Humoral and cellular immunity in convalescent and vaccinated COVID-19 people with multiple sclerosis: Effects of disease modifying therapies.
To determine anti-SARS-Cov2 antibodies and T-cell immunity in convalescent people with multiple sclerosis (pwMS) and/or pwMS vaccinated against Covid-19, depending on the disease modifying therapy, and in comparison to healthy controls (HC). 75 participants were enrolled: Group 1-29 (38.7%) COVID-19 convalescent participants; Group 2-34 (45.3%) COVID-19 vaccinated; Group 3-12 (16.0%) COVID-19 convalescent participants who were later vaccinated against COVID-19. Cellular immunity was evaluated by determination of number of CD4+ and CD8+ cells secreting TNFα, IFNγ, and IL2 after stimulation with SARS-CoV-2 peptides. pwMS treated with ocrelizumab were less likely to develop humoral immunity after COVID-19 recovery or vaccination. No difference was observed in the cellular immunity in all studied parameters between pwMS treated with ocrelizumab compared to HC or pwMS who were treatment naïve or on first line therapies. These findings were consistent in convalescent, vaccinated, and convalescent+vaccinated participants. COVID-19 vaccinated convalescent pwMS on ocrelizumab compared to COVID-19 convalescent HC who were vaccinated did not show statistically difference in the rate of seroconversion nor titers of SARS-CoV-2 antibodies. Presence of cellular immunity in pwMS on B-cell depleting therapies is reassuring, as at least partial protection from more severe COVID-19 outcomes can be expected.


Primary Neuroendocrine Carcinoma of Pineal Gland With Extensive Meningeal Metastasis Detected by 18F-NOTATATE PET/CT.
Primary neuroendocrine tumor of the pineal gland is a rare disease. A 44-year-old woman with right cerebellopontine angle metastatic small cell neuroendocrine carcinoma underwent 18F-FDG and 18F-NOTATATE PET/CT scans. 18F-NOTATATE PET/CT showed intense uptake in the pineal gland lesions and multiple foci of intense focus of uptake in the intracranial leptomeningeal and whole spinal canal. However, the lesions are less impressive on 18F-FDG PET/CT.


Stratification of Stage III colon cancer may identify a patient group not requiring adjuvant chemotherapy.
Adjuvant chemotherapy for colon cancer with lymph node involvement (Stage III) has been the standard of care since the 1990s. Meanwhile, considerable evolvement of surgery combined with dedicated histopathological examinations may have led to stage migration. Furthermore, prognostic factors other than lymph node involvement have proven to affect overall survival. Thus, adjuvant chemotherapy in Stage III colon cancer should be reconsidered. The objective was to compare recurrence rates and survival in stage III colon cancer patients treated with or without adjuvant chemotherapy. Further, to assess the impact of extensive mesenterectomy, lymph node stage and vascular invasion on outcome. Consecutive patients operated for Stage III colon carcinoma between 31 December 2005 and 31 December 2015 were identified in the pathological code register by matching colon (T67) and either adenocarcinoma (M81403) or mucinous adenocarcinoma (M84803), with lymph node (T08) and metastasis of adenocarcinoma (M81406 or M84806). Medical records of all identified patients were reviewed. Of 216 identified patients, 69 received no postoperative adjuvant chemotherapy (group NC), 69 insufficient adjuvant chemotherapy (FLV or < minimum recommended 6 cycles FLOX, group IC), and 78 sufficient adjuvant chemotherapy (≥ 6 cycles FLOX, group SC). When adjusted for age and comorbidity, 5-year overall survival did not differ statistically significant between groups (76% vs. 83% vs. 85%, respectively). Vascular invasion and a high lymph node ratio significantly reduced overall survival. The findings imply that subgroups of Stage III colon cancer patients have good prognosis also without adjuvant chemotherapy. For definite conclusions about necessity of adjuvant chemotherapy, prospective trials are needed.


Arterial oxygenation differences with carbon dioxide-induced versus voluntary increases in minute ventilation in chronic airway obstruction.
Two groups of patients with similar degrees of chronic airway obstruction exhibited different degrees of increased arterial oxygenation with CO2-induced hyperpnea versus voluntary increases in ventilation matched for ventilatory pattern. Patients who failed to increase arterial PO2 as much with voluntary hyperventilation as with CO2 challenge also had a lower dynamic compliance with the voluntary maneuver, whereas those with similar increases in arterial PO2 had similar dynamic compliances during the 2 periods of increased minute ventilation. The differences between the 2 groups are believed to be related to different effects of hypocapnia on collateral ventilation.


