Enhanced removal of mercury and lead by a novel and efficient surface-functionalized imogolite with nanoscale zero-valent iron material.
A novel hybrid nanomaterial, nanoscale zero-valent iron (nZVI)-grafted imogolite nanotubes (Imo), was synthesized via a fast and straightforward chemical procedure. The as-obtained nanomaterial (Imo-nZVI) was characterized using transmission electron microscopy (TEM), electrophoretic mobility (EM), and vibrating sample magnetometry (VSM). The prepared Imo-nZVI was superparamagnetic at room temperature and could be easily separated by an external magnetic field. Sorption batch experiments were performed for single- and multicomponent systems and demonstrated that Hg2+ and Pb2+ could be quantitatively adsorbed at pH 3.0. For multicomponent systems, maximum adsorption capacities of 61.6 mg·g-1 and 76.9 mg·g-1 were obtained for Hg2+ and Pb2+ respectively. It was observed that the functional groups in Imo-nZVI interact preferentially with analytes according to the Misono softness parameter. The higher performance of Imo-nZVI compared with Imo and nZVI is related to the increased number of adsorption sites in the functionalized nanomaterial. The sorption equilibrium data obeyed the Langmuir model, while kinetic studies demonstrated that the sorption processes of Hg2+ and Pb2+ followed the pseudo-second-order model. This study suggests that the Imo-nZVI composite can be used as a promising sorbent to provide a simple and fast separation method to remove Hg and Pb ions from contaminated water.


Biological effects of shock waves: kidney damage by shock waves in dogs--dose dependence.
The effect of shock waves on normal canine kidneys was examined in three groups of dogs whose right kidneys were exposed to 500, 1500, or 3000 shock waves. Autopsy was performed 24-30 h later. The kidneys were enlarged with haemorrhages in the outer and inner renal capsule and intraparenchymally. Macroscopically intraparenchymal haemorrhages were restricted to the high pressure field of the shock wave and consisted of haematomas up to 18 mm diameter (most frequently 6 mm or less) and diffuse haemorrhages. Histologically, haemorrhages were shown to originate from interlobular and arcuate veins. Venous thrombosis, tubular dilatation, and diffuse interstitial haemorrhage occurred in the same area. The number of haematomas was larger, and diffuse haemorrhages were more extended after the application of 1500 and 3000 than after 500 shock waves. No difference was seen between 1500 and 3000 shock waves.


Analysis of acute pain scores and skin conductance measurements in infants.
Skin conductance (SC) has been previously used to measure acute post-operative pain in adults and older children (>1year old).We have investigated the ability of SC to predict the severity of post-operative pain scores in the exclusively infant population. Infants (ages 6-12months) scheduled for elective surgery were recruited for the study. Data for behavioral pain scores and SC values - frequency of electrodermal responses per second (EDR/s), peak and basal levels, were recorded in the post-anesthesia care unit (PACU). Blood samples were collected for genomic studies, including single nucleotide polymorphisms (SNP) in morphine opioid receptor (MOR) A118G and the catechol-O-methyltransferase (COMT) G1947A genes. 31 infants, mean age 8.9months (±1.9); mean weight 8.5kg (±1.1) were included in the final study analysis. With every 0.1 unit increase in peak values noted on SC, the odds of higher pain scores were found to be 5% greater (p=0.03). For predictability of moderate to severe pain, the area under the curve, sensitivity and specificity were 0.64, 90.9% and 51.4% respectively for peak values and 0.66, 54.5% and 79.4% respectively for EDR/s values. Genotyping performed in 16 out of 31 infants demonstrated that the carriers of MOR 118G allele had consistently higher basal SC values in the PACU. Peak SC values may serve as indicators of unmitigated pain. Further studies are needed to fully investigate the effect of MOR A118G SNP on the post operative pain scores and SC values in the larger infant population in order to validate both the clinical significance of the skin conductance for routine pain assessment in infants and the observed genetic effect.


[Mandibular fibrous dysplasia: a monostotic form].
The onset of one or several diastema in adults with no link of etiology to tooth loss or to a periodontal problem can be the first evocative sign of an acromegaly or a benign or malignant tumoral process. A 40-year-old patient consulted for an implant to solve an esthetic problem caused by a diastema. The complementary exams revealed an osteolytic lesion marked by condensing areas. The biopsy proved the diagnosis of fibrous dysplasia. Etiologies of fibrous dysplasia are varied. They can be related to a congenital defect of osteo mesenchyma development or be the consequence of trauma, reaction to infection, or an endocrine or metabolic disorder.


Engineering Yarrowia lipolytica for production of medium-chain fatty acids.
Lipids are naturally derived products that offer an attractive, renewable alternative to petroleum-based hydrocarbons. While naturally produced long-chain fatty acids can replace some petroleum analogs, medium-chain fatty acid would more closely match the desired physical and chemical properties of currently employed petroleum products. In this study, we engineered Yarrowia lipolytica, an oleaginous yeast that naturally produces lipids at high titers, to produce medium-chain fatty acids. Five different acyl-acyl carrier protein (ACP) thioesterases with specificity for medium-chain acyl-ACP molecules were expressed in Y. lipolytica, resulting in formation of either decanoic or octanoic acid. These novel fatty acid products were found to comprise up to 40 % of the total cell lipids. Furthermore, the reduction in chain length resulted in a twofold increase in specific lipid productivity in these engineered strains. The medium-chain fatty acids were found to be incorporated into all lipid classes.


Short synthesis of the CDEF ring system of lactonamycin.
[reaction: see text]. A synthesis of the CDEF fragment of lactonamycin is achieved in eight steps (six pots) from the known and readily available anhydride 4 via a Diels-Alder reaction between tricycle 13 and 2,3-dimethylbenzoquinone.


