Urological complications of obesity and diabetes in males and females of three mouse models: temporal manifestations.
Diabetic bladder dysfunction is a frequent complication of diabetes. Although many mouse models of diabetes now exist, there has been little systematic effort to characterize them for the timing of onset and severity of bladder dysfunction. We monitored metabolic status and tested bladder function by void spot assay and limited anesthetized cystometry in both male and female mice of three models of obesity and diabetes: a type 1 diabetes model (the Akita mouse) and two type 2 diabetes models [the diet-induced obese (DIO) model and the ob/ob mouse]. Akita mice had insulin pellets implanted subcutaneously every 3 mo to mimic poorly controlled type 1 diabetes in humans. Mice were hyperglycemic by 48 days after implants. Female mice exhibited no bladder dysfunction at any age up to 20 mo and gained weight normally. In contrast, by 7 mo, male Akita mice developed a profound polyuria and failed to show normal weight gain. There were no observable signs of bladder dysfunction in either sex. DIO mice on high/low-fat diets for 16 mo exhibited mild hyperglycemia in female mice (not in male mice), mild weight gain, and no evidence of bladder dysfunction. Ob/ob mice were followed for 8 mo and became extremely obese. Male and female mice were glucose intolerant, insulin intolerant, and hyperinsulinemic at 4 mo. By 8 mo, their metabolic status had improved but was still abnormal. Urine volume increased in male mice but not in female mice. Bladder dysfunction was observed in the spotting patterns of female mice at 4 and 6 mo of age, resolving by 8 mo. We conclude there are dramatic sex-related differences in lower urinary tract function in these models. Male Akita mice may be a good model for polyuria-related bladder remodeling, whereas female ob/ob mice may better mimic storage problems related to loss of outlet control in a setting of type 2 diabetes complicated by obesity.


Carotid traumatic aneurysm treated by detachable balloon.
The authors report the case of a young man who developed a large infraclinoid carotid aneurysm following a blunt head injury and presented with epistaxis. The aneurysm was occluded by a detachable balloon resulting in a good recovery.


[Community health and social action in the epidemiologic control of infantile trachoma, Spain (1932-1939)].
Within the context of the endemic trachoma that affected different regions of Spain until the 1960s, this paper analyses the epidemiological determinants of child trachoma and its treatment, based on a preventive care model which incorporated the concept of community health that took shape during the interwar period. Early detection of cases, together with preventive measures, education, therapy and inspections, such as those carried out by visiting nurses, all helped to control the disease. Our results reaffirm the validity of the horizontal intervention strategies used for improving the sanitary conditions and environmental factors responsible for this prevalence of trachoma.


Investigation of pathogenesis and therapeutic targets of acute myeloid leukemia based on untargeted plasma metabolomics and network pharmacology approach.
Acute myeloid leukemia (AML) is a malignant disease originating from bone marrow hematopoietic stem cells, characterized by anemia, hemorrhage, fever, and infection, with low survival rate. However, the pathogenesis of AML is not fully understood at present. In this work, an integrated approach based untargeted metabolomics and network pharmacology was adopted to elucidate the pathogenesis of AML. Metabolic profiling of plasma samples from 14 patients and 16 healthy individuals were performed based on UHPLC-MS platform. As a result, 23 metabolites were identified by using the human metabolite database based on PLS-DA (partial least squares discriminant analysis) and independent sample test. And metabolic pathways related to AML mainly included fatty acid metabolism, amino acid metabolism, energy metabolism and lipid metabolism. Meanwhile, biomarkers-targets-pathways-disease network was constructed, 75 biomarker targets and 122 disease targets were identified. Furthermore, 30 pathways were predicted, some of which were consistent with these in metabolomics. This is the first time that metabolomics and network pharmacology approach have been combined to investigate the pathogenesis and therapeutic targets of AML. ALDH, CYP2E1 and CYP3A4 were potential therapeutic targets for AML, which provide available way to elucidate the pathogenesis and treatment of AML.


Managing the care of patients with irreversible dementia during hospitalization for comorbidities.
Caring for the patient with AD hospitalized with comorbidities is a nursing challenge. By educating staff, using the PLST model, working with families, and implementing patient-focused care, positive outcomes are not only possible but probable. It is important for staff to work with caregivers in all aspects of care of the patient incorporating the patient's personal and medical historical knowledge into the care plan. Nursing facilities and families can provide a wealth of information, and communication before and after hospitalization maximizes positive outcomes for all concerned.


Clinical trial designs: is it possible to have a unified approach and common end points?
The accelerating development during the last 5 y of new compounds for the medical treatment of erectile dysfunction (ED) demands standardized high-quality protocols for evaluation of the therapeutic effect of these treatments. Outcome analyses have to rely on prospective, placebo-controlled trials within predefined populations, where the results are based on good biostatistics, self-administered questionnaires that include partner assessments, quality-of-life measures, and treatment satisfaction. Currently, we have access to different drug application procedures for clinical use in the treatment of ED, and soon we will have new competitive analogues for optional oral treatment. From a wider perspective, we will naturally see second- and third-generation compounds and drugs related to different effector mechanisms. In many subpopulations, ED has a close relation to specific comorbidities, such as cardiovascular diseases and diabetes. Regarding these aspects, the baseline for all clinical trials should be unified and structured not only to evaluate the clinical outcome assessment (subjective and objective) and adverse events as end points, but also to relate the defined therapeutic response to good current clinical practice.


Assessment of tyrosinase variants and skin cancer risk in a large cohort of French subjects.
Tyrosinase (TYR) is a key pigmentation gene that is highly polymorphic and responsible for the most common form of autosomal recessive albinism, OCA1. To assess the role of frequent and rare TYR variants in predisposition to skin cancer (SK) in the French population. We genotyped a frequent TYR variant (p.R402Q) in 1273 patients {1047 cutaneous melanoma (CM) and 226 basal cell carcinoma (BCC)} and 925 controls, and the full coding region of TYR was sequenced in 287 patients suspected of genetic predisposition to SK (familial and/or multiple SK and/or onset before 40 years) and 187 controls. The homozygous p.R402Q variant was significantly associated with SK risk (P value=0.008; OR=1.57), and was mostly associated with multiple CM risk (P value=0.021; OR=2.50) and familial CM risk (P value=0.022; OR=2.16). In addition, 19 rare TYR variants, mainly albinism mutations, were identified in 15 patients and 8 controls. Among these, 3 clearly deleterious mutations (1 non-sense and 2 affecting mRNA splicing) were identified in 3 patients, one of which was homozygous. Our data confirmed the association of TYR p.R402Q with SK risk in the French population, and support that rare deleterious TYR variants may also play a role in multi-factorial genetic predisposition to SK. These results should be confirmed by replications studies.


Discovery of rosavirus 2, a novel variant of a rodent-associated picornavirus, in children from The Gambia.
We describe the identification of a novel picornavirus recovered from the fecal specimen of a child in The Gambia, provisionally named rosavirus 2. Comparison of the rosavirus 2 complete genome demonstrated 71.9% nucleotide identity to its closest relative rosavirus M-7, an unclassified picornavirus identified from rodent fecal material. A unique RNA structure was predicted in the 3' UTR of rosavirus 2 that was conserved with rosavirus M-7 and cadiciviruses. We detected rosavirus 2 in four pediatric fecal specimens (0.55% prevalence) in a Gambian diarrheal case-control cohort, but we did not detect it in a panel of 634 pediatric diarrheal stool specimens from the USA. There was no statistical evidence that rosavirus 2 was associated with diarrheal cases. This study broadens our understanding of unknown viruses present in children in developing country settings.


Prenatal progesterone II. Its role in the treatment of pre-eclamptic toxaemia and its effect on the off-spring's intelligence: a reappraisal.
Dalton's results concerning the beneficial effect of progesterone supplementation in preventing pre-eclamptic toxaemia [16] and in enhancing intellectual potential [17,18] were reappraised. We could find no evidence in the data that progesterone supplementation was any better at preventing pre-eclamptic toxaemia than treating the disorder symptomatically. Nor could we find any convincing evidence that excess progesterone enhances development at 1 yr of age, academic attainment at 9--10 yr of age, or success in school leaving examinations and improves the chances of continuing further full-time education after leaving school.


Altered ovarian transcriptome is linked to early mortality and abnormalities in zebrafish embryos after maternal exposure to gamma irradiation.
Recent laboratory studies focusing on multigenerational approach demonstrated drastic phenotypic effects after chronic fish irradiation exposure. No irradiation effect at phenotypic scale was observed for F0 (reproductive performances) while early mortality and malformations were observed in F1 offspring whether they were irradiated or not. The objective was to study molecular mechanisms likely to be involved in these phenotypic effects induced by parental irradiation. Thus, F0 adult zebrafish were irradiated for ten days until reproduction and maternal involvement in offspring development was assessed. Levels of maternal provided cortisol and vitellogenin, needed for embryo development, were not impacted by irradiation. However, maternal transcriptome highlighted irradiation effect on processes involved in oocyte development, as well as on essential maternal factors needed for offspring development. Therefore, this study highlighted the importance of parental exposure on offspring fate and of the importance of multigenerational exposure in risk assessment.


[Device for the quantitative analysis of sum total pulse activity].
The authors present a circuit and the work principle of a device analysing the sum total electrical activity of the nerves. The device works by the principle of a frequency meter, it is made of integral elements, has a simple scheme, and is linear.


Comparative analysis of 2 commercial molecular tests for the detection of gastroenteric viruses on stool samples.
Our purpose was to compare the performance of 2 recently introduced molecular tests for the identification of gastrointestinal viral infections. One hundred fecal samples from pediatric patients were analyzed using 2 workflows, each including nucleic acids extraction and multiplex Real-Time PCR: Allplex™ GI-Virus Assay and FTD Viral gastroenteritis. The agreement was evaluated calculating Cohen's kappa and applying McNemar's test. Allplex and FTD assays showed 100% overall agreement for Norovirus GI/GII and Sapovirus (κ: 1.00), and 99% for Astrovirus (κ: 0.66). A lower agreement was detected for Adenovirus (89%; κ: 0.72) and Rotavirus (91%, k: 0.53), owing to samples resulted positive only with FTD test. The discrepancies were attributed to a different efficiency of extraction/amplification and to the different Adenovirus serotype specificity of the tests since Allplex detects only AdVF40 and AdVF41. FTD test should be used when non enteric adenovirus could have a clinical significance.