Tubulins in Trichomonas vaginalis: molecular characterization of alpha-tubulin genes, posttranslational modifications, and homology modeling of the tubulin dimer.
We have isolated and analysed an alpha-tubulin-encoding gene (atub1) in an early-diverging eukaryote, Trichomonas vaginalis. The complete atub1 open reading frame included 1.356 bp encoding a polypeptide of 452 amino-acyl residues. A second alpha-tubulin gene (atub2) was amplified by PCR using primers derived from consensus alpha-tubulin amino acid sequences. Both T. vaginalis alpha-tubulin sequences showed high identity to those described in other parabasalids (94.4%-97.3%), and exhibited a high degree of similarity to sequences from Metazoa (such as pig brain) and diplomonads (such as Giardia). Despite large evolutionary distances previously observed between trichomonads and mammals, the three-dimensional model of the T. vaginalis tubulin dimer was very similar to that of pig brain. Possible correlations between alpha-tubulin sequences and posttranslational modifications (PTMs) were examined. Our observations corroborated previous data obtained in T. vaginalis using specific anti-PTMs antibodies. As described in the related species Tritrichomonas mobilensis, microtubules are likely acetylated, non-tyrosinated, glutamylated, and non-glycylated in T. vaginalis. Evolutionary considerations concerning the time of appearance of these tubulin PTMs are also discussed since trichomonads are potentially one of the earliest diverging eukaryotic lineages.


The use of animals in medical education and research.
After noting why the issue of the use of animals in medical education and research needs to be addressed, this article briefly reviews the historical positions on the role of animals in society and describes in more detail the current positions in the wide spectrum of positions regarding the role of animals in society. The spectrum ranges from the extremes of the animal exploitation position to the animal liberation position with several more moderate positions in between these two extremes. Then the philosophical issue of the moral agency of animals is discussed in terms of an explication of the concept of rights and the concept of personhood. Further research is suggested concerning institutional policies regarding medical students who refuse to do physiology dog labs or other assignments which involve the suffering and/or death of animals.


Self-reported Racial Discrimination and Healthy Behaviors in Black Adults Residing in Rural Persistent Poverty Areas.
Racism is a social determinant of health inequities and associated with poorer health and health behaviors. As a domain of racism, self-reported racial discrimination affects health through unhealthy behaviors (e.g., smoking) but the understudied impact of self-reported racial discrimination's relationship with healthy behaviors (e.g., cancer screening) precludes a comprehensive understanding of racism's impact on health inequities. Understanding how self-reported racial discrimination impacts healthy behaviors is even more important for those living in rural persistent poverty areas (poverty rates of 20% or more of a population since 1980), who have a higher disease burden due to poverty's interaction with racism. The distinct sociocultural context of rural persistent poverty areas may result in differential responses to self-reported racial discrimination compared to those in non-persistent poverty areas. A community-engaged process was used to administer a survey to a convenience sample of 251 Black adults residing in 11 rural persistent poverty counties in the state of Arkansas. Self-reported racial discrimination, fruit and vegetable intake, colorectal cancer screening, cervical cancer screening, and screening mammography were assessed. Stress and religion/spirituality were also assessed as potential mediators or moderators in the relationship between self-reported racial discrimination and healthy behaviors. In adjusted models, those reporting more self-reported racial discrimination had a higher probability of having had a test to check for cervical cancer (situation discrimination: OR = 1.23, 95% CI: 1.04-1.5; frequency discrimination: OR = 1.06, 95% CI: 1.02-1.12). Stress and religion/spirituality were not significant mediators/moderators. Greater self-reported racial discrimination was associated with a higher odds of cervical cancer screening. Black adults residing in rural persistent poverty areas may have greater self-reported racial discrimination-specific coping and racial identity attitudes.