Handling missing values in machine learning to predict patient-specific risk of adverse cardiac events: Insights from REFINE SPECT registry.
Machine learning (ML) models can improve prediction of major adverse cardiovascular events (MACE), but in clinical practice some values may be missing. We evaluated the influence of missing values in ML models for patient-specific prediction of MACE risk. We included 20,179 patients from the multicenter REFINE SPECT registry with MACE follow-up data. We evaluated seven methods for handling missing values: 1) removal of variables with missing values (ML-Remove), 2) imputation with median and unique category for continuous and categorical variables, respectively (ML-Traditional), 3) unique category for missing variables (ML-Unique), 4) cluster-based imputation (ML-Cluster), 5) regression-based imputation (ML-Regression), 6) missRanger imputation (ML-MR), and 7) multiple imputation (ML-MICE). We trained ML models with full data and simulated missing values in testing patients. Prediction performance was evaluated using area under the receiver-operating characteristic curve (AUC) and compared with a model without missing values (ML-All), expert visual diagnosis and total perfusion deficit (TPD). During mean follow-up of 4.7 ± 1.5 years, 3,541 patients experienced at least one MACE (3.7% annualized risk). ML-All (reference model-no missing values) had AUC 0.799 for MACE risk prediction. All seven models with missing values had lower AUC (ML-Remove: 0.778, ML-MICE: 0.774, ML-Cluster: 0.771, ML-Traditional: 0.771, ML-Regression: 0.770, ML-MR: 0.766, and ML-Unique: 0.766; p < 0.01 for ML-Remove vs remaining methods). Stress TPD (AUC 0.698) and visual diagnosis (0.681) had the lowest AUCs. Missing values reduce the accuracy of ML models when predicting MACE risk. Removing variables with missing values and retraining the model may yield superior patient-level prediction performance.


Cold-water coral diversity along the continental shelf margin of northwestern South China Sea.
Scleractinian cold-water corals (CWCs) are one of the most important habitat engineers of the deep sea. Although the South China Sea (SCS) abuts the biodiversity center of scleractinian CWCs in the western Pacific, only a few sporadic records are available. We discovered new CWC sites by means of trawl sampling and video observation along the continental shelf of the northwestern SCS. All trawled scleractinian CWC specimens were identified to species level according to skeleton morphology and structure. The living CWCs and associated fauna recorded in the video were -identified to a higher level of classification. Scleractinian corals were identified to genus level, while non-scleractinian CWCs were identified to family level and given general names such as gorgonian corals, bamboo corals and black corals. Associated benthic dwellers were divided into major categories. A total of 28 scleractinian CWC species were identified to 7 families, 15 genera, and 1 additional subgenus. Among them, 13 species were colonial, including important habitat-forming species in the genera Eguchipsammia, Dendrophyllia and Cladopsammia. Non-scleractinian CWCs were identified to 7 families, including 4 families gorgonian corals, 1 family bamboo corals, and 2 families black corals. Gorgonian corals were the most abundant non-scleractinian CWCs in this region. Meanwhile, starfish, sea anemones, fish, gastropods, echinoderms, and other associated benthic fauna were recorded in the CWC habitats, with starfish belonging to the order Brisingida being most common. New scleractinian CWC assemblages were discovered along the continental seabed mounds in the northwestern SCS. This study highlights the remarkable diversity of cold-water scleractinian corals in the whole SCS, and shows the potential widespread distribution and conservation prospect of CWC habitats in this region.


Peripheral blood mononuclear cells from IgE- and non-IgE-associated allergic atopic eczema/dermatitis syndrome (AEDS) demonstrate increased capacity of generating interleukin-13 but differ in their potential of synthesizing interferon-gamma.
A subgroup of patients with allergic atopic eczema/dermatitis syndrome (AEDS) are known to have normal total and specific IgE levels and negative skin prick tests towards common environmental allergens. This form of the disease has been termed non-IgE-associated allergic AEDS. Although allergic mechanisms appear to be important, the pathogenesis of both IgE- and non-IgE-associated forms of the disease is unknown. We have compared the cytokine production pattern of peripheral blood mononuclear cells (PBMC) from IgE-associated AEDS, non-IgE-associated AEDS, and normal control individuals. PBMC were stimulated with anti-CD3 and/or anti-CD28 monoclonal antibodies (mAb) and cytokine production was measured by immunoassays in supernatants of 24-h cultures. Compared to healthy subjects and non-IgE-associated AEDS patients, stimulated PBMC from IgE-associated AEDS patients produced less interferon (IFN)-gamma. However, stimulated PBMC from both IgE-associated AEDS and non-IgE-associated AEDS patients produced more interleukin (IL)-13 than PBMC from control individuals. Moreover, IL-5 production was significantly increased in non-IgE-associated AEDS but not in IgE-associated AEDS patients. The underlying mechanism leading to increased differentiation of T helper (Th) 2 cells may involve a deficient capacity in producing IFN-gamma in IgE-associated AEDS but not in non-IgE-associated AEDS patients. IL-13 may be a key cytokine in the pathogenesis of both allergic forms of AEDS.