[Closing-wedge high tibial osteotomy with a modified Weber technique].
Deceleration of the progression of medial gonarthritis via transfer of the mechanical load axis from the medial to the lateral femorotibial compartment and by reduction of compressive stresses in the medial compartment. Isolated early-stage unicompartmental medial gonarthritis. Symptomatic varus deformity. Adjustment of the mechanical load axis in reconstructive surgery such as autologous chondrocyte transplantation. Correction of posttraumatic varus deformities. Concomitant patellofemoral arthritis, lateral femorotibial arthritis, or other painful conditions of the knee. Limited range of motion. Knee instabilities, since a rapid development of a tricompartmental gonarthritis is likely to occur. Advanced osteoporosis. Poor peripheral circulation with an absent foot pulse. Lateral meniscectomy. Lateral approach. Subcapital osteotomy of the fibula. Preparation of the lateral tibial head. Partial osteotomy of the proximal one third of the tibial tuberosity. Marking of the joint line. A semitubular plate is placed over a guide wire parallel to the joint line, 1.5 cm distal to it, and is gently hammered into the tibial head with just the last hole seen outside. The lateral end of the plate is bent downward. Ascending osteotomy of the tibial head in an inferolateral to craniomedial direction. The osteotomy starts 2.5 cm distal to the plate and ends directly below the guide wire. The medial cortex remains intact. Excision of a lateral-based bone wedge according to the preoperative planning. The osteotomy is gently closed under valgus stress. A 4.5-mm cortical screw is aimed through the lateral hole of the plate into the distal fragment of the tibia and tightened until the osteotomy is brought under compression. During hospitalization, there is a periodic treatment with continuous passive motion without any limitation of range of motion and isometric training is taken up. Mobilization is permitted with partial load of 15 kg with two crutches during 6 weeks postoperatively. Ambulatory physical training with active and passive motion exercises. After 6 weeks, the load can be increased stepwise depending on the consolidation as seen on the control radiographs. Full weight bearing is generally reached after 10 weeks. During this time, thromboembolism prophylaxis with low-molecular-weight heparin is necessary. A retrospective analysis of the own patients treated with the described surgical technique was performed. On the basis of Kaplan-Meier survival analysis, it could be demonstrated that there is a correlation between the patients' level of activity and the long-term survival rate 10-15 years after the osteotomy. Moreover, the extent of correction has a direct influence on the long-term result.


Integration of gene expression profile data to screen and verify immune-related genes of chicken erythrocytes involved in Marek's disease virus.
Chicken erythrocytes participated in immunity, but the role of erythrocytes in the immunity of Marek's disease virus (MDV) has not been reported related to the immunity genes. The purpose of this study was to screen and verify the immune-related genes of chicken erythrocytes which could be proven as a biomarker in MDV. The datasets (GPL8764-Chicken Gene Expression Microarray) were downloaded from the GEO profile database for control and MDV infected chickens to obtain differentially expressed genes (DEGs) through bioinformatics methods. Kyoto Encyclopedia of Genes and Genomes (KEGG) was performed to find enriched pathways, including Gene Ontology (GO). Based on enriched pathways, the top 19 immune-related genes were screened-out and process further to construct the protein-protein interaction (PPI) networks. The screened genes were validated on RT-PCR and qPCR. Results suggested that the mRNA transcription of Toll-like receptors 2, 3, 4, 6 (TLR2, TLR3, TLR4, TLR6), major histocompatibility complex-II (MHCII), interleukin-7 (IL-7), interferon-βeta (IFN-β), chicken myelomonocytic growth factor (cMGF) and myeloid differentiation primary response 88 (MyD88) were significantly up-regulated. The expression of toll-like receptor 5, 7 (TLR5, TLR7) interleukin-12 (IL-12 p40), interleukin-13 (IL-13), and interferon-αlpha (IFN-α) were significantly down-regulated in the erythrocytes of the infected group (P < 0.05). In contrast, the expression of toll-like receptor-1, 15, 21 (TLR1, TLR15, TLR21), major histocompatibility complex I (MHCI) and Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) were not significant. In conclusion, it has been verified on qRT-PCR results that 19 immune-related genes, which included TLRs, cytokines and MHC have immune functions in MDV infected chickens.


Does the Serum Metallothionein Level Reflect the Stage of Testicular Germ Cell Tumor?
Increased levels of metallothionein (MT) have recently been found in the blood serum of men with newly diagnosed testicular germ cell tumors (TGCT). In light of previously published results, the aim of this study was to investigate the difference in serum MT levels among patients with different stages of TGCT and compare MT with commonly used markers (α-fetoprotein, β-human chorionic gonadotropin and lactate dehydrogenase). The concentration of total MT was determined in the serum of 25 men with TGCT (seminoma or non-seminoma) by differential pulse voltammetry. Serum samples were obtained prior to chemotherapy, after two cycles of chemotherapy and 1 year after chemotherapy. A statistically significant difference in MT levels in patients with different stages of TGCT was observed in the serum of patients with non-seminoma obtained before chemotherapy. Although not significant, an increase in serum MT levels commensurate with the disease stage increase was also observed in patients with seminomatous TGCT. The results indicate that, in combination with the existing markers, MT could be useful for the identification of the histological type of tumor and stage of the disease before biopsy diagnosis.


Common elements on the surface of glycolytic enzymes from Trypanosoma brucei may serve as topogenic signals for import into glycosomes.
In Trypanosoma brucei, a major pathogenic protozoan parasite of Central Africa, a number of glycolytic enzymes present in the cytosol of other organisms are uniquely segregated in a microbody-like organelle, the glycosome, which they are believed to reach post-translationally after being synthesized by free ribosomes in the cytosol. In a search for possible topogenic signals responsible for import into glycosomes we have compared the amino acid sequences of four glycosomal enzymes: triosephosphate isomerase (TIM), glyceraldehyde-phosphate dehydrogenase (GAPDH), phosphoglycerate kinase (PGK) and aldolase (ALDO), with each other and with their cytosolic counterparts. Each of these enzymes contains a marked excess of positive charges, distributed in two or more clusters along the polypeptide chain. Modelling of the three-dimensional structures of TIM, PGK and GAPDH using the known structural coordinates of homologous enzymes from other organisms indicates that all three may have in common two 'hot spots' about 40 A apart, which themselves include a pair of basic amino acid residues separated by a distance of about 7 A. The sequence of glycosomal ALDO, for which no three-dimensional information is available, is compatible with the presence of the same configuration on the surface of this enzyme. We propose that this feature plays an essential role in the import of enzymes into glycosomes.


Theragnostic significance of tumor-infiltrating lymphocytes and Ki67 in BRAFV600-mutant metastatic melanoma (BRIM-3 trial).
We conducted a retrospective tumor tissue analysis as part of the BRIM3 trial to evaluate the theragnostic significance of tumor-infiltrating lymphocytes (TILs) and melanoma cell proliferation. Using manual semi-quantitative analyses, we assessed the density of TILs by pathology review of tissue sections stained with hematoxylin and eosin (H&E TIL score) and by immunohistochemistry (IHC) with an anti-CD8 antibody (CD8 TIL score); also, the melanoma cell proliferation by IHC with an anti-Ki67 antibody. Three hundred and fifty-three, 280, and 172 patients' tumor tissue samples were available for H&E, CD8, and Ki67 IHC analysis, respectively. There was no association between high (2+, 3+) peritumoral and intratumoral H&E and/or TIL CD8 score or high Ki67 proliferation index (>15%) with serum LDH level and stage IV melanoma. Neither high Ki67 proliferation, nor high peritumoral and/or intratumoral TIL score was significantly associated with objective antitumor response in any treatment arm. High intratumoral and high peritumoral CD8 TIL score was significantly associated with progression-free survival (PFS) only in DTIC-treated patients (P = 0.002 and 0.037, respectively); in vemurafenib-treated patients, high intratumoral and/or peritumoral CD8 TIL score was not significant (log-rank P = 0.053 and 0.062, respectively). Nevertheless, a high peritumoral CD8 TIL score was a significant predictor of PFS and overall survival after adjustment for age, sex, serum LDH, ECOG performance status, and treatment arm in a Cox regression model. Vemurafenib does not only benefit patients bearing brisk TILs; even vemurafenib-treated patients with absent and/or non-brisk TILs tend to have longer PFS compared to DTIC-treated patients with brisk TILs. High peritumoral CD8 TIL score is a favorable prognostic factor independent of well-established AJCC staging factors.


Inappropriate use of antibiotics and its predictors in pediatric patients admitted at the Central Hospital of Nampula, Mozambique.
Antibiotics are synthetic or natural substances used to treat bacterial infectious diseases. When used incorrectly, they can be a factor in the development of antimicrobial resistance, increased treatment time, costs, and mortality. The present study aimed to assess the pattern of inappropriate use of antibiotics and their predictors in pediatric patients admitted to the Central Hospital in Nampula, Mozambique. A cross-sectional, retrospective study with a quantitative approach was conducted between January and July 2019. The population consisted of children ages 0-10 years hospitalized in the pediatric ward I. Binary logistic regression was used to determine risk factors for the inappropriate use of antibiotics with 95% confidence interval. The prevalence of antibiotic use among pediatric patients was 97.5%. Of the 464 antibiotics prescribed, 39.9% were for patients suffering from gastroenteritis, 21.8% and 9.1% for those affected with pneumonia and malaria, respectively. Most antibiotics were for parenteral use (95.9%, 445/464). Many (36.5%) of the prescriptions had errors, primarily in the duration of treatment (74.0%) or dosage (24.4%). Binary logistic regression analysis revealed that patients prescribed ≥ 3 antibiotics (OR = 2.83, 95% CI 1.245-6.462, p-value = 0.013) or hospitalized for a short time (OR = 1.88, 95% CI 1.133-2.3140, p-value = 0.015) were more likely to experience inappropriate use of antibiotics. The study showed both a high prevalence of antibiotic use and a high error rate in prescriptions, especially among patients prescribed ≥ 3 antibiotics or hospitalized for a short time. These results are concerning, since inappropriate and excessive use of antibiotics is a major factor in the development of antibiotic-resistant microorganisms. Therefore, policies to reduce the inappropriate and excessive use of antibiotics are necessary.