Epithelial tension in the second heart field promotes mouse heart tube elongation.
Extension of the vertebrate heart tube is driven by progressive addition of second heart field (SHF) progenitor cells to the poles of the heart. Defects in this process cause a spectrum of congenital anomalies. SHF cells form an epithelial layer in splanchnic mesoderm in the dorsal wall of the pericardial cavity. Here we report oriented cell elongation, polarized actomyosin distribution and nuclear YAP/TAZ in a proliferative centre in the posterior dorsal pericardial wall during heart tube extension. These parameters are indicative of mechanical stress, further supported by analysis of cell shape changes in wound assays. Time course and mutant analysis identifies SHF deployment as a source of epithelial tension. Moreover, cell division and oriented growth in the dorsal pericardial wall align with the axis of cell elongation, suggesting that epithelial tension in turn contributes to heart tube extension. Our results implicate tissue-level forces in the regulation of heart tube extension.


Antimalarial diterpene alkaloids from the seeds of Caesalpinia minax.
Two new diterpene alkaloids, caesalminines A (1) and B (2), possessing a tetracyclic cassane-type furanoditerpenoid skeleton with γ-lactam ring, were isolated from the seeds of Caesalpinia minax. Their structures were determined by different spectroscopic methods and ECD calculation. The plausible biosynthetic pathway of caesalminines A and B was proposed. The anti-malarial activity of compounds 1 and 2 is presented with IC50 values of 0.42 and 0.79 μM, respectively.


Correlation of Peripheral Vein Tumour Marker Levels, Internal Iliac Vein Tumour Marker Levels and Radical Prostatectomy Specimens in Patients with Prostate Cancer and Borderline High Prostate-Specific Antigen: A Pilot Study.
To correlate prostate-specific antigen (PSA), free to total PSA percentage (fPSA%) and prostatic acid phosphatase (PAP) levels from peripheral and pelvic venous samples with prostatectomy specimens in patients with prostate adenocarcinoma and borderline elevation of PSA. In this prospective institutional review board approved study, 7 patients with biopsy proven prostate cancer had a venous sampling procedure prior to prostatectomy (mean 3.2 days, range 1-7). Venous samples were taken from a peripheral vein (PVS), the right internal iliac vein, a deep right internal iliac vein branch, left internal iliac vein and a deep left internal iliac vein branch. Venous sampling results were compared to tumour volume, laterality, stage and grade in prostatectomy surgical specimens. Mean PVS PSA was 4.29, range 2.3-6 ng/ml. PSA and PAP values in PVS did not differ significantly from internal iliac or deep internal iliac vein samples (p > 0.05). fPSA% was significantly higher in internal iliac (p = 0.004) and deep internal iliac (p = 0.003) vein samples compared to PVS. One of 7 patients had unilateral tumour only. This patient, with left-sided tumour, had a fPSA% of 6, 6, 6, 14 and 12 in his peripheral, right internal iliac, deep right internal iliac branch, left internal iliac and deep left internal iliac branch samples respectively. There were no adverse events. fPSA%, unlike total PSA or PAP, is significantly higher in pelvic vein compared to peripheral vein samples when prostate cancer is present. Larger studies including patients with higher PSA values are warranted to further investigate this counterintuitive finding.


New therapeutic aspect for carvedilol: antifibrotic effects of carvedilol in chronic carbon tetrachloride-induced liver damage.
Portal hypertension is a common complication of chronic liver diseases associated with liver fibrosis and cirrhosis. At present, beta-blockers such as carvedilol remain the medical treatment of choice for protection against variceal bleeding and other complications. Since carvedilol has powerful antioxidant properties we assessed the potential antifibrotic effects of carvedilol and the underlying mechanisms that may add further benefits for its clinical usefulness using a chronic model of carbon tetrachloride (CCl4)-induced hepatotoxicity. Two weeks after CCl4 induction of chronic hepatotoxicity, rats were co-treated with carvedilol (10mg/kg, orally) daily for 6weeks. It was found that treatment of animals with carvedilol significantly counteracted the changes in liver function and histopathological lesions induced by CCl4. Also, carvedilol significantly counteracted lipid peroxidation, GSH depletion, and reduction in antioxidant enzyme activities; glutathione-S-transferase and catalase that was induced by CCl4. In addition, carvedilol ameliorated the inflammation induced by CCl4 as indicated by reducing the serum level of acute phase protein marker; alpha-2-macroglobulin and the liver expression of nuclear factor-kappa B (NF-κB). Finally, carvedilol significantly reduced liver fibrosis markers including hydroxyproline, collagen accumulation, and the expression of the hepatic stellate cell (HSC) activation marker; alpha smooth muscle actin. In conclusion, the present study provides evidences for the promising antifibrotic effects of carvedilol that can be explained by amelioration of oxidative stress through mainly, replenishment of GSH, restoration of antioxidant enzyme activities and reduction of lipid peroxides as well as amelioration of inflammation and fibrosis by decreasing collagen accumulation, acute phase protein level, NF-κB expression and finally HSC activation.