Opioid agonist therapy and mortality among First Nations and other residents with concurrent alcohol use disorder in British Columbia, Canada: A population-based cohort study.
Despite the prevalence of alcohol use among people with opioid use disorder (PWOUD) engaged in opioid agonist therapy (OAT), clinical care guidance for concurrent alcohol use disorder (AUD) and OUD is scarce. We assessed the prevalence and risk of mortality for concurrent AUD among PWOUD who accessed OAT in British Columbia (BC). Data were obtained from six linked population-level health administrative datasets to identify PWOUD from January 1996 to March 2020. All-cause age and sex standardized mortality ratios (SMR) were calculated to determine the mortality risk by OAT status (on vs. discontinued), stratified by First Nations and other residents with concurrent AUD and OUD. Adjusted risk ratios compared the relative risk of mortality by AUD status (AUD detected vs. not) among First Nations and other residents. We identified 62,110 PWOUD who received OAT, including 6305 (10.2%) First Nations. OAT substantially lowered the SMR among First Nations (SMR=6.6, 95% CI: 5.4-8.1) and other residents (SMR=6.6; 95% CI: 6.2-7.0) with concurrent AUD and OUD, compared to those who discontinued (SMR=22.7, 95% CI: 20.4-25.1, SMR=17.5, 95% CI: 16.8-18.2 respectively). The risk of mortality was 1.9 (95% CI: 1.6-2.2) times higher for First Nations and 2.0 (95% CI: 1.8-2.2) times higher for other residents with concurrent OUD and AUD compared to those without an indication of AUD. The protective effect of OAT remained despite the presence of a concurrent AUD among both First Nations and other residents with OUD. Findings have implications for clinical care management of concurrent disorders.


Phthalate exposure and childhood overweight and obesity: Urinary metabolomic evidence.
Metabolomics may unravel global metabolic changes in response to environmental exposures and identify important biological pathways involved in the pathophysiology of childhood obesity. Phthalate has been considered an obesogen and contributing to overweight and obesity in children. The purpose of this study is to evaluate changes in urine metabolites in response to the environmental phthalate exposure among overweight or obese children, and to investigate the metabolic mechanisms involved in the obesogenic effect of phthalate on children at puberty. Within the national Puberty Timing and Health Effects in Chinese Children (PTHEC) study, 69 overweight/obese children and 80 normal weight children were selected into the current study according to their puberty timing and WGOC (The Working Group for obesity in China) references. Urinary concentrations of six phthalate monoesters (MMP, MEP, MnBP, MEHP, MEOHP and MEHHP) were measured using API 2000 electrospray triple quadrupole mass spectrometer (ESIMS/MS). Metabolomic profiling of spot urine was performed using gas chromatography-mass spectrometry. Differentially expressed urinary metabolites associated with phthalate monoesters exposure were examined using orthogonal partial least square-discriminant analysis and multiple linear regression models. In addition, the candidate metabolites were regressed to obesity indices with multiple linear regression models and logistic regression models in all subjects. Compared with normal weight children, higher levels of MnBP were detected in urinary samples of children with overweight and obesity. After adjusting for confounders including chronological age, gender, puberty onset, daily energy intake and physical activity and socio-economic level, positive association remained between urinary MnBP concentration and childhood overweight/obesity [OR = 1.586, 95% CI:1.043,2.412]. We observed elevated MnBP concentration was significantly correlated with increased levels of monostearin, 1-monopalmitin, stearic acid, itaconic acid, glycerol 3-phosphate, 5-methoxytryptamine, kyotorphin, 1-methylhydantoin, d-alanyl-d-alanine, pyrrole-2-carboxylic acid, 3,4-Dihydroxyphenylglycol, and butyraldehyde. Meanwhile, increased MnBP concentration was also significantly correlated with decreased levels of lactate, glucose 6-phosphate, d-fructose 6-phosphate, palmitic acid, 4-acetamidobutyric acid, l-glutamic acid, n-acetyl-l-phenylalanine, iminodiacetic acid, hydroxyproline, pipecolinic acid, l-ornithine, n-acetyl-l-glutamic acid, guanosine, cytosin, and (s)-mandelic acid in the normal weight subjects. The observations indicated that MnBP exposure was related to global urine metabolic abnormalities characterized by disrupting arginine and proline metabolism and increasing oxidative stress and fatty acid reesterification. Among the metabolic markers related to MnBP exposure, 1-methylhydantoin, pyrrole-2-carboxylic acid and monostearin were found to be positively correlated with obesity indices, while hydroxyproline, l-ornithine, and lactate were negatively associated with overweight/obesity in children. Our results suggested that the disrupted arginine and proline metabolism associated with phthalate exposure might contribute to the development of overweight and obesity in school-age children, providing insights into the pathophysiological changes and molecular mechanisms involved in childhood obesity.


Concentrations and isotope ratios of mercury in sediments from shelf and continental slope at Campos Basin near Rio de Janeiro, Brazil.
Mercury (Hg) may originate from both anthropogenic and natural sources. The measurement of spatial and temporal variations of Hg isotope ratios in sediments may enable source identification and tracking of environmental processes. In this study we establish the distribution of mercury concentrations and mercury isotope ratios in surface sediments of three transects along the continental shelf and slope in Campos Basin-RJ-Brazil. The shelf showed on average lower total Hg concentrations (9.2 ± 5.3 ng g-1) than the slope (24.6 ± 8.8 ng g-1). MMHg average concentrations of shelf 0.15 ± 0.12 ng g-1 and slope 0.13 ± 0.06 ng g-1 were not significantly different. Distinct differences in Hg isotope ratio signatures were observed, suggesting that the two regions were impacted by different sources of Hg. The shelf showed more negative δ202Hg and Δ199Hg values ranging from -0.59 to -2.19‰ and from -0.76 to 0.08‰, respectively. In contrast, the slope exhibited δ202Hg values from -0.29 to -1.82‰ and Δ199Hg values from -0.23 to 0.09‰. Mercury found on the shelf, especially along the "D" and "I" transects, is depleted in heavy isotopes resulting in more negative δ202Hg compared to the slope. Isotope ratios observed in the "D" and "I" shelf region are similar to Hg ratios commonly associated with plants and vegetation and very comparable to those detected in the estuary and adjoining mangrove forest, which suggests that Hg exported from rivers may be the dominating source of Hg in near coastal regions along the northern part of the shelf.