Minimal residual disease directed therapy for childhood acute myeloid leukaemia: the time is now.
The continued improvement in the prognosis of childhood acute myeloid leukaemia (AML) has been paralleled by the use of increasingly intensive therapy. This has led to attempts to develop risk-directed strategies in which the most intensive treatment is reserved for those at highest risk of relapse. Unfortunately, current approaches, which rely on cytogenetic sub-grouping and morphological assessment of response to therapy, are inaccurate. New prognostic factors are needed. This annotation proposes that the introduction of protocols based on the measurement of minimal residual disease (MRD) holds the key to progression from an era of 'cure at all costs' to a more individualised approach. However, the full potential of MRD technologies will only be realised through properly designed studies with scrupulous attention to logistics and quality assurance. The article illustrates which children may benefit most from MRD analysis in AML and explores practical issues that should be addressed in the design of clinical trials.


Patient reported outcomes in randomized controlled cancer trials in advanced disease: a structured literature review.
In advanced cancer quality of life (QoL) is the most important goal of care. It is measured by patient-reported-outcomes (PRO). This structured review evaluated how randomized controlled trials (RCTs) on anti-cancer therapy in advanced cancer reported PRO. Search was performed in MEDLINE via PubMed for RCTs with median patient survival of ≤2 years. Reporting was rated with the Consolidated Standards of Reporting Trials (CONSORT) PRO extension. Of 370 retrieved publications, 117 were eligible, but only 30/117 (26%) reported PRO. QoL was most frequently measured (29/30). On average, 4.4 (SD 2.5) of the 14 CONSORT items were met. PRO are insufficiently reported in advanced cancer trials. Yet, this is paramount to enable an informed and patient-oriented decision making process.


Synthesis of novel fluorinated coumarins: excellent UV-light excitable fluorescent dyes.
Two new fluorinated fluorescent dyes, 6,8-difluoro-7-hydroxy-4-methylcoumarin (Marina Blue) and 3-carboxy-6,8-difluoro-7-hydroxycoumarin (Pacific Blue), exhibit excellent photophysical properties among a series of novel fluorinated 7-hydroxycoumarins. Most of these fluorinated coumarins have quantum yields (0.63 to 0.89) equal to or higher than that of the parent compound (0.63), which, in combination with their lower pKaS and higher photostability, make them superior fluorescent dyes for use as reporter molecules in biological systems.


Skin sympathetic nerve activity in patients with obstructive sleep apnea.
Obstructive sleep apnea (OSA) is associated with increased cardiac arrhythmia and sudden cardiac death. We recently developed a new method (neuECG) to noninvasively measure electrocardiogram and skin sympathetic nerve activity (SKNA). The purpose of this study was to test the hypothesis that SKNA measured during sleep study is higher in patients with OSA than in those without OSA. We prospectively recorded neuECG and polysomnography in 26 patients undergoing a sleep study. Sleep stages were scored into rapid eye movement (REM), and non-REM sleep stages 1 (N1), 2 (N2), and 3 (N3). Average voltage of skin sympathetic nerve activity (aSKNA) and SKNA burst area were calculated for quantification. Apnea/hypopnea index (AHI) >5 per hour was used to diagnose OSA. There was a positive correlation (r = 0.549; P = .018) between SKNA burst area and the arousal index in OSA but not in the control group. aSKNA during sleep was 0.61 ± 0.09 μV in OSA patients (n = 18) and 0.53 ± 0.04 μV in control patients (n = 8; P = .025). Burst area was 3.26 (1.90-4.47) μV·s/min in OSA patients and 1.31 (0.67-1.94) μV·s/min in control (P = .047). More apparent differences were found during N2, when the burst area in OSA (3.06 [1.46-5.52] μV·s/min) was much higher than that of the control (0.89 [0.79-1.65] μV·s/min; P = .03). OSA patients have higher SKNA activity than control patients, with the most pronounced differences observed during N2. Arousal at the end of apnea episodes is associated with large SKNA bursts. Overlaps of aSKNA and SKNA burst area between groups suggest that not all OSA patients have increased sympathetic tone.


Biofeedback for ophthalmologic disorders.
The possible applications of biofeedback to the treatment of ophthalmologic disorders is reviewed. Studies have suggested utility in the management of blepharospasms, strabismus, nystagmus, and other eye movement disorders as well as the training of voluntary control of accommodation. Limitations of the current literature are discussed, as are prospects for the clinical use of biofeedback in ophthalmologic practice.


Electrochemical determination of heme-linked pKa values and the importance of using fluoride binding in heme proteins.
The ultraviolet-visible (UV-vis) spectroelectrochemical measurements of heme proteins in the presence of a heme-bound fluoride ion can be used as a probe for heme-linked ionizations of acid-base groups in the heme pocket. A detailed study of the pH dependence of the midpoint potential of skeletal horse myoglobin (Mb) with a heme-bound fluoride ion (Mb-F) reveals how protonation of the distal histidine (H64) changes the redox properties of the protein with a determined pKa of 5.3. In addition, fluoride binding in myoglobin provides a stabilization of -1.9 kcal/mol of the ferric Mb-F relative to ferric Mb without fluoride.


The regulation of lipid metabolism by a hypothetical P-loop NTPase and its impact on fecundity of the brown planthopper.
Insect fecundity can be regulated by multiple genes in several important signaling pathways which form an extremely complicated regulatory network. However, there are still many genes that have significant impact on insect fecundity but their action mode are still unknown. Quantitative real-time PCR (qRT-PCR), immunofluorescence and western blot were used to study the expression profile of Nl23867 in the brown planthopper, Nilaparvata lugens. RNA interference (RNAi), RNA-seq and isobaric tags for relative and absolute quantification (iTRAQ) were performed to investigate the action mode of Nl23867 in the regulation of fecundity. High performance liquid chromatography (HPLC) analysis was performed to detect the fatty acid contents. We show that knockdown of Nl23867, a gene encoding a hypothetical P-loop NTPase, significantly decreased fecundity of N. lugens. Underdeveloped ovaries, fewer eggs laid and reduction in vitellogenin (Vg) protein expression were observed after RNAi knockdown of Nl23867, and most of the affected genes and pathways are fatty acid metabolism-related. We further determined that Nl23867 directly impacts the palmitic acid biosynthesis by regulating the expression of palmitoyl-protein thioesterase (PPT), subsequently affecting the content of total lipids in N. lugens. Nl23867 regulates the fecundity of N. lugens by modulating the biosynthetic pathway of palmitic acid and affecting lipid metabolism during vitellogenesis and oocyte development. The presented study pioneers the exploration into how a function-unknown gene takes part in the regulation of fecundity in an insect, and will contribute to the construction of gene regulatory network for insect fecundity.


Ultrastructural aspects of in vitro fertilization in sheep.
Fertilization events of the sheep oocyte have been analyzed by electron microscopy. In the fertilization cone, near the decondensing sperm nucleus, several areas composed of electron-dense filamentous material (FA) were observed. Moreover aster-like structures were present in the vicinity of the sperm neck and proximal midpiece. During swelling of the pronuclei, redistribution of cytoplasmic organelles occurred near the male pronucleus in a region facing the center of the egg. In this region, containing the sperm midpiece, large aggregates of Golgi complexes and cisternae of endoplasmic reticulum were associated with FA, microtubule foci, and abundant microtubules, suggesting cytaster formation. This complex migrated with the male pronucleus and the proximal sperm midpiece toward the center of the egg. A potential role of these subcellular structures, in the process of pronuclear migration, is proposed.


Changes in body fat and muscle in manual workers at and after retirement.
The changes in body fat and muscle in 73 men retiring from manual work have been measured in a longitudinal anthropometric study. Body fat increased by about 3% and body muscle decreased by about 1% between measurements made just before retirement and again 1 year later. The decline in muscle was even greater in a subgroup of 22 men who reported that their activity was less after retirement: but a subgroup of 11 whose activity was said to have been greater after retirement showed an increase in body muscle. A sub-sample of 26 men were measured on five further annual occasions (Fig. 1). The initial increase in body fat was reversed, and fat measurements fell back significantly to or below the pre-retirement values. Body muscle, however, continued to decline steadily at the initial rate, and the ratio of thigh muscle area to body mass fell significantly in retirement in the group as a whole. The possible contributions of ageing and of changes in energy balance and physical activity to these findings are discussed.


An infundibulum of thalamoperforator arteries: Importance of angiographic images for appropriate diagnosis.
The identification of infundibula on noninvasive imaging modalities may be challenging. Because these lesions have generally been viewed as nonpathological, distinguishing them from small or micro-aneurysms is important. A 39-year-old male was diagnosed with recurrence of typical orgasmic headache. An outpoutching arising from the distal part of the right P1 at the take-off of thalamoperforator arteries was visualized on noninvasive investigations. The patient was referred to neurosurgery for surgical management of a right P1 aneurysm. Its unusual location and morphology led to be suspicious of an infundibular dilatation. Catheter angiography with 2D projections and 3D rotational reconstruction revealed an infundibulum at the common origin of two thalamoperforators, giving rise to a double-peaked shape, mimicking a true aneurysm, rather than the more characteristic conical shape of an infundibulum. Although noninvasive modalities may identify typical infundibula, the catheter angiogram with 2D projections was critical to establishing the diagnosis. The 3D rotational reconstruction enabled a straightforward understanding of the 3D vascular anatomy. This pyramidal variant of infundibular dilatation should be included in the differential diagnosis of a wide-based nonsaccular arterial contour deformities located in an area of multiple perforators.


Resources and Support for Sexual Assault Survivors Receiving Services From the U.S. Air Force: What Survivors Say They Need for Recovery.
Sexual assault (SA) is a serious challenge faced by the U.S. military. Participants in this study included men and women who volunteered in response to a call for survivors of SA. Participants included active duty and reserve U.S. Air Force (USAF) members, spouses of service members, or civilian employees for the USAF (beneficiaries). The primary research question was, "if you could design the perfect response system to support survivors, what would be included in this system?" The research team conducted in-depth interviews with nine survivors. Next, 82 survivors completed a survey agreeing or disagreeing with strategies identified by interview participants to improve services for survivors and offered additional suggestions. Analysis revealed survivor recommendations to improve SA services.