Aberrant epigenetic landscape in intellectual disability.
In recent decades, epigenetics has emerged as a broad-ranging regulatory layer that modulates the whole genome and transcriptome. It largely determines the firing of transcription start sites, the splicing processes, and the binding of transcription factors, among many other processes. Its wide spectrum of action has provided us with the keys to new doors to investigate many diseases, including intellectual disability syndromes. The involvement of epigenetic factors in Rett syndrome is already well established, and its involvement in alpha-thalassemia/mental retardation-X-linked and Rubinstein-Taybi syndromes is also being elucidated. Down syndrome is not an exception, and the most recent reports suggest that epigenetic factors may play a crucial role in its etiology and also have the potential to provide new panels of biomarkers and tailored treatments.


Age-related changes in duodenal adaptation after distal small bowel resection in rat.
Two groups of male Fisher 344 rats (young: 4 months old; aged: 25 months old) underwent either 70% distal small bowel resection or sham operation (small bowel transection). Rats from each treatment group of each age were sacrificed on the 10th (N = 15: young rats; N = 13: aged rats) or 20th (N = 15: young; N = 13: aged) postoperative day (POD), and the duodenal mucosa was weighed and assayed for DNA, RNA, and protein contents, as well as for specific activities of the disaccharidase, sucrase, maltase, and lactase. Compared to the sham operation, distal small bowel resection significantly increased DNA by 48%, RNA by 122%, and protein by 75% in young rats and DNA by 40%, RNA by 92%, and protein by 71% in aged rats on the 20th POD. Both young and aged rats showed similar adaptive hyperplasia on the 10th POD. On the 20th POD after distal small bowel resection, specific activities of all tested enzymes were significantly increased in young rats (sucrase +86%, maltase +110% and lactase +64%), but showed no significant changes in aged rats. These findings suggest that the duodenum of aged rats may have sufficient proliferative potential to respond to distal small bowel resection, but that the mechanisms governing return of function in response to distal small bowel resection are inhibited in aged rats, compared to those mechanisms in the young.


Development in life expectancy with good and poor cognitive function in the elderly European Population from 2004-05 to 2015.
Living not just longer, but also cognitively healthier, and more independent lives is essential if European countries are to cope with the financial challenges that the shifting age composition of Europe's population presents. Here we investigate the change in life expectancy (LE) spent with good and poor cognitive function among older adults across Europe. LE with good/poor cognitive function was estimated by the Sullivan Method. Cross-sectional data on cognitive functioning was obtained from 23,213 (wave 1, 2004-05) and 40,874 (wave 6, 2015) 50+-year-olds of the Survey of Health, Ageing and Retirement in Europe (SHARE). Information on mortality was obtained from the Eurostat Database. Results for 70+-year-olds were emphasized. LE with good cognitive function increased with 1.6 years from 10.7 years (95% CI: 10.6-10.9) in 2004-05 to 12.4 years (95% CI: 12.3-12.5) in 2015 for 70+-year-olds. Disparity was observed across sex and region. In 2004-05, a 70+-year-old woman could expect to spend 30.9% (95% CI: 29.4-32.4) of her remaining LE with poor cognitive function compared to 27.7% (95% CI: 26.0 -29.4) for men. In 2015, women (24.4% (95% CI: 23.4-25.3)) had considerably caught up with men (24.8% (95% CI:126.96.36.199)), shifting the pattern in favor of women. In 2004-05 and 2015, Northern Europeans had the lowest LE with poor cognitive function while Southern Europeans had the highest, but made the most improvement during the period. Overall we find that LE with poor cognitive function has been compressed in the European population of 70+-year-olds.