Mediterranean Talitrus saltator (Crustacea, Amphipoda) as a biomonitor of heavy metals contamination.
The use of sandhoppers and beachfleas as biomonitors of heavy metals contamination is relatively recent. Using adult individuals of Talitrus saltator from nine localities on the northern Mediterranean Sea, we studied the concentrations of eight trace elements: Al, Cd, Cr, Fe, Hg, Pb, Cu, Zn, both in the substratum and in the individuals. We also carried out a preliminary investigation of the correspondence between the sandhoppers' genetic variability and heavy metal contamination at the sampling sites. T. saltator accumulated Cd, Cu, Zn and Hg (at higher concentrations than in the sand) and also Al and Fe (at lower concentrations than in the sand). It seems that Mediterranean sandhoppers do not accumulate Pb and Cr. An intraspecific comparison between northern European (Baltic) and Mediterranean populations of T. saltator was made. Finally, we observed a tendency to a positive correlation between the sandhoppers' genetic variability and heavy metals contamination.


Outcome after total knee arthroplasty in haemophilic patients with stiff knees.
Advanced haemophilic arthropathy of the knee is associated with progressive joint stiffness. Results after total knee arthroplasty (TKA) in stiff knees are considered to be inferior compared to those with less restricted preoperative range of motion (ROM). There is only very limited data on the results of primary TKA in haemophilic patients with stiff knees. The purpose of this retrospective study was to evaluate the clinical outcome after TKA performed in haemophilic patients with preoperative ROM of 50° or less. Twenty one patients (23 knees) undergoing TKA with stiff knees were retrospectively evaluated. Mean follow-up was 8.3 years (range, 2-25). Clinical assessment included ROM, degree of flexion contracture and complication rate. Functional evaluation and pain status were assessed using the Knee Society's Scoring System (KSS). Range of motion improved from 26.7° preoperatively to 73.0° postoperatively. Flexion contracture decreased from 21.7° to 8.3°. KSS increased from 22.9 to 72.9 points. Evaluation of pain revealed a decrease from 8.4 points preoperatively to 2.1 points postoperatively. All these differences were statistically significant (P < 0.005). The complication rate was 8.7% including one late periprosthetic infection, and one aseptic implant loosening. Nine patients who required VY-quadricepsplasty for knee exposure developed a mean postoperative extensor lag of 7°. Total knee arthroplasty in haemophilic patients presenting with stiff knees results in significant improvement of function and reduction in pain. Although the clinical outcome is inferior compared to nonstiff knees reported in the literature, joint replacement surgery can be successfully performed in this particular group of patients.


Molecular and serological characterization of the first Leptospira santarosai strain isolated from a dog.
Leptospirosis is a zoonotic disease of global importance caused by pathogenic Leptospira species. Dogs can become asymptomatically infected, acting like reservoir hosts for pathogenic Leptospira, notably Leptospira interrogans serovar Canicola. Identification of such individuals and characterization of leptospires involved in chronic infections may unravel the role of dogs in the epidemiology of particular leptospiral strains. The aim of the present work was to describe the first Leptospira santarosai strain isolated from a dog. The dog was kept in a public shelter in São Paulo city, Brazil, and presented asymptomatic urinary shedding detected by PCR. Prospective evaluation was performed to fully characterize its chronic carrier state. The dog did not present anti-Leptospira titles or clinical/laboratorial abnormalities during the evaluations; nevertheless long-term urinary shedding was confirmed by PCR and leptospires were recovered from two occasions. The isolated strain was molecularly characterized by partial 16S rRNA and secY gene sequencing and MLST analysis. Serogroup identification was performed using polyclonal antibodies. The strain was identified as Leptospira santarosai, serogroup Sejroe. This is the first evidence in the literature of the isolation of L. santarosai in dogs. Our findings show that dogs can persistently harbor leptospires other than L. interrogans.


Process Mapping - The Foundation for Effective Quality Improvement.
Process maps are a key quality improvement tool used to visualize how healthcare, and its complex processes, are delivered. It is used for determining the step by step flow of the process, its timing, handoffs, and identifying outputs that can be visualized, measured, and studied. Due to the complexity of healthcare, process mapping must be a foundational element of both healthcare process design and quality improvement.


Detection of orthodontically induced inflammatory root resorption-associated biomarkers from the gingival crevicular fluid by proteomics analysis: a randomized-controlled clinical trial.
Orthodontically induced inflammatory root resorption (OIIRR) is an undesirable complication of orthodontic treatment (OT) with an ambiguous aetiologic mechanism. This study aimed to identify OIIRR-associated biomarkers in the gingival crevicular fluid (GCF) using proteomic analysis. In this randomized clinical trial, the upper first premolars (UFP) were exposed either to light or heavy force. The GCF was collected at 1 h, 1 day, 7 days, 14 days, 21 days, and 28 days following force application. After extraction of UFP, roots were imaged and resorption premolar, was used to deliver either light forcecraters were measured. Proteomic analysis of GCF was performed using 2D gel electrophoresis with MALDI-TOF/TOF MS/MS. Results were further analyzed by bioinformatics analyses showing the biological functions and predicted pathways. The predicted canonical pathways showed that the expression of immunoglobulin kappa (IGKC), neutrophil gelatinase-associated lipocalin (NGAL), neurolysin mitochondrial (NEUL), keratin, type II cytoskeletal 1 (K2C1), S100-A9, and the extracellular calcium-sensing receptor (CASR) were significantly associated with a range of biological and inflammatory processes. In conclusion, up-regulation of S100A9, CASR, and K2C1 suggested a response to force-related inflammation, chemotactic activities, osteoclastogenesis, and epithelial cell breakdown. Meanwhile, the up-regulation of IGKC, NGAL, and K2C1 indicated a response to the inflammatory process, innate immunity activation, and epithelial cell breakdown. The online version contains supplementary material available at 10.1007/s13205-023-03572-5.