How the spatial frequency of polarization influences the induction of reentry in cardiac tissue.
Influences of spatial frequency of polarization. The mechanism by which an electric field induces a rotor during cross-field stimulation of cardiac tissue is not entirely known. Different heterogeneous aspects of cardiac tissue have been offered as possible theories, a prominent one being fiber curvature. The polarization produced when an electric field is applied to a sheet of tissue is varied over many spatial frequencies, depending upon the fiber angle. This article compares the effect of high and low spatial frequencies of polarization on reentry induction. We incorporate a randomized fiber angle geometry into a two-dimensional active cardiac tissue model with unequal anisotropy ratios already exhibiting smooth, curving fibers. We simulate cross-field stimulation to initiate reentry in the tissue model, and compare the electric field thresholds at different S1-S2 intervals for tissue with randomized fiber angles, tissue with a smooth fiber geometry, and tissue with randomized fiber angles plus smooth, curving fibers. The tissue with both small, random fiber angles and curving fibers has a significantly lower threshold for reentry at certain intervals on the strength-interval curve than for the two cases individually. Cardiac tissue exhibiting a random fiber geometry in conjunction with a smooth fiber geometry includes high and low spatial frequencies of polarization that may have an effect on the mechanism for reentry at certain S1-S2 intervals. Low spatial frequency regions of hyperpolarization carve out excitable pathways, and high spatial frequency regions provide the large gradient of transmembrane potential required to initiate break excitation.


Autoimmune and viral risk factors are associated with achalasia: A case-control study.
Achalasia is a rare esophageal motility disorder of uncertain etiology. While past studies have indicated that autoimmune conditions and viral infections may be associated with development of achalasia, these associations are yet to be examined in large, population-based studies. A matched case-control study was performed using administrative claim data from the IBM MarketScan Commercial Claims and Encounters Database between 2000 and 2019. A history of selected autoimmune conditions and viral infections was assessed using past medical claims. Multivariable conditional logistic regression was used to account for the matched nature of the study design and further control for confounding by demographic and clinical characteristics when reporting adjusted odds ratios (aORs). Among 6769 cases and 27,076 controls, presence of any of the autoimmune conditions studied was associated with increased odds of achalasia (aOR = 1.26, 95% CI: 1.11, 1.42). Scleroderma or systemic sclerosis (aOR = 8.13, 95% CI: 3.34, 19.80) and Addison's disease (aOR = 3.83, 95% CI: 1.83, 8.04) had the strongest associations with achalasia. Presence of any of the viral infections studied was also associated with an increased risk of achalasia (aOR = 1.58, 95% CI: 1.23, 2.01). Varicella zoster virus (aOR = 3.84, 95% CI: 1.94, 7.62) and human papillomavirus (aOR = 1.77, 95% CI: 1.15, 2.73) both had strong relationships with achalasia. These findings suggest that achalasia may have autoimmune and viral components contributing to its etiology. Future mechanistic studies could target specific diseases and agents highlighted by this research.


Neuronal Histone Methyltransferase EZH2 Regulates Neuronal Morphogenesis, Synaptic Plasticity, and Cognitive Behavior in Mice.
The histone methyltransferase enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2)-mediated trimethylation of histone H3 lysine 27 (H3K27me3) regulates neural stem cell proliferation and fate specificity through silencing different gene sets in the central nervous system. Here, we explored the function of EZH2 in early post-mitotic neurons by generating a neuron-specific Ezh2 conditional knockout mouse line. The results showed that a lack of neuronal EZH2 led to delayed neuronal migration, more complex dendritic arborization, and increased dendritic spine density. Transcriptome analysis revealed that neuronal EZH2-regulated genes are related to neuronal morphogenesis. In particular, the gene encoding p21-activated kinase 3 (Pak3) was identified as a target gene suppressed by EZH2 and H3K27me3, and expression of the dominant negative Pak3 reversed Ezh2 knockout-induced higher dendritic spine density. Finally, the lack of neuronal EZH2 resulted in impaired memory behaviors in adult mice. Our results demonstrated that neuronal EZH2 acts to control multiple steps of neuronal morphogenesis during development, and has long-lasting effects on cognitive function in adult mice.


High intake of dietary tyramine does not deteriorate glucose handling and does not cause adverse cardiovascular effects in mice.
Tyramine is naturally occurring in food and induces pressor responses. Low-tyramine diets are recommended for patients treated with MAO inhibitors to avoid the fatal hypertensive crisis sadly known as "cheese effect". Hence, tyramine intake is suspected to have toxicological consequences in humans, while its administration to type 1 diabetic rodents has been reported to improve glucose tolerance. We investigated in mice whether prolonged tyramine ingestion could alter glucose homeostasis, insulin sensitivity, adipose tissue physiology or cardiovascular functions. Tyramine was added at 0.04 or 0.14 % in the drinking water since this was estimated to increase by 10- to 40-fold the spontaneous tyramine intake of control mice fed a standard diet. Ten to 12 weeks of such tyramine supplementation did not influence body weight gain, adiposity or food consumption. Both doses (reaching approx. 300 and 1100 μmol tyramine/kg bw/day) decreased nonfasting blood glucose but did not modify glucose tolerance or fasting levels of glucose, insulin or circulating lipids. Blood pressure was not increased in tyramine-drinking mice, while only the higher tested dose moderately increased heart rate without change in its variability. Markers of cardiac tissue injury or oxidative stress remained unaltered, except an increased hydrogen peroxide production in heart preparations. In isolated adipocytes, tyramine inhibited lipolysis similarly in treated and control groups, as did insulin. The lack of serious adverse cardiovascular effects of prolonged tyramine supplementation in normoglycemic mice together with the somewhat insulin-like effects found on adipose cells should lead to reconsider favourably the risk/benefit ratio of the intake of this dietary amine.


[Study on direct electrochemical behaviors and the electroanalytical method of matrine type alkaloids at glassy carbon electrode].
To investigate the direct electrochemical behaviors of matrine (MT), oxymatrine (OMT), sophoridine (SR) and oxysophoridine (OSR) at a glassy carbon electrode in a physiological medium, and to determine the contents of commercial MT and SR pharmaceutical products were determined. Their electrochemical behaviors and contents in 0.15 mol x L(-1) NaCl aqueous solutions were obtained by cyclic voltammetry (CV) and square wave voltammetry (SWV) methods. The electrochemical experimental results show that the two totally irreversible oxidation peaks for both MT and SR were observed, which potential values are 0.81 V and 0.92 V, and the electrode reaction processes were diffusion-controlled. But for both OMT and OSR, they have no oxidation peaks observed in the same condition as well. The linear range of the concentration of MT and SR and the contents in their products were obtained by SWV. The research results can be applied in determination of the contents of commercial MT and SR pharmaceutical products.


ARF after retrograde pyelography: a case report and literature review.
Acute renal failure (ARF) occasionally occurs after intravenous injection of contrast medium, but complications are rare after retrograde pyelography. After reviewing the reports in the English-language literature, the authors found very few on those complications after retrograde pyelography. The authors present a patient who had ARF after the technique. The patient had a history of hypopharyngeal cancer with underlying serum creatinine level at the high end of the normal limits. Bilateral flank pain and decreased urine amount were noted soon after the procedure of retrograde pyelography. Subsequently, blood urea nitrogen and creatinine levels both elevated, and hemodialysis was needed. Several days later, diuretic phase took place. Thereafter, the symptoms subsided gradually. Pyelorenal extravasation of contrast medium was remarkable during the procedure. There was no evidence of hydronephrosis during the course of ARF. Early awareness and management may prevent the complications of ARF such as acute lung edema and hyperkalemia. Therefore, clinical physicians should be aware of the occurrence of ARF and its clinical presentation after performing retrograde pyelography.


Epistaxis Treatment Options: Literature Review.
Epistaxis means bleeding from nostrils, nasal cavity or nasopharynx. To summarize the available epistaxis treatment options. Methods: 61 articles published in the last 20 years were included. Duplicate records, irrelevant and inaccessible ones were excluded. Epistaxis can be treated with first aid measures such as external pressure and ice packing and applying topical agents, e.g. oxymetazoline that stops 65-75% of nosebleeds in A&E. Also, with electrocautery which is more effective and has fewer recurrences (14.5% vs. 35.1%) than chemical cauterization and applying tranexamic acid that promotes hemostasis in 78% of patients, versus 35% and 31% respectively in patients treated with oxymetazoline and nasal packing. Furthermore, nasal packing can be applied with non-absorbable materials, e.g. petroleum jelly, BIPP gauze, PVA nasal tampons (Merocel), Foley catheter, balloons (Rapid-Rhino), absorbable materials, e.g. nasal tampon (Nasopore), and with newer hemostatic materials which are more effective and with fewer complications, e.g. hemostatic gauzes (Surgicel), thrombin matrix (Floseal), gelatin sponge (Spongostan) and fibrin glue. Moreover, epistaxis can be achieved with endoscopic ligation of arteries, mainly SPA, which is more effective than conventional nasal packing (97% vs. 62%), and with endoscopic cauterization which is more effective than ligation. Finally, for intractable cases embolization can be applied using gelatin sponge, foam, PVA and coils with 80% success rate and comparable efficacy and complications to surgical methods. Epistaxis can be dealt with various methods depending on patient's history and available resources. Newer hemostatic agents in combination with endoscopic methods have advantages over traditional methods.


Diabetes knowledge, attitude and practice (KAP) study among Iranian in-patients with type-2 diabetes: A cross-sectional study.
Recent studies highlight barriers of diabetes educational programs in Iran and also present some successful experiences carried out for improving the knowledge, attitude, and practice (KAP) of type-2 diabetic patients. Hence, evaluation of patients' KAP seems to be needed. We designed a multicenter study evaluating level of KAP in type-2 diabetic patients in the capital city of Tehran and identifying variables that affect this KAP level. This multicenter analytical cross-sectional study was approved by Shahid Beheshti University of Medical Sciences Ethics Committee. Questionnaires were designed for evaluation of diabetes-related KAP in patients. After validating the questionnaires by endocrinologists, test-retest method was used for questionnaire reliability by checking in 15 diabetic patients. Two hundred type-2 diabetic patients admitted to 4 hospitals of Tehran filled out the questionnaires. Using SPSS software, the level of KAP and its confounders were evaluated in patients. Two hundred type-2 diabetic patients with the mean age of 60.17 years were evaluated (106 male and 94 female). The mean diabetes duration was 13.06 years. The levels of patients' good knowledge, attitude, and practice were 61.41%, 50.44% and 52.23%, respectively. Age, treatment methods, DM duration, and existence of diabetic retinopathy had significant correlations with KAP level. The results of this study showed that recent educational programs in Iran improved KAP level. Patients' KAP increases as their condition worsens/progresses. Hence education should be considered as a priority for newly diagnosed patients and those with lower KAP levels before occurrence of diabetes complications.