Process effects on activated carbon with large specific surface area from corn cob.
The main factors that affect the large specific surface area (SSA) of the activated carbon from agricultural waste corn cobs were studied by chemically activated method with solution of KOH and soap which acted as surfactant. The experiment showed that not only the activation temperature, activation time and the mass ratio of KOH to the carbonized material, but also the activated methods using activator obviously influenced the SSA of activated carbon. The experimental operating conditions were as follows: the carbonized temperature being 450 degrees C and keeping time being 4 h using N2 as protective gas; the activation temperature being 850 degrees C and holding time being 1.2 h; the mass ratio of KOH to carbonized material being 4.0; the time of soaking carbonized material in the solution of KOH and soap being 30 min. Under the optimal conditions, the SSA of activated carbon from corn cobs reached 2700 m2/g. And the addition of the soap as surfactant may shorten the soaking time. The structure of the activated carbon prepared had narrow distribution of pore size and the micro-pores accounted for 78%. The advantages of the method described were easy and feasible.


A method of simultaneous dual-radionuclide cardiac imaging with technetium 99m and thallium 201. I: Analysis of interradionuclide crossover and validation in phantoms.
Simultaneous dual-radionuclide technetium 99m/thallium 201 scintigraphy can potentially produce perfectly aligned stress and rest images in less time than conventional protocols. However, interradionuclide crossover limits diagnostic accuracy. Accordingly, we evaluated 99mTc and 201Tl crossover in line and heart phantoms. 99mTc crossover in the 201Tl imaging window constituted as much as one half of the counts in the 99mTc window, varied significantly with attenuation, and was spatially incoherent. 201Tl crossover was relatively small, less variable, and spatially similar to the primary image. Based on these findings, the following simultaneous dual-radionuclide 99mTc/201Tl method was developed, and validated in line and heart phantoms. The 99mTc source is imaged first into dual 201Tl/99mTc windows, followed by 201Tl administration and dual-radionuclide imaging. The single-radionuclide 99mTc image in the 201Tl window is count-normalized for acquisition time and then subtracted from the dual-radionuclide 201Tl image to specifically correct for 99mTc crossover. Image quality of the corrected dual-radionuclide 201Tl images approached their single-radionuclide counterparts. Correction for 201Tl crossover was relatively unimportant. Simultaneous dual-radionuclide 99mTc/201Tl myocardial scintigraphy is feasible with 99mTc crossover correction specific to each acquisition. The proposed dual-radionuclide 99mTc/201Tl method and the principles on which it is based can be applied to a broad range of dual-radionuclide pairs.


Maternal obesity and infant outcomes.
Obesity (Body mass index (BMI) above 30) is one of the major health issues of the 21st century. Over 1.1 billion of the world's population are now classified as obese. In the UK, women are more likely to be obese than men; over 50% of women of reproductive age are overweight or obese. Maternal obesity and the plethora of associated conditions, have a serious impact on the health and development of their offspring. In this review we describe the direct and indirect impact of maternal obesity on the health of the baby. Maternal obesity affects conception, duration and outcome of pregnancy. Offspring are at increased risk of both immediate and long term implications for health. We also briefly review potential mechanisms drawing on data from human and animal studies, and on the outcomes of clinical interventional studies.


Mode of action and human relevance assessment of male CD-1 mouse renal adenocarcinoma associated with lifetime exposure to empagliflozin.
Inhibition of sodium-glucose cotransporter-2 (SGLT2) has been shown to be a safe and efficacious approach to support managing Type 2 diabetes. In the 2-year carcinogenicity study with the SGLT2 inhibitor empagliflozin in CD-1 mice, an increased incidence of renal tubular adenomas and carcinomas was identified in the male high-dose group but was not observed in female mice. An integrated review of available nonclinical data was conducted to establish a mode-of-action hypothesis for male mouse-specific tumorigenesis. Five key events were identified through systematic analysis to form the proposed mode-of-action: (1) Background kidney pathology in CD-1 mice sensitizes the strain to (2) pharmacology-related diuretic effects associated with SGLT2 inhib ition. (3) In male mice, metabolic demand increases with the formation of a sex- and species-specific empagliflozin metabolite. These features converge to (4) deplete oxidative stress handling reserve, driving (5) constitutive cellular proliferation in male CD-1 mice. The proposed mode of action requires all five key events for empagliflozin to present a carcinogenicity risk in the CD-1 mouse. Considering that empagliflozin is not genotoxic in the standard battery of genotoxicity tests, and not all five key events are present in the context of female mice, rats, or humans, nor for other osmotic diuretics or other SGLT2 inhibitors, the observed male mouse renal tumors are not considered relevant to humans.