Protective effect of small peptides from Periplaneta americana on cyclophosphamide-induced premature ovarian failure.
To investigate the protective effect of small peptides from Periplaneta americana (SPPA) on cyclophosphamide (CP)-induced premature ovarian failure (POF) in mice. Silent mating type information regulation 2 homolog 1 (SIRT1) /tumor-associated protein 53 (p53) signaling pathway plays an important role in delaying POF. Hematopoietic progenitor cell antigen (CD34) reflects ovarian aging from the side. However, whether SPPA inhibits POF in mice by influencing the SIRT1/p53 pathway and CD34 expression remains to be studied. Forty female Kun Ming (KM) mice were divided into four groups: a control group (normal saline, n = 10), POF model group (160 mg/kg CP, n = 10), SPPA low-dosage group (160 mg/kg CP + 100 mg/kg SPPA, n = 10), and SPPA high-dosage group (160 mg/kg CP + 200 mg/kg SPPA, n = 10). CP administration route is intraperitoneal injection, and SPPA administration route is intragastric. Eyeball enucleation blood samples and the ovaries of mice were collected by midline laparatomy and oopherectomy, and the malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), follicle-stimulating hormone (FSH), and anti-Müllerian hormone (AMH) concentrations were tested. Immunohistochemical tests for the expressions of SIRT1, p53, and CD34 were carried out. Finally, ovarian mRNA levels of SIRT1 and p53 were detected with real-time fluorescence quantification PCR (qRT-PCR). A mouse model of POF was generated using 160 mg/kg of CP. Compared with POF group, we found that plasma NO, MDA, and FSH decreased, while AMH and SOD increased in the SPPA low-dose group. Compared with the POF group, the SPPA low- and high-dosage groups achieved significant growth in the number of primordial, primary, and total number of healthy follicles at all levels, but sharp reductions in the number of atretic follicles. In addition, we found downregulated protein and mRNA expression of SIRT1, and upregulated that of p53 were observed in ovarian tissues of treated mice with POF, in immunohistochemistry experiments and qPCR experiments. In contrast, high protein and mRNA expression of SIRT1, and low that of p53 were observed in SPPA treatment groups. And the results of CD34 protein expression were consistent with that of SIRT1. In total, SPPA significantly inhibited POF caused by CP in mice via activation of the SIRT1/p53 signaling pathway in the mouse ovary.


Unique molecular alteration patterns in von Hippel-Lindau (VHL) gene in a cohort of sporadic renal cell carcinoma patients from Pakistan.
Renal cell carcinoma (RCC) is the most frequent form of kidney cancer in adults. Somatic mutations that inactivate the von Hippel-Lindau (VHL) gene are the most common cause of RCC. The frequencies of molecular changes in the VHL gene in RCCs vary among different populations. So far, a single chromosomal-based study has been reported from a South Asian population. This report presents, for the first time, the somatic changes and promoter hypermethylation in VHL in a cohort of 300 RCC patients from Pakistan. To identify mutations in the VHL gene, direct DNA sequencing was carried out. Epigenetic silencing was investigated by using methylation-specific polymerase chain reaction. Our data showed molecular alterations in the VHL gene in 163 (54%) renal cell carcinoma patients. Somatic mutations were found in 87 (29%) patients and 35 novel mutations were identified. VHL promoter hyper-methylation analysis showed epigenetic changes in 106 (35%) out of 300 patients. Patients who had no evidence of molecular alterations in the VHL gene were significantly younger than patients who carried some molecular change. Molecular alterations in the VHL gene were not restricted to clear-cell RCCs (ccRCCs). This is the first report that identifies molecular aberrations in the VHL gene from a South Asian population. The frequency of somatic mutation is lower and that of promoter hypermethylation is higher when compared with data from other parts of the world. The data has important implications in the population-specific application of tailored preventive and therapeutic regimens in non-familial RCCs.


Computed tomography arthrography in traumatic hip dislocation. Intra-articular and capsular findings.
The newer diagnostic modalities such as computed tomography and magnetic resonance imaging are becoming increasingly used in the evaluation of joint trauma. The combination of computed tomography and arthrography can also be of significant diagnostic value in certain specific situations. In our case report, we describe its use in post-traumatic recurrent hip dislocation and its value, not only in depicting a posterior capsular tear, but also in the diagnosis of an internal joint derangement which may contribute to incongruous reduction of the hip joint.


A Multicenter Evaluation of the Impact of Sex on Abdominal and Fracture Pain Care.
Previous studies examining sex-based disparities in emergency department (ED) pain care have been limited to a single pain condition, a single study site, and lack rigorous control for confounders. A multicenter evaluation of the effect of sex on abdominal pain (AP) and fracture pain (FP) care outcomes. A retrospective cohort review of ED visits at 5 US hospitals in January, April, July, and October 2009. A total of 6931 patients with a final ED diagnosis of FP (n=1682) or AP (n=5249) were included. The primary predictor was sex. The primary outcome was time to analgesic administration. Secondary outcomes included time to medication order, and the likelihood of receiving an analgesic and change in pain scores 360 minutes after triage: Multivariable models, clustered by study site, were conducted to adjust for race, age, comorbidities, initial pain score, ED crowding, and triage acuity. On adjusted analyses, compared with men, women with AP waited longer for analgesic administration [AP women: 112 (65-187) minutes, men: 96 (52-167) minutes, P<0.001] and ordering [women: 84 (41-160) minutes, men: 71 (32-137) minutes, P<0.001], whereas women with FP did not (Administration: P=0.360; Order: P=0.133). Compared with men, women with AP were less likely to receive analgesics in the first 90 minutes (OR=0.766; 95% CI, 0.670-0.875; P<0.001), whereas women with FP were not (P=0.357). In this multicenter study, we found that women experienced delays in analgesic administration for AP, but not for FP. Future research and interventions to decrease sex disparities in pain care should take type of pain into account.