Tipping the balance of autism risk: potential mechanisms linking pesticides and autism.
Autism spectrum disorders (ASDs) have been increasing in many parts of the world and a portion of cases are attributable to environmental exposures. Conclusive replicated findings have yet to appear on any specific exposure; however, mounting evidence suggests gestational pesticides exposures are strong candidates. Because multiple developmental processes are implicated in ASDs during gestation and early life, biological plausibility is more likely if these agents can be shown to affect core pathophysiological features. Our objectives were to examine shared mechanisms between autism pathophysiology and the effects of pesticide exposures, focusing on neuroexcitability, oxidative stress, and immune functions and to outline the biological correlates between pesticide exposure and autism risk. We review and discuss previous research related to autism risk, developmental effects of early pesticide exposure, and basic biological mechanisms by which pesticides may induce or exacerbate pathophysiological features of autism. On the basis of experimental and observational research, certain pesticides may be capable of inducing core features of autism, but little is known about the timing or dose, or which of various mechanisms is sufficient to induce this condition. In animal studies, we encourage more research on gene × environment interactions, as well as experimental exposure to mixtures of compounds. Similarly, epidemiologic studies in humans with exceptionally high exposures can identify which pesticide classes are of greatest concern, and studies focused on gene × environment are needed to determine if there are susceptible subpopulations at greater risk from pesticide exposures.


A phase I trial of oral ridaforolimus (AP23573; MK-8669) in combination with bevacizumab for patients with advanced cancers.
This phase I dose-escalation study was designed to evaluate the combination of the mammalian target of rapamycin inhibitor ridaforolimus with the vascular endothelial growth factor inhibitor bevacizumab. Seventeen adult patients with refractory advanced solid tumours received oral ridaforolimus (30 or 40 mg) once daily for 5 days per week (QDx5/wk) combined with intravenous bevacizumab (10 mg/kg every 2 weeks [Q2wk] or 15 mg/kg every 3 weeks [Q3wk]). Patients were evaluated for dose-limiting toxicities, safety and anti-tumour activity. A 40 mg dose of ridaforolimus with either bevacizumab dosing schedule was the recommended phase II dose. No dose-limiting toxicities were reported; the most common drug-related adverse events were mucosal inflammation and anorexia. Seven patients, with clinical features that included primary tumour of the abdominal origin (colorectal, pancreatic or gynaecological cancers) and previous abdominal radiotherapy, reported serious adverse events related to bowel perforations. There were no objective responses, but 65% of patients had a best response of stable disease. Oral ridaforolimus (40 mg QDx5/wk) is feasible to combine with standard doses of bevacizumab, although careful patient selection would be needed to mitigate the risk of bowel perforation-related adverse events. Combination therapy produced prolonged stable disease in several heavily pretreated patients.


Street drug abuse leading to critical illness.
Critical care physicians are frequently confronted with intoxicated patients who have used street drugs. In the last decade there has been an upward trend in the use of these substances, particularly amongst adolescents and young adults in large urban areas. In excess quantities all street drugs can lead to critical illness. Early and appropriate medical attention by emergency medicine physicians and intensivists can improve outcomes. In this review article we intend to familiarize critical care physicians with the most common street drugs such as amphetamines, ecstasy, cocaine, gamma hydroxybutyrate, opioids, and phencyclidine.


Re-engineering the process of medical imaging physics and technology education and training.
The extensive availability of digital technology provides an opportunity for enhancing both the effectiveness and efficiency of virtually all functions in the process of medical imaging physics and technology education and training. This includes degree granting academic programs within institutions and a wide spectrum of continuing education lifelong learning activities. Full achievement of the advantages of technology-enhanced education (e-learning, etc.) requires an analysis of specific educational activities with respect to desired outcomes and learning objectives. This is followed by the development of strategies and resources that are based on established educational principles. The impact of contemporary technology comes from its ability to place learners into enriched learning environments. The full advantage of a re-engineered and implemented educational process involves changing attitudes and functions of learning facilitators (teachers) and resource allocation and sharing both within and among institutions.


Effect of race on outcome of orthotopic liver transplantation: a cohort study.
There is significant evidence to suggest that long-term survival after renal transplantation is significantly lower in African Americans than in other races. We aimed to establish whether there was a difference in survival in African Americans compared with other races after orthotopic liver transplantation (OLT) and whether race was an independent predictor of survival. We collected data from the United Network of Organ Sharing transplant registry for all liver transplants done between 1988 and 1996 in the USA. We also recorded information on age, sex, race, blood group, and cause of death for the donors and recipients. 2-year graft survival was significantly lower for African Americans (601 of 884, 68%) and Asians (266 of 416, 64%) compared with white Americans (8703 of 11762, 74%) and Hispanics (878 of 1220, 72%). 2-year and 5-year patient survival were significantly lower for African Americans (654 of 884 [74%], 270 of 565 [48%]) and Asians (287 of 416 [69%], 92 of 252 [37%]) compared with white Americans (9786 of 11762 [83%], 4357 of 7514 [58%]) and Hispanics (964 of 1220 [79%], 341 of 657 [52%]). Compared with white Americans, African American (hazard ratio 1.36, 95% CI 1.16-1.60, p<0.0001) and Asian (1.25, 1.01-1.56, p=0.03) race were independent predictors of poor survival at 2 years. African Americans and Asians have a worse outcome after OLT compared with white Americans and Hispanics. The higher rate of chronic rejection in African Americans and a relatively worse outcome in other minority races merits further examination.


CD4+ T cell activation, function, and metabolism are inhibited by low concentrations of DMSO.
Dimethyl sulfoxide (DMSO) is a polar organic solvent used in a wide range of biological applications. DMSO is routinely used as a cryoprotectant for long-term cell freezing as well as to dissolve peptides and drugs for immune cell functional assays. Here, human CD4+ T cell activation, cytokine production, proliferation, and metabolism were investigated after stimulation in the presence of 0.01% to 1%, DMSO, representing concentrations commonly used in vitro. Surface expression of the activation markers CD69, CD25 and CD154 after polyclonal activation of CD4+ T cells was inhibited by 0.25% or higher concentrations of DMSO. The frequencies of IL-21+, IL-4+, and IL-22+ CD4+ T cells, following polyclonal activation were variably inhibited by DMSO at concentrations ranging from 0.25% to 1%, whereas IFNγ+ cells were unaffected. CD4+ T cell proliferation after anti-CD3 or antigen stimulation was inhibited by 0.5% DMSO and abolished by 1% DMSO. After polyclonal stimulation, glucose uptake was inhibited in the presence of 1% DMSO, but only minor effects on CD4+ T cell respiration were observed. Consistent with the immune effects, the gene expression of early signaling and activation pathways were inhibited in CD4+ T cells in the presence of 1% DMSO. Our study revealed that DMSO at concentrations generally used for in vitro studies of T cells impacts multiple features of T cell function. Therefore, we urge care when adding DMSO-containing preparations to T cell cultures.


Recently developed methods for the detection of babesial infections.
During the acute phase of babesiosis the direct identification of the causative agent is possible by examination of stained blood smears. An improved identification procedure for the diagnosis of Babesia bovis using DNA hybridization has been reported recently. For the diagnosis of both acute and chronic babesiosis, various serodiagnostic techniques have been developed. Recent advances in serodiagnosis designed for the detection of anti-Babesia antibodies were partly achieved by improving and standardizing the indirect immunofluorescence and complement fixation tests. The use of soluble antigens derived from Babesia culture supernatants or enriched, purified merozoites in the micro-enzyme-linked immunosorbent assay, solid phase radioimmunoassay and latex agglutination test has provided increased sensitivity and specificity in detecting anti-Babesia antibodies. Immunoblots and monoclonal antibodies have been used for the characterization and identification of babesial antigens and antigenic determinants. The advantages and disadvantages as well as the area of application of the currently available test systems will be discussed.


Relationship between the hypothalamic-pituitary-adrenal-axis and fatty acid metabolism in recurrent depression.
Alterations in hypothalamic-pituitary-adrenal (HPA)-axis activity and fatty acid (FA)-metabolism have been observed in (recurrent) major depressive disorder (MDD). Through the pathophysiological roles of FAs in the brain and cardiovascular system, a hypothesized relationship between HPA-axis activity and FA-metabolism could form a possible missing link accounting for the association of HPA-axis hyperactivity with recurrence and cardiovascular disease in MDD. In 137 recurrent MDD-patients and 73 age- and sex-matched controls, we therefore investigated associations between salivary cortisol (morning and evening) and the following indicators of FA-metabolism measured in the red blood cell membrane: (I) three main FAs [eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA)], and (II) structural FA indices (unsaturation, chain length, peroxidation) calculated from concentrations of 29 FAs to delineate overall FA-characteristics. In addition, we compared these associations in patients with those in controls. In patients, evening cortisol concentrations were significantly negatively associated with DHA (B=-1.358; SE=0.499; t=-2.72; p=.006), the unsaturation index (B=-0.021; SE=0.009; t=-2.42; p=.018), chain length index (B=-0.060; SE=0.025; t=-2.41; p=.019), and peroxidation index (B=-0.029; SE=0.012; t=-2.48; p=.015). The relations between cortisol and the latter three variables were significantly negative in patients relative to controls. Significance remained after correction for confounders. Our results suggest a relationship between HPA-axis activity and FA-metabolism in recurrent MDD. Future randomized experimental intervention studies using clinical outcome measures could help to further elucidate the suggested effects of hypercortisolemia in the brain and cardiovascular system in recurrent MDD.


Pyrazolyl conjugates of bombesin: a new tridentate ligand framework for the stabilization of fac-[M(CO)3]+ moiety.
We have described the synthesis of tridentate pyrazolyl ligand frameworks for coordination to the fac-[*M(CO)(3)](+) metal fragment (*M=(186/188)Re or (99m)Tc). These ligands impart a degree of kinetic inertness on the metal center, warranting their study in biological systems. We herein report in vitro/in vivo radiolabeling investigations of a new series of pyrazolyl bombesin (BBN) conjugates radiolabeled via the Isolink kit. These new conjugates are based on the general structure [(99m)Tc-pyrazolyl-X-BBN[7-14]NH(2)], where X=beta-alanine, serylserylserine or glycylglycylglycine. The pyrazolyl ligand is a tridentate ligand framework that coordinates the metal center through nitrogen donor atoms. The results of these investigations demonstrate the ability of these new conjugates to specifically target the gastrin-releasing peptide receptor subtype 2, which is overexpressed on human prostate PC-3 cancerous tissues. Therefore, these studies suggest the tridentate pyrazolyl ligand framework to be an ideal candidate for the design and development of low-valent (99m)Tc-based diagnostic radiopharmaceuticals based on BBN or other targeting vectors.