Daylight-mediated photodynamic therapy in Spain: advantages and disadvantages.
Photodynamic therapy (PDT) is an option for the treatment of actinic keratosis, Bowen disease, and certain types of basal cell carcinoma. It is also used to treat various other types of skin condition, including inflammatory and infectious disorders. The main disadvantages of PDT are the time it takes to administer (both for the patient and for health professionals) and the pain associated with treatment. Daylight-mediated PDT has recently been reported to be an alternative to the conventional approach. Several studies have shown it to be similar in efficacy to and better tolerated than classic PDT for the treatment of mild to moderate actinic keratosis. Nevertheless, most of these studies are from northern Europe, and no data have been reported from southern Europe. The present article reviews the main studies published to date, presents the treatment protocol, and summarizes our experience with a group of treated patients.


Active uptake of MPP+, a metabolite of MPTP, by brain synaptosomes.
Mouse brain synaptosomal preparations were used to study uptake of N-methyl-4-phenylpyridine (MPP+), a metabolite of the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). The uptake of [3H]-MPP+ by striatal synaptosomes was approximately 25 X greater than that of [3H]-MPTP, with a KM of 0.48 microM and a Vmax of 5.3 nmoles/g tissue/min. Uptake was Na+ dependent and inhibited by ouabain, cocaine and dopamine (Ki 0.12 microM). Synaptosomes prepared from the corpus striatum accumulated [3H]-MPP+ at a rate 5-10 times higher than preparations from other brain regions. This selective uptake of MPP+ may contribute to the specificity of the toxic effects of MPTP on nigrostriatal dopaminergic neurons.


5-Year survival in Danish patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitor monotherapy.
Convincing results from randomized controlled trials (RCTs) have led to increasing use of immune checkpoint inhibitors (ICI) as part of standard therapies in real-world (RW) scenarios. However, RW patients differ clinically from RCT populations and might have reduced long-term survival. Currently, only sparse data on 3-5-year survival rate for RW patients with advanced non-small cell lung cancer (NSCLC) treated with ICI exist. A multicenter study was performed including 729 patients with advanced NSCLC receiving monotherapy with ICI (retrospective data (n = 566) and prospective data (n = 163)). Detailed baseline clinical characteristics, programmed death-ligand 1 (PD-L1) tumor proportion score (TPS), and baseline haematological count were registered. Kaplan-Meier estimates and log-rank test were used for survival analyses, Cox regression for determination of prognostic factors. Median time of follow-up (FU) was 48.7 months (IQR 37.2-54.3). Median overall survival (OS) in first line treatment was 20.4 months (IQR 8.5-45.0) compared to 11.4 months (IQR 4.6-27.1) in ≥2nd line (HR 1.48, 95% CI 1.25-1.75). Estimated probability of OS was 30% at 3 years, 23% at 4 years, and 13% at 5 years in first line compared to 17, 13, and 11% in ≥2nd line, respectively. For those with performance status (PS) 2, the 2-year OS rate was 32% (95% CI 0.22-0.43) compared to 5% (95% CI 0.01-0.15) in patients with PD-L1 ≥ 50% versus <50%, respectively. Compared to RCTs, long-term OS and PFS rates are lower in real-world patients treated with ICI in first line but much improved compared to historic rates on chemotherapy. A promising flattening of both the OS and progression free survival curves illustrates that also a subset of real-world patients obtain long-term remission. Patients with PS 2 and PD-L1 ≥ 50% may obtain clinically meaningful 2-year PFS and OS rates.


The use of quinolones in respiratory tract infections.
In a prospective (and continuing) trial, a total of 271 patients with acute purulent exacerbations of chronic respiratory disease (bacteriologically confirmed) were treated with various new oral quinolones including enoxacin (26), pefloxacin (50), ciprofloxacin (80) and ofloxacin (115). Various therapeutic schedules were employed, with differing drug dosages, frequencies of administration and durations of treatment. All patients were investigated microbiologically during and immediately after treatment and after 7 days of follow-up. The best clinical results were noted after ofloxacin 800 mg once daily for 7 days, which showed excellent gastrointestinal absorption and rapid penetration through to the sputum. Some of the treatment failures with enoxacin and pefloxacin could be ascribed to the development of resistance during treatment, rises in minimal inhibitory concentrations (MICs) being noted with Streptococcus pneumoniae and Pseudomonas aeruginosa.