Changes in the hepatic copper conent after treatment with foreign compounds.
The effects of dimercaprol, CaNa2EDTA, D-penicillamine, diethyldithiocarbamate, disulfiram, pyrazole and phenobarbital on the hepatic copper content were studied. Adult male albino rats were given these compounds subcutaneously or intragastrically for 4 or 7 days, and the copper content in the hepatic crude homogenate was measured with an atomic absorption spectrophotometer. The metal chelating compounds dimercaprol, D-penicillamine and diethyldithiocarbamate only slightly decreased the level of copper in the liver. CaNa2 EDTA caused no change in the copper content. A slight decrease was found also after phenobarbital treatment. On the contrary, disulfiram and pyrazole increased the copper content 3- and 2-fold, respectively. It is suggested that the accumulation of copper in the liver is due to the cholestatic action of disulfiram and pyrazole.


Hematogenous vertebral osteomyelitis. Pasteurella multocida as the causative agent.
Human disease caused by Pasteurella multocida is well documented, and a wide variety of clinical syndromes have been described. We describe herein a patient with vertebral osteomyelitis, discitis, and paravertebral abscess caused by P multocida, a presentation that has not been described previously, to our knowledge.


Multi-echo balanced SSFP with a sequential phase-encoding order for functional MR imaging at 7T.
To develop a 2D multi-echo passband balanced SSFP (bSSFP) sequence using an echo-train readout with a sequential phase-encoding order (sequential multi-echo bSSFP), and evaluate its performance in fast functional brain imaging at 7 T. As images of sequential multi-echo bSSFP exhibit multiple ghosts due to periodic k-space modulations, a GRAPPA-based reconstruction method was proposed to eliminate ghosting artifacts. MRI experiments were performed to compare the image quality of multi-echo bSSFP and conventional single-echo bSSFP. Submillimeter-resolution fMRI using a checkerboard visual stimulus was conducted to compare the activation characteristics of multi-echo bSSFP, conventional single-echo bSSFP and standard gradient-echo EPI (GE-EPI). A higher mean structural similarity index was found between images of single-echo bSSFP and multi-echo bSSFP with a shorter echo train length (ETL). Multi-echo bSSFP (ETL = 3) showed higher temporal SNR (tSNR) values than GRAPPA-accelerated single-echo bSSFP (R = 2). In submillimeter-resolution fMRI experiments, multi-echo bSSFP (ETL = 3) approached the imaging speed of GRAPPA-accelerated single-echo bSSFP (R = 2), but without tSNR penalty and reduced activation due to acceleration. The median t-value and the number of significantly activated voxels were comparable between GE-EPI and multi-echo bSSFP (ETL = 3) that provides virtually distortion-free functional images and inherits the activation patterns of conventional bSSFP. Sequential multi-echo bSSFP (ETL = 3) is suitable for fast fMRI with submillimeter in-plane resolution, and offers an option to accelerate bSSFP imaging without tSNR penalty like parallel imaging.


Triple, simultaneous, very late coronary stent thrombosis.
Coronary artery stent thrombosis is an uncommon but potentially catastrophic complication. The risk of very late stent thrombosis (VLST) raises important safety issues regarding the first generation of drug-eluting stents (DES). Although several complex mechanisms for VLST have been suggested and various predictors have been described, its pathophysiology is not completely understood and it is not known whether longer-term dual antiplatelet therapy reduces the risk. We present a rare case of simultaneous very late DES thrombosis in the three vascular territories, following discontinuation of antiplatelet therapy seven years after stent placement, presenting as cardiogenic shock.


Intrathoracic complications of acute pancreatitis.
Acute pancreatitis has an incidence of approximately 50 cases per million of the United Kingdom population and a mortality of 10-18%. Intrathoracic complications have been implicated as the major factor in 22-29% and a contributing factor in a further 29-39% of all deaths. Sixty per cent of deaths occur in the first week of hospital admission and in these the pleuropulmonary complication rate is 94%. In the survivors there is little residual lung damage and the recovery of the pulmonary function is invariably complete. Knowledge of the pleuropulmonary complications of acute pancreatitis may aid with the identification of high risk groups so that supportive measures (including mechanical ventilation) can be implemented early in the course of the illness. This article reviews the major intrathoracic complications of acute pancreatitis (Fig. 1) under the broad headings of: 1. pleural effusion 2. acute pulmonary dysfunction (a) hypoxaemia without pulmonary infiltrates (b) hypoxaemia with pulmonary infiltrates (including the adult respiratory distress syndrome; ARDS).


Postnatal short stature, microcephaly, severe syndactyly of hands and feet, dysmorphic face, and mental retardation: a new syndrome?
We report on a 2 year old boy with an apparently previously undescribed multiple congenital anomaly/mental retardation syndrome characterised by postnatal short stature, postnatal microcephaly, dysmorphic face, syndactyly 2/5 of the hands and 1/4 of the feet, and brachymesophalangy of fingers 2 and 5.