Psychophysical tests in X-linked retinitis pigmentosa carrier status.
Psychophysical tests were performed in 22 normal women and 17 X-linked carriers of retinitis pigmentosa. The tests consisted of luminance contrast sensitivity, grating at the fovea and broken annulus at the periphery, color contrast sensitivity, letters for the fovea and broken annulus for the periphery, along the three known confusion axes of protan, deutan and tritan observers. Statistical analysis of the data shows that there were significant differences between the carriers and age-similar normal subjects with all the tests. The most significant differences (P < 0.001) were found with the color contrast sensitivity at the periphery along the protanopic and deutanopic axes and the luminance contrast sensitivity at the periphery. The influence of the age is discussed.


SHPS-1/SIRP1alpha contributes to interleukin-6 signalling.
The transmembrane glycoprotein signal regulatory protein/SHP2-substrate (SIRP1alpha/SHPS-1) has been implicated in growth factor- and cell adhesion-induced signalling. Here we report on the contribution of SIRP1alpha to IL-6 type cytokine signalling. SIRP1alpha binds the protein tyrosine phosphatase SHP2 upon treatment with interleukin-6 in a stimulation-dependent manner. Mouse embryonic fibroblasts expressing a SIRP1alpha protein which lacks the intracellular part show enhanced SHP2 phosphorylation and ERK1/2 activation in response to IL-6, suggesting that SIRP1alpha affects IL-6-signalling through SHP2. Whereas SHP2 phosphorylation is enhanced in SIRP1alpha-deficient cells STAT3 activation is delayed and STAT3-dependent gene induction is reduced which correlates with reduced STAT3 serine phosphorylation. Our results indicate that SIRP1alpha contributes to IL-6 signalling by counteracting SHP2 phosphorylation which consequently affects ERK-activation and STAT3-dependent transactivation as well as target gene expression. Our observations will help to understand the tight balance of MAPK- and STAT3-activation in response to IL-6 which was found to be misbalanced in many autoimmune diseases, inflammatory proliferative diseases and cancer.


Combined treatment with octreotide LAR and pegvisomant in patients with pituitary gigantism: clinical evaluation and genetic screening.
Pituitary gigantism is a rare condition caused by growth hormone secreting hypersecretion, usually by a pituitary tumor. Acromegaly and gigantism cases that have a genetic cause are challenging to treat, due to large tumor size and poor responses to some medical therapies (e.g. AIP mutation affected cases and those with X-linked acrogigantism syndrome). We performed a retrospective study to identify gigantism cases among 160 somatotropinoma patients treated between 1985 and 2015 at the University Hospital of Caracas, Venezuela. We studied clinical details at diagnosis, hormonal responses to therapy and undertook targeted genetic testing. Among the 160 cases, eight patients (six males; 75 %) were diagnosed with pituitary gigantism and underwent genetic analysis that included array comparative genome hybridization for Xq26.3 duplications. All patients had GH secreting pituitary macroadenomas that were difficult to control with conventional treatment options, such as surgery or primary somatostatin receptor ligand (SRL) therapy. Combined therapy (long-acting SRL and pegvisomant) as primary treatment or after pituitary surgery and radiotherapy permitted the normalization of IGF-1 levels and clinical improvement. Novel AIP mutations were the found in three patients. None of the patients had Xq26.3 microduplications. Treatment of pituitary gigantism is frequently challenging; delayed control increases the harmful effects of GH excess, such as, excessive stature and symptom burden, so early diagnosis and effective treatment are particularly important in these cases.


Learning and organization of within-session sequences by pigeons (Columba livia).
Most animals engage in complex activities that are the combination of simpler actions expressed over a period of time. The mechanisms organizing such sequential behavior have been of long-standing biological and psychological interest. Previously, we observed pigeons' anticipatory behavior with a within-session sequence involving four choice alternatives suggestive of a potential understanding of the overall order and sequence of the items within a session. In that task, each colored alternative was correct for 24 consecutive trials as presented in a predictable sequence (i.e., A first, then B, then C, then D). To test whether these four already-trained pigeons possessed a sequential and linked representation of the ABCD items, we added a second four-item sequence involving new and distinct colored choice alternatives (i.e., E first for 24 trials, then F, then G, then H) and then alternated these ABCD and EFGH sequences over successive sessions. Over three manipulations, we tested and trained trials composed of combinations of elements from both sequences. We determined that pigeons did not learn any within-sequence associations among the elements. Despite the availability and explicit utility of such sequence cues, the data suggest instead that pigeons learned the discrimination tasks as a series of temporal associations among independent elements. This absence of any sequential linkage is consistent with the hypothesis that such representations are difficult to form in pigeons. This pattern of data suggests that for repeated sequential activities in birds, and potentially other animals including humans, there are highly effective, but underappreciated, clock-like mechanisms that control the ordering of behaviors.


The ERN is the ERN is the ERN? Convergent validity of error-related brain activity across different tasks.
Error-processing is increasingly examined using the error-related negativity (ERN) and error positivity (Pe) - event-related potentials (ERPs) that demonstrate trait-like properties and excellent reliability. The current study focuses on construct validity by applying a multitrait-multimethod approach, treating error-related ERPs (i.e., ERN, Pe and the difference between error minus correct, referred to as ΔERN and ΔPe, respectively) as traits measured across multiple tasks (i.e., Flanker, Stroop, and Go/NoGo). Results suggest convergent validity of these ERPs ranging between .62 and .64 for ΔERN. Values were somewhat smaller for ERN (range .33-.43), Pe (range .37-.49) and ΔPe (range .30-.37). Further, the correlations for ERN and Pe are higher within components across tasks than between different components suggesting discriminant validity. In conclusion, the present study revealed evidence for convergent and discriminant validity of error-related ERPs, further supporting the use of these components as psychophysiological trait markers.


[The echotomographic study of the vessels of the liver and the biliary tract (author's transl)].
As long as a clearly defined protocol is followed, exploration of the hepatic veins and biliary canals by echotomography (grey scale) is practically always possible. It should be incorporated in any echotomographic study of the hepatic parenchyma and reciprocally. This method of investigation is harmless, rapid, reproducible and low in cost.


Single-particle tracking for studying the dynamic properties of genomic regions in live cells.
The appropriate functioning of living cells depends on a variety of dynamic processes that necessitate delicate motion, transportation, association, and disassociation in time and space. Different dynamic patterns such as directed motion, normal diffusion, and restricted diffusion take part at different length scales, and their identification serves as a tool for exploring biochemical processes. Here we describe single-particle tracking which is a powerful method that allows the characterization of dynamic processes on the single-molecule or single-particle level with nanometer spatial and sub-second temporal precision. In particular, we describe the cell preparation procedures, microscopy imaging, and image analysis processes for following telomere dynamics in living mammalian cells.


Long-Term Results in Recipients of Late Conversion to a Calcineurin Inhibitor-Free Regimen with Everolimus After Kidney Transplantation.
Conversion to a calcineurin inhibitor (CNI)-free regimen in cases of CNI nephrotoxicity (CNIT) is a strategy to improve the long-term outcomes of kidney transplantation. However, the long-term results of late conversion to a CNI-free regimen using everolimus (EVR) remain uncertain. Nine kidney transplant recipients with biopsy-confirmed CNIT were enrolled. The median time of CNIT diagnosis was 9.0 years. All recipients underwent a conversion from CNI to EVR. We evaluated the clinical outcomes, development of donor-specific antibody (DSA), the incidence of rejection, alternative arteriolar hyalinosis (aah) scores, renal function changes, and T cell responses by mixed lymphocyte reaction (MLR) assay after conversion. The median follow-up after conversion was 5.4 years. Currently, 7 of 9 recipients have received a CNI-free regimen for 1.6 to 9.5 years. In the other 2 recipients, one experienced graft loss due to CNIT 3.8 years after conversion, and the other had to resume CNI due to acute T cell-mediated rejection (ATMR) a year after conversion. None of the recipients developed DSA. No rejection was observed in the kidney allograft histology except for the ATMR case. Moreover, improvement in aah scores was noted in one patient. Furthermore, serum creatinine levels were stable in recipients without proteinuria before the EVR add-on. In the MLR analysis, low responses against donors were observed in stable patients. Late conversion to an EVR-based regimen without CNI may be a promising therapeutic strategy against CNIT, particularly for recipients without proteinuria before the EVR add-on.


Long-term efficacy and safety of tretinoin emollient cream 0.05% in the treatment of photodamaged facial skin: a two-year, randomized, placebo-controlled trial.
Long-term (>1 year) placebo-controlled studies of tretinoin in the treatment of photodamaged skin have not been conducted. Recently, we conducted a 2-year placebo-controlled study of tretinoin emollient cream 0.05%, including histopathologic assessment of safety and analysis of markers of collagen deposition. The objective of the study was to determine the long-term safety and efficacy of tretinoin emollient cream 0.05% in the treatment of moderate to severe facial photodamage. A total of 204 subjects were treated with tretinoin or placebo (vehicle emollient cream) applied to the entire face once a day for up to 2 years. Clinical and histologic effects were assessed at regularly scheduled clinic visits. Treatment with tretinoin resulted in significantly greater improvement relative to placebo in clinical signs of photodamage (fine and coarse wrinkling, mottled hyperpigmentation, lentigines, and sallowness), overall photodamage severity, and investigator's global assessment of clinical response (p<0.05). Histologic evaluation showed no increase in keratinocytic or melanocytic atypia, dermal elastosis, or untoward effects on stratum corneum following treatment with tretinoin compared with placebo. Immunohistochemistry studies, conducted at three study centers, showed a significant increase relative to placebo in facial procollagen 1C terminal, a marker for procollagen synthesis, at month 12 (p=0.0074). Long-term treatment with tretinoin emollient cream 0.05% is safe and effective in subjects with moderate to severe facial photodamage.