The influence of a membrane environment on the structure and stability of a prokaryotic potassium channel, KcsA.
The lack of a membrane environment in membrane protein crystals is considered one of the major limiting factors to fully imply X-ray structural data to explain functional properties of ion channels [Gulbis, J.M. and Doyle, D. (2004) Curr. Opin. Struct. Biol. 14, 440-446]. Here, we provide infrared spectroscopic evidence that the structure and stability of the potassium channel KcsA and its chymotryptic derivative 1-125 KcsA reconstituted into native-like membranes differ from those exhibited by these proteins in detergent solution, the latter taken as an approximation of the mixed detergent-protein crystal conditions.


Lacosamide-induced valproic acid toxicity.
Valproic acid is commonly used in the treatment of both focal and generalized epilepsies and is often well tolerated. There are many reported cases of hyperammonemic encephalopathy and other well-known side effects reported during use of valproic acid either alone or in combination with other antiepileptics. This case report demonstrates valproic acid toxicity in the presence of lacosamide, which has not previously been reported. Full recovery occurred after withdrawal of both valproic acid and lacosamide.


Mouse models of SMA: tools for disease characterization and therapeutic development.
Mouse models of human disease are an important tool for studying disease mechanism and manifestation in a way that is physiologically relevant. Spinal muscular atrophy (SMA) is a neurodegenerative disease that is caused by deletion or mutation of the survival motor neuron gene (SMN1). The SMA disease is present in a spectrum of disease severities ranging from infant mortality, in the most severe cases, to minor motor impairment, in the mildest cases. The variability of disease severity inversely correlates with the copy number, and thus expression of a second, partially functional survival motor neuron gene, SMN2. Correspondingly, a plethora of mouse models has been developed to mimic these different types of SMA. These models express a range of SMN protein levels and extensively cover the severe and mild types of SMA, with neurological and physiological manifestation of disease supporting the relevance of these models. The SMA models provide a strong background for studying SMA and have already shown to be useful in pre-clinical therapeutic studies. The purpose of this review is to succinctly summarize the genetic and disease characteristic of the SMA mouse models and to highlight their use for therapeutic testing.


Overview of Anti-Müllerian hormone (AMH) and association with fertility in female cattle.
Anti-Müllerian hormone (AMH) is produced by granulosa cells of early-antral follicles found on the ovary. After production, it enters circulation and can be detected from a blood sample with an ELISA. Multiple works have found that circulating AMH is a reliable marker of the antral follicle population (AFP) of an animal as well as directly correlated to an animal's response to a superovulation protocol. Research has also found high repeatability within an animal's oestrous cycle. Further use of AMH may be valuable as a reproductive management tool, based on previous research linking productive life with circulating AMH in heifers and success to various breeding protocols by AMH concentration. The aim of this review was to summarize previous works describing basic function of AMH as well as explore recent research examining AMH as a reproductive tool and measurement of fertility in dairy animals.


[Intrahippocampal injection of NGF accelerates spontaneous alteration ontogenesis and the maturation of septohippocampal cholinergic innervation in rats].
A single intrahippocampal injection of nerve growth factor (NGF), performed on postnatal (PND) 8 or 13, accelerated the development of spontaneous alternation in rats. This precocity was of approximately 5 days, appearing on the 4th day after the treatment and persisting through to the end of the development (PND 40). Combined microinjections of NGF and an antimuscarinic (atropine) or an antinicotinic (mecamylamine) substance have indicated that NGF probably acts through accelerating the development of the septo-hippocampal cholinergic fibers involved in this behavior.


[Polymorphism of immunogenetic and biochemical markers in Siberian (Tobol-Irtysh) Tatars].
The polymorphism of immunogenetic and biochemical markers has been studied in nine populations of five ethnic-geographic groups of Siberian (Tobol-Irtysh) Tatars. Data on the frequency distributions of 33 alleles and 6 haplotypes of 14 loci (ABO, RHD, RHC, RHE, P, KEL, HP, C'3, TF, GLO1, ESD, ACP, PGD, and PGM1) in sample of 354 subjects have been obtained. Comparison with other ethnic groups has shown that the gene pool of Tobol-Irtysh Tatars contains an ancient autochthonic genetic stratum similar to that found in the neighboring Ob' Ugrian population. Genetic relationships of various strengths with Central Asian Turks and the ethnic groups of the Volga region have been found, which apparently reflect different stages of the ethnogenesis of the Tobol-Irtysh Tatars.