Effect of flip angle on the accuracy and repeatability of hepatic proton density fat fraction estimation by complex data-based, T1-independent, T2*-corrected, spectrum-modeled MRI.
To evaluate the effect of flip angle (FA) on accuracy and within-examination repeatability of hepatic proton-density fat fraction (PDFF) estimation with complex data-based magnetic resonance imaging (MRI). PDFF was estimated at 3T in 30 subjects using two sets of five MRI sequences with FA from 1° to 5° in each set. One set used 7 msec repetition time and acquired 6 echoes (TR7/E6); the other used 14 msec and acquired 12 echoes (TR14/E12). For each FA in both sets the accuracy of MRI-PDFF was assessed relative to MR spectroscopy (MRS)-PDFF using four regression parameters (slope, intercept, average bias, R(2) ). Each subject had four random sequences repeated; within-examination repeatability of MRI-PDFF for each FA was assessed with intraclass correlation coefficient (ICC). Pairwise comparisons were made using bootstrap-based tests. Most FAs provided high MRI-PDFF estimation accuracy (intercept range -1.25 to 0.84, slope 0.89-1.06, average bias 0.24-1.65, R(2) 0.85-0.97). Most comparisons of regression parameters between FAs were not significant. Informally, in the TR7/E6 set, FAs of 2° and 3° provided the highest accuracy, while FAs of 1° and 5° provided the lowest. In the TR14/E12 set, accuracy parameters did not differ consistently between FAs. FAs in both sets provided high within-examination repeatability (ICC range 0.981-0.998). MRI-PDFF was repeatable and, for most FAs, accurate in both sequence sets. In the TR7/E6 sequence set, FAs of 2° and 3° informally provided the highest accuracy. In the TR14/E12 sequence set, all FAs provided similar accuracy.


Actin organization in migrating corneal epithelium of rabbits in situ.
We have found previously that fibronectin enhances the migration of rabbit corneal epithelium both in vitro and in vivo. In this paper we report a change of actin localization in migrating corneal epithelium as determined by immunofluorescent microscopy. Rabbit cornea was cut into small blocks and cultured in TC-199 medium. In the normal cornea, actin was detected as diffuse fluorescence at each epithelial layer. After 8 hr of cultivation epithelial cells had not started to migrate significantly, but actin had accumulated at the cell membrane. After 24 hr, epithelial migration had begun, and actin-specific fluorescence was detected mainly in the basal cell layer at the leading edge. When fibronectin or epidermal growth factor was added to the culture medium, epithelial migration began 8 hr after initiation of culture, and at 24 hr actin-specific fluorescence at the basal side of the migrating epithelial cells appeared stronger than that of a control group cultured in TC-199 unsupplemented medium. At the same time, fibronectin-specific fluorescence was more intense beneath the migrating epithelial cells. It is known that fibronectin has an affinity to collagen, and thus it might coat the cut surface of the stroma. Epithelial cells may attach then to the stroma via coated fibronectin. When a large quantity of exogenous fibronectin is added or when fibronectin is synthesized by the addition of epidermal growth factor, it may further stimulate the organization of intracellular actin from globular form (G-actin) to fibrilar form (F-actin). As a result, the change of intracellular localization and appearance of organized actin molecule might lead to cellular migration.


Graphene-Assisted Thermal Interface Materials with a Satisfied Interface Contact Level Between the Matrix and Fillers.
Reduced graphene oxide (RGO) and three-dimensional graphene networks (3DGNs) are adopted to improve the performance of thermal interface materials (TIMs). Therein, the 3DGNs provide a fast transport network for phonons, while the RGO plays as a bridge to enhance the phonon transport ability at the interface between the filler and matrix. The types of surface functional groups of the RGO are found to exert a remarkable influence on the resulting thermal performance; the carboxyl groups are found in the optimal selection to promote the transport process at the interface area because a strong chemical bond will form between the graphene basal plane and epoxy resin (ER) through this kind of group. The resulting thermal conductivity reaches 6.7 Wm-1 K-1 after optimizing the mass fraction and morphology of the filler, which is 3250% higher than that of the pristine ER. Moreover, the mechanical properties of these as-prepared TIMs are also detected, and the specimens by using the RGO(OOH) filler display the better performances.


Basic training in gastrointestinal endoscopy: recording images.
I read with interest the special article published in your journal back in 2019, dealing with basic training in gastrointestinal endoscopy for resident physicians specializing in gastroenterology, which has prompted me to offer the following comments: The sections encompassing the theoretical skills that residents must acquire, both regarding upper and lower endoscopy, include report writing and image recording. The structure and contents of a report for an endoscopic procedure faithfully reflect the endoscopist's technical expertise level. An endoscopy report represents the best quality control measure for any endoscopist. It includes text and recorded images. The structure and content of the text have been properly established by clinical practice guidelines. With regard to endoscopic images, these are not always recorded. Different scientific societies and guidelines suggest very different approaches, usually involving image-rich contents, which is usually overlooked because of both space and time constraints.


Establishment of a new prostatic carcinoma cell line (TSU-Pr1).
A new epithelial cell line, TSU-Pr1, from a human prostatic adenocarcinoma metastatic to lymph node has been established in long term tissue culture. The cultured cells show loss of contact inhibition, rapid growth in vitro and growth in athymic nude mice. Karyotypic analysis demonstrated an aneuploid karyotype with a modal chromosome number of 80 including a Y-chromosome and at least 10 marker chromosomes. The cells produced only a small amount of prostatic acid phosphatase, and heterotransplanted tumors did not have nuclear androgen receptors.