Engineering Hematopoietic Stem Cells: Lessons from Development.
Cell engineering has brought us tantalizingly close to the goal of deriving patient-specific hematopoietic stem cells (HSCs). While directed differentiation and transcription factor-mediated conversion strategies have generated progenitor cells with multilineage potential, to date, therapy-grade engineered HSCs remain elusive due to insufficient long-term self-renewal and inadequate differentiated progeny functionality. A cross-species approach involving zebrafish and mammalian systems offers complementary methodologies to improve understanding of native HSCs. Here, we discuss the role of conserved developmental timing processes in vertebrate hematopoiesis, highlighting how identification and manipulation of stage-specific factors that specify HSC developmental state must be harnessed to engineer HSCs for therapy.


Earliest renin containing cell differentiation during ontogenesis in the rat. An immunocytochemical study.
The differentiation of renin containing cells was studied by immunocytochemistry in normal rat fetuses by the use of highly specific renin, angiotensin I and II antisera. Renin synthesizing cells were detectable as early as the 15th day of gestation outside the nephrogen territories within the walls of mesonephrotic-gonadic and renal arteries. Intrarenal differentiation began at the 17th day and progressed along the intrarenal arterial tree. AII immunostaining appeared concomitantly in the renin containing cells and developed considerably during ontogenesis, suggesting intracellular biosynthesis. It can be suggested that in the fetus newly synthesized AII may contribute to the early systemic and renal blood pressure regulation.


Influence of dicarboxylic phosphatidylcholines on phosphatidylcholine liposomes as revealed by gel chromatography and electron microscopy.
The effect of dicarboxylic phosphatidylcholines (glutarylphosphatidylcholine) on the structural changes of phosphatidylcholine liposomes is examined by using multilamellar liposomes prepared with egg phosphatidylcholine or dipalmitoylphosphatidylcholine and by varying the surface charge by addition of dicetyl phosphate. Investigations are performed by gel chromatography and electron microscopy. Glutarylphosphatidylcholine is in micellar form (rod-like micelles or globular micelles). The structures obtained depend on the fatty acid saturation of liposomes and on the charge of liposome (addition or not of dicetyl phosphate). With egg phosphatidylcholine/glutarylphosphatidylcholine dispersions, an aspect more similar to myelinic figures than liposomes is observed, while in the presence of dicetyl phosphate, liposomes similar to control egg phosphatidylcholine liposomes are obtained. Gel chromatography on Sepharose 4B and turbidity measurements prove that dicetyl phosphate increases the stability of egg phosphatidylcholine/glutarylphosphatidylcholine mixtures. On the other hand, in dipalmitoylphosphatidylcholine/glutarylphosphatidylcholine dispersions, incorporation of dicetyl phosphate destabilizes bilayer structure and the formation of mixed micelles occurs. Viscosity measurement shows, in the presence of dicetyl phosphate, an increased fluidity for dipalmitoylphosphatidylcholine/glutarylphosphatidylcholine dispersions, in agreement with the micellar organization. These data confirm that the disorganization of liposomal membranes by dicarboxylic phosphatidylcholine depends on the fatty acid composition of phosphatidylcholine and on the presence of dicetyl phosphate.


CRISPR-FISH: A CRISPR/Cas9-Based In Situ Labeling Method.
Fluorescence in situ hybridization (FISH) has been widely used to visualize target DNA sequences in fixed chromosome samples by denaturing the dsDNA to allow complementary probe hybridization, thus damaging the chromatin structure by harsh treatments. To overcome this limitation, a CRISPR/Cas9-based in situ labeling method was developed, termed CRISPR-FISH. This method is also known as RNA-guided endonuclease-in situ labeling (RGEN-ISL). Here we present different protocols for the application of CRISPR-FISH on acetic acid: ethanol or formaldehyde-fixed nuclei and chromosomes as well as tissue sections for labeling repetitive sequences in a range of plant species. In addition, methods on how immunostaining can be combined with CRISPR-FISH are provided.


Spread of varicella-zoster virus DNA to the environment from varicella patients who were treated with oral acyclovir.
The purpose of the present study was to determine the degree of spread of varicella-zoster virus to the environment (VZV) from varicella patients who received oral acyclovir treatment. Over a period of 8 months, seven healthy children (two girls and five boys, 23-64 months of age) with varicella who visited Fujita Health University School of Medicine were treated with routine doses of oral acyclovir (ACV) for 5 days, commencing within 24 h after onset of the disease. Swab samples from the throats of patients and their family members as well as from air purifier filters in their houses were collected for 7 days as frequently as possible after starting treatment for the disease. The VZV DNA in the samples was identified by a sensitive polymerase chain reaction amplification assay. The VZV DNA was detected in 33-100% of throat swab samples from varicella patients by day 7 of the disease, in 17-32% of throat swab samples from family members by day 4 and in 29% of filters from air purifiers by day 3. The results suggest a broad spread of VZV, probably by the airborne route, from the patients with varicella even after the administration of oral ACV.


[Insulinotropic action of hippocampal cholinergic neurostimulating peptide mediated by activated type 3 muscarinic receptor in INS-1 cells].
[corrected] To characterize the insulinotropic action of hippocampal cholinergic neurostimulating peptide (HCNP) and analyze the role of type 3 muscarinic receptor (M(3)R) pathway in the action of HCNP. INS-1 cells were incubated in routine RPMI 1640 medium (control group), RPMI 1640 supplemented with 50 pg/ml synthetic HCNP (HCNP group), or HCNP-containing medium with the addition of PMA 18 h prior to insulin release assay. The insulin levels in the medium was measured using radioimmunoassay following stimulation with different concentrations of glucose. Real-time quantitative PCR was used for detecting the gene expression of HCNP-pp, choline acetyltransferase (ChAT) and M(3)R in HCNP group and control group. After stimulation with different concentrations of glucose (5.6 and 16.7 mmol/L), HCNP group showed significantly higher insulin levels than the control and HCNP+ PMA groups. Compared with those in the control group, the mRNA levels of HCNP-pp, ChAT, and M(3)R were all lowered in HCNP group. HCNP can promote insulin release in INS-1 cells by increasing ChAT activity and activating M(3)R, and this effect is inhibited by PMA.


Interaction between proteins and detergents which contain a hydrocarbon chain longer than 16 carbon atoms. II. Difference spectra of various proteins in cetyldimethyl-benzylammonium chloride.
The detergents which contain a hydrocarbon side chain longer than 16 cabron atoms were used as a perturbant for the study of protein structure. ta low concentration of cetyldimethylbenzylammonium chloride (CDBA) caused difference spectra for Ac-Trp-OEt and AC-Tyr-OEt. The delta e values at their difference maxima became constant above 30 mM of cetyldimethylbenzylammonium chloride, 1430 at 294 nm for Ac-Trp-OEt and 450 at 288 nm for Ac-Tyr-OEt. These delta e values are higher than any other delta e values resulting from solvent effects by such a remarkably low concentration of organic reagents described in the literature so far. The absence of denaturation blue shift in the difference spectra and the fact that the optical rotatory dispersion of the proteins examined in the present study was not changed significantly by cetyldimethylbenzylammonium chloride indicate that the secondary and tertiary structures of the proteins were not destroyed by cetyldimethylbenzylammonium chloride. These characteristics, together with small overlapping of their difference spectra at 288 and 294 nm were advantageous in the determination of tryptophan and tyrosine residues exposed in glucagon, insulin and alcohol dehydrogenase from yeast. No tyrosine residues in ribonuclease A was accessible to cetyldimethylbenzylammonium chloride. Unusual difference spectrum with a peak at 298 nm was observed for lysozyme which is known to contain tryptophan residues in special environments. Ovalbumin gave a novel unusual difference spectrum with a peak at 290 nm and a shoulder at 298 nm, showing the existence of unusual tryptophan and probably tyrosine residues in the molecule.


Column spacing in normal and visually deprived monkeys.
A recent model for the development of the pattern of eye-dominance domains in primary visual cortex predicts that stimulus conditions during early visual life determine the spacing (or periodicity) of ocular dominance columns (ODC). The model predicts that normal binocular visual experience consists of highly correlated binocular stimulation and leads to relatively narrow ODC spacing, while abnormal binocular visual stimulation attendant with strabismus consists of non-correlated, incoherent, and asynchronous stimulation and leads to wider than normal ODC spacing. Evidence in support of the model has been presented for strabismus in the kitten. We tested the predictions of the model in normal monkeys and others subjected to various forms of abnormal visual experience during infancy. We identified and measured the inter-column spacing (or periodicity) in the V1 cortex of 19 adult monkeys (M. mulatta) using the cytochrome-oxidase (CO) histochemical method. There were no significant differences in the V1 inter-column spacing between normal adult monkeys (n=5) and other adult monkeys having had monocular-form deprivation (n=5), experimental anisometropia (n=5), or experimental strabismus (n=4) early in life. The quality of early binocular visual experience is not a significant determinant of the inter-column spacing in primate V1 cortex. Therefore, the model predicting an increase in the ODC periodicity with strabismus is not supported.


Implementation outcome instruments for use in physical healthcare settings: a systematic review.
Implementation research aims to facilitate the timely and routine implementation and sustainment of evidence-based interventions and services. A glaring gap in this endeavour is the capability of researchers, healthcare practitioners and managers to quantitatively evaluate implementation efforts using psychometrically sound instruments. To encourage and support the use of precise and accurate implementation outcome measures, this systematic review aimed to identify and appraise studies that assess the measurement properties of quantitative implementation outcome instruments used in physical healthcare settings. The following data sources were searched from inception to March 2019, with no language restrictions: MEDLINE, EMBASE, PsycINFO, HMIC, CINAHL and the Cochrane library. Studies that evaluated the measurement properties of implementation outcome instruments in physical healthcare settings were eligible for inclusion. Proctor et al.'s taxonomy of implementation outcomes was used to guide the inclusion of implementation outcomes: acceptability, appropriateness, feasibility, adoption, penetration, implementation cost and sustainability. Methodological quality of the included studies was assessed using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. Psychometric quality of the included instruments was assessed using the Contemporary Psychometrics checklist (ConPsy). Usability was determined by number of items per instrument. Fifty-eight publications reporting on the measurement properties of 55 implementation outcome instruments (65 scales) were identified. The majority of instruments assessed acceptability (n = 33), followed by appropriateness (n = 7), adoption (n = 4), feasibility (n = 4), penetration (n = 4) and sustainability (n = 3) of evidence-based practice. The methodological quality of individual scales was low, with few studies rated as 'excellent' for reliability (6/62) and validity (7/63), and both studies that assessed responsiveness rated as 'poor' (2/2). The psychometric quality of the scales was also low, with 12/65 scales scoring 7 or more out of 22, indicating greater psychometric strength. Six scales (6/65) rated as 'excellent' for usability. Investigators assessing implementation outcomes quantitatively should select instruments based on their methodological and psychometric quality to promote consistent and comparable implementation evaluations. Rather than developing ad hoc instruments, we encourage further psychometric testing of instruments with promising methodological and psychometric evidence. PROSPERO 2017 CRD42017065348.