Age as a potential predictor of acute side effects during chemoradiotherapy in primary cervical cancer patients.
Toxicity during chemoradiotherapy (CRT) in cervical cancer patients might limit the chances of receiving an optimal treatment and to be cured. Few studies have shown relationships between acute side effects and patient's age. Here, the association between age and acute side effects such as nausea/vomiting, diarrhea and weight loss during CRT was analysed in cervical cancer patients. This study included 93 patients with primary cervical cancer stage IBI to IVA who received CRT from 2013 to 2019. The frequency of symptoms/toxicity grade was analysed by using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Patients ≥ 52 years had a significantly higher frequency of nausea/vomiting and increased grade ≥ 3 toxicity during CRT compared to younger patients (p < 0.001, p = 0.001). Toxicity grade ≥ 3 of nausea/vomiting was associated with increased frequency of weight loss (p = 0.001), reduced ADL (p = 0.001) and dose modifications of both radiotherapy (RT) (p = 0.020) and chemotherapy (CT) (p = 0.030) compared to toxicity grade 2. The frequency of diarrhea (p = 0.015) and weight loss (p = 0.020) was higher in older patients compared to younger. Older patients have an increased risk of acute side effects as nausea/vomiting, diarrhea and weight loss. Age could be useful in predicting acute side effects in primary cervical cancer patients with CRT.


Genomics as public health? Community genetics and the challenge of personalised medicine in Cuba.
Making use of a comparative perspective on the emergence of 'breast cancer genetics' in the different cultural context of the UK and Cuba, this article examines the tensions between the modern promise of genomics as personalised medicine and a commitment to public health. Focusing primarily on the Cuba context and drawing on ethnographic research as part of a collaborative project working with genetic professionals and publics, the article examines the particular technologies, identities and socialities at stake in an emerging and evolving field of genetic medicine. It highlights how long-standing continuities in the commitment to the equitable provision of public health, particularly as this relates to 'family medicine', are central to understanding the scope and expansion of 'community genetics' interventions, even when at the level of local practice, public health is also now subject to the unequal dynamics of economic necessity through the working out of 'lo informal'. Illuminating the different ways agency, risk, responsibility, citizenship and activism get configured by and between publics and health professionals in Cuba, the article reveals the challenges and opportunities posed by predictive genomic medicine in relation to the dynamic and shifting terrain of public health.


Phytoliths analysis in root, culm, leaf and synflorescence of Rostraria cristata (Poaceae).
Phytoliths (siliceous structures) present in the plants have been employed in the fields of taxonomy and archaeology for many decades. Rostraria cristata is an economically important grass species (Poaceae) which accumulates silica in its different organs in the form of phytoliths. In order to understand the pattern of phytolith production and biochemical architecture of silica in R. cristata, leaf epidermis (blade) using the clearing solution method and different organs using the dry ashing method, X-ray diffraction and Fourier-transform infrared spectroscopy techniques were analyzed. Both abaxial and adaxial leaf epidermis showed the presence of acute bulbosus, rectangular sinuate and stomata phytolith morphotypes. Leaf including sheath and blade had the highest silica content. Characteristic phytolith morphotypes were present in different organs. A total of 34 phytolith morphotypes were present among which nine (9) were articulated and 25 were isolated forms. The most abundant were elongate scrobiculate (48.20%) in root and rectangular sinuate (26.16%) in leaf part. Other common phytolith morphotypes present in different organs of R. cristata were articulated elongate irregular, articulated elongate scrobiculate, acute bulbosus, and polygonal rondel etc. Leaf and synflorescence had the highest similarity based on presence/absence of phytolith morphotypes (Jaccard's similarity index). XRD studies revealed the presence of cristobalite, quartz, tridymite, zeolite etc. forms of silica in different organs. FTIR spectra showed that inplane stretching vibration of Si-C was unique to root, anti-symmetric stretching vibration of C-H was unique to leaf and Al2O3.SiO2 was found in synflorescence only. Our results show the characteristic pattern of phytoliths production in R. cristata.