Ceramide kinase regulates TNFα-stimulated NADPH oxidase activity and eicosanoid biosynthesis in neuroblastoma cells.
A persistent inflammatory reaction is a hallmark of chronic and acute pathologies in the central nervous system (CNS) and greatly exacerbates neuronal degeneration. The proinflammatory cytokine tumor necrosis factor alpha (TNFα) plays a pivotal role in the initiation and progression of inflammatory processes provoking oxidative stress, eicosanoid biosynthesis, and the production of bioactive lipids. We established in neuronal cells that TNFα exposure dramatically increased Mg(2+)-dependent neutral sphingomyelinase (nSMase) activity thus generating the bioactive lipid mediator ceramide essential for subsequent NADPH oxidase (NOX) activation and oxidative stress. Since many of the pleiotropic effects of ceramide are attributable to its metabolites, we examined whether ceramide kinase (CerK), converting ceramide to ceramide-1-phosphate, is implicated both in NOX activation and enhanced eicosanoid production in neuronal cells. In the present study, we demonstrated that TNFα exposure of human SH-SY5Y neuroblastoma caused a profound increase in CerK activity. Depleting CerK activity using either siRNA or pharmacology completely negated NOX activation and eicosanoid biosynthesis yet, more importantly, rescued neuronal viability in the presence of TNFα. These findings provided evidence for a critical function of ceramide-1-phospate and thus CerK activity in directly linking sphingolipid metabolism to oxidative stress. This vital role of CerK in CNS inflammation could provide a novel therapeutic approach to intervene with the adverse consequences of a progressive CNS inflammation.


Orthodontic-aided extraction of impacted third molar to improve the periodontal status of the neighboring tooth.
In the present clinical report, we describe the management and the long-term (3-year) outcome of a periodontally compromised lower second molar healed by orthodontic-aided extraction of the neighboring impacted third molar. A healthy 21-year-old woman referred signs and symptoms of pericoronitis of impacted tooth 48 and periodontal injury on the distal aspect of tooth 47. The wisdom tooth was surgically exposed, and an orthodontic appliance was anchored to the neighboring teeth to stimulate eruption. After 5 months, third molar could be easily extracted. Three years after extraction, clinical and radiographic controls revealed a complete healing of the periodontal defect. Orthodontic-aided extraction of impacted third molars may improve the periodontal status of the neighboring tooth. This protocol is not free from drawbacks and limitations and should be applied only when third-molar extraction is associated with a concrete risk of postoperative complications.


Multiple pulmonary thromboembolism and severe depression.
Depression is known to have a bidirectional relationship with cardiovascular disease. Severe major depression associated with psychomotor retardation and immobility can be a risk factor for pulmonary embolism; the reverse pathway has not been reported. We report a case of a 61-year-old man diagnosed with multiple pulmonary thromboembolism finally attributed to a right pulmonary artery intraluminal sarcoma. One month after the onset of presenting symptoms, the patient suddenly developed an episode of severe, melancholic depression, which remitted in six weeks under treatment with venlafaxine 225 mg/day. Pathophysiological mechanisms implicated in the development of depression in our patient might resemble those postulated for post-myocardial infarction depression; in line with the "vascular depression" hypothesis, cerebral damage in the limbic circuitry caused by transient hypoxia, an inflammatory response or both may have contributed. Multiple pulmonary thromboembolism seems to have a bidirectional relationship with major depression, in a similar way as myocardial infarction does.


Characterization of GII.4 noroviruses circulating among children with acute gastroenteritis in Pune, India: 2005-2013.
Genogroup II genotype 4 noroviruses (GII.4 NoVs), an important cause of sporadic childhood gastroenteritis worldwide, undergo continuous evolution leading to the periodic emergence of novel variants. The present study was undertaken for surveillance of GII.4 NoVs and identification and characterization of GII.4 variants circulating among children with sporadic gastroenteritis in Pune, India during 2005-2013. Among the 12 GII genotypes detected in the study, GII.4 was predominant. Sequencing and phylogenetic analysis of ORF2 (major capsid protein VP1 gene) of the GII.4 NoVs revealed circulation of seven GII.4 variants, Hunter_2004 (2005-2007), Yerseke_2006a (2006), DenHaag_2006b (2007), Osaka_2007 (2007-2009), Apeldoorn_2007 (2008), New Orleans_2009 (2008-2012) and Sydney_2012 (2013), with the Pune strains grouping with the contemporary global reference strains. The Hunter_2004, Osaka_2007 and New Orleans_2009 variants showed prolonged circulation, with the Hunter_2004 and New Orleans_2009 variants differentiating into temporally separated sub-clusters. Analysis of VP1 sequences and predicted structures of the GII.4 variants identified variant specific amino acid positions, particularly in and near (within 8A(°)) the epitopes A-E, displaying differences in the sequence and physicochemical characteristics of the different variants. Comparison with the reference strains of each of the GII.4 variants revealed up to 11 amino acid substitutions at the variant specific positions in the GII.4 strains from Pune. Amino acid variations were also noted among the strains of the same GII.4 variant in Pune. The strains of different sub-clusters identified in the Hunter_2004 and New Orleans_2009 variants showed differences in sequence and physicochemical properties of either or all of the epitopes A, C and E. The study thus describes the temporal variations and diversity of the GII.4 strains in Pune and emphasizes continuous monitoring and analysis of the GII.4 variants.


Planning for the unexpected: Strategies for maintaining a robust clinical trial program.
During our entire history, Puerto Rico has suffered from being in the path of Hurricanes. The implications of these events during the conduction of clinical trials present a great challenge. On September 20, 2017 Puerto Rico suffered its most devastating hurricane in decades. We identified four main challenges faced as a result of the natural disaster: infrastructure damage, shortage of basic necessities, transportation difficulties and communication failure. By assessing the needs of each participant, we were able to aid with food, water and medicine. Protocols were resumed shortly after the disaster, participants were located and transportation to the research center was arranged for participants. Development of emergency plans within research protocols, allocation of emergency budgets, including transportation and communication costs, may overcome some of the challenges created by a natural disaster.


Subcellular distribution of radio-labelled iron during intestinal absorption in guinea-pig enterocytes with special reference to the mitochondrial localization of the iron.
1. 59Fe-labelled ferric chloride was introduced into tied loops of guinea-pig jejunum. 2. After 5--30 min the loop was removed, the enterocytes were isolated, homogenized and subjected to analytical subcellular fractionation. 3. Uptake of 59Fe was extremely rapid and after 5 min 45% of the radioactivity sedimented in the mitochondrial fraction. 4. Density gradient centrifugation indicated that approximately 80% of this radioactivity was associated with the mitochondria themselves; the remainder was in brush-border fragments. 5. Selective disruption of the mitochondria demonstrates that the iron is localized to the matrix and the inner membrane, indicating transport of the absorbed iron into the organelle. 6. It is suggested that mitochondria are actively implicated at an early stage in the intestinal transport of iron.


Levetiracetam pharmacokinetics in critically ill patients undergoing renal replacement therapy.
To determine clearance of levetiracetam in patients requiring continuous renal replacement therapy (CRRT) or sustained low efficiency dialysis (SLED). Adult patients with acute kidney injury or end stage renal disease requiring either CRRT or SLED and levetiracetam were eligible for inclusion. Simultaneous arterial, venous, and effluent samples for analysis of levetiracetam concentrations were collected every two hours for up to 6-8 h. Levetiracetam clearance (CL) and half-life (t1/2) were calculated for each modality. Eight CRRT patients and 4 SLED patients completed the study: 67% male, mean age 50 ± 13 years, and 83% had AKI. Seven CRRT patients received continuous venovenous hemodiafiltration (CVVHDF) [median pre-replacement rate 700 mL/h (range 500-1000), post-replacement rate 500 mL/h (range 200-1000), effluent rate 2500 mL/h (range 1700-3650) and delivered CRRT dose 27 mL/kg/h (range 19-54)] and one patient received CVV hemofiltration (CVVH). The mm mean levetiracetam CL during CVVHDF was 31.2 ± 8.5 mL/min, and the and the mean t1/2 was 10.4 ± 2.2 h. For the patient requiring CVVH, clearance and t1/2 were 22.5 mL/min and 9.5 h, respectively. Mean levetiracetam CL during SLED performed at a blood flow rate of 250 mL/min and a dialysate flow rate of 100 mL/min was 74.0 ± 25.3 mL/min and t1/2 was 4.8 ± 2.3 h. Levetiracetam clearance was substantial with both modalities under the operating conditions reported. There is the potential for subtherapeutic concentrations with current recommended dosing strategies that account only for kidney function and not these extracorporeal routes of elimination.


Why solid-state fermentation is more advantageous over submerged fermentation for converting high concentration of glycerol into Monacolin K by Monascus purpureus 9901: A mechanistic study.
The underlying mechanisms by which solid-state fermentation (SSF) was more advantageous over submerged fermentation (SmF) for converting high concentration of glycerol into Monacolin K by Monascus purpureus were investigated innovatively. First, the established kinetic models and kinetic parameters showed that the cell growth, Monacolin K formation and glycerol consumption in SSF were more rapid than those in SmF. Secondly, the comparison of fatty acid composition of mycelial cells indicated a better fluidity and permeability of the cell membrane in SSF than that of SmF, which was also consistent with the difference in the ratio of extracellular/intracellular Monacolin K between the two systems. Thirdly, the phenomenon of glycerol concentration gradient was verified in SSF, which could well explain the resistance effect to high concentration of glycerol in SSF. These new findings provide some important insights to the elucidation of the advantages of SSF for the synthesis of fungal secondary metabolites.


Comparison of three molecular methods used for subtyping of Legionella pneumophila strains isolated during an epidemic of Legionellosis in Rome.
In the summer of 2003 a community-acquired outbreak of Legionella pneumophila occurred in Rome, Italy. Three molecular typing methods, pulse-field gel electrophoresis, amplified fragment length polymorphism analysis, and sequence-based typing (SBT), were used to establish the clonal correlation among the isolates of the epidemic cluster. By comparison of the methods, SBT was the most rapid and the easiest to perform and provided unambiguous results.