Impact of a national population-based carrier-screening program on spinal muscular atrophy births.
Spinal muscular atrophy (SMA) is a genetic neurodegenerative disease. Population carrier screening for SMA was introduced in Israel in 2008 through health-care services' insurance plans and expanded to the entire Israeli population in 2013 by a national health program. The aim of the study was to evaluate the impact of carrier screening on reducing the rate of birth of infants with SMA. All cases of prenatal and postnatal diagnosis of SMA in 2008-2017 were identified from databases of relevant government organizations, genetic laboratories in medical centers, and health care systems in Israel. Since 2013, screening was performed in 309,352 individuals, of whom 5741 were found to be carriers (carrier rate 1:54). Given an average of 180,000 live births annually, the predicted rate of SMA diagnosis was 15 cases per year. Prior to 2013, the average rate of prenatally diagnosed SMA was 4.66 cases per year, compared with 7.75 cases per year following population-wide provision of screening. The annual rate of postnatally diagnosed cases remained steady since 2008, with an average of 7- 7.25 cases per year. Screening has been effective in increasing prenatal detection of SMA but has had no effect on the rate of confirmed postnatal diagnoses. We speculate that screening rates may be affected by social, cultural, and religious factors.


Oerskovia xanthineolytica endocarditis in a renal transplant patient: case report and review of the literature.
Oerskovia species were, until recently, only rarely associated with human disease. This gram-positive bacillus can be easily misidentified as a diphtheroid, a common contaminant in blood cultures. There have been 17 reports of invasive Oerskovia infection in immunocompromised hosts. We report a case of Oerskovia xanthineolytica endocarditis in a renal transplant patient and review the microbiologic and clinical characteristics of this potential pathogen.


The contrast-to-noise in relaxation time, synthetic, and weighted-sum MR images.
The contrast-to-noise ratio (CNR) in three types of computed MR images is compared in a computer simulation. The original data consist of two spin-echo or two saturation-recovery images. Each pair of images is used to generate a relaxation time image, a synthetic image at arbitrary echo or repetition time, and an image which is a weighted sum of the original images. The CNR produced by these three methods is compared for signals spanning a wide range of relaxation times. In every comparison an optimally weighted sum produces the highest CNR that is statistically attainable. The CNR in the optimum synthetic image equals this bound only if contrast reversal does not occur in the original images. The CNR in relaxation time images is always less than the statistical bound and can be less than the CNR in the original images.


Changes in the hyoid bone, tongue, and oropharyngeal airway space after mandibular setback surgery evaluated by cone-beam computed tomography.
Mandibular setback surgery can change the position of the mandible which improves occlusion and facial profile. Surgical movement of the mandible affects the base of the tongue, hyoid bone, and associated tissues, resulting in changes in the pharyngeal airway space. The aim of this study was to analyze the 3-dimensional (3D) changes in the hyoid bone and tongue positions and oropharyngeal airway space after mandibular setback surgery. A total of 30 pairs of cone-beam computed tomography (CBCT) images taken before and 1 month after surgery were analyzed by measuring changes in the hyoid bone and tongue positions and oropharyngeal airway space. The CBCT images were reoriented using InVivo 5.3 software (Anatomage, San Jose, USA) and landmarks were assigned to establish coordinates in a three-dimensional plane. The mean age of the patients was 21.7 years and the mean amount of mandibular setback was 5.94 mm measured from the B-point. The hyoid bone showed significant posterior and inferior displacement (P < 0.001, P < 0.001, respectively). Significant superior and posterior movements of the tongue were observed (P < 0.05, P < 0.05, respectively). Regarding the velopharyngeal and glossopharyngeal spaces, there were significant reductions in the volume and minimal cross-sectional area (P < 0.001). The anteroposterior and transverse widths of the minimal cross-sectional area were decreased (P < 0.001, P < 0.001, respectively). In addition, the amount of mandibular setback positively correlated with the amount of posterior and inferior movement of the hyoid bone (P < 0.05, P < 0.05, respectively). There were significant changes in the hyoid bone, tongue, and airway space after mandibular setback surgery.


Effect of pre-harvest inactivated yeast treatment on the anthocyanin content and quality of table grapes.
Due to the global warming, more and more often the red-pink grape varieties grown in the Mediterranean basin reveal an insufficient accumulation of anthocyanins and thus a scarce coloration. Nowadays, this is becoming an important technological issue, which may result in the reduction of the fresh market value of table grape. This study aimed at assessing the effect of the pre-harvest treatment by specific inactivated yeasts (YE) on the qualitative parameters and anthocyanin pattern of three red table grape varieties, which typically present poor and/or incomplete coloration during warm years. An increment of anthocyanins level up to almost seven folds corresponding to an improvement of red skin appearance was observed in all the treated table grapes, which was preserved after cold storage, too. While, no significant influence on chemical composition and berry texture and dimensions was found, meaning that YE did not cause appreciable taste changes in grapes.


Effects of Louisiana crude oil on the sheepshead minnow (Cyprinodon variegatus) during a life-cycle exposure to laboratory oiled sediment.
Determining the long-term effects of crude oil exposure is critical for ascertaining population-level ecological risks of spill events. A 19-week complete life-cycle experiment was conducted with the estuarine sheepshead minnow (Cyprinodon variegatus) exposed to reference (uncontaminated) sediment spiked with laboratory weathered South Louisiana crude (SLC) oil at five concentrations as well as one unspiked sediment control and one seawater (no sediment) control. Newly hatched larvae were exposed to the oiled sediments at measured concentrations of < 1 (sediment control), 50, 103, 193, 347, and 711 mg total polyaromatic hydrocarbons (tPAH)/kg dry sediment. Juveniles were exposed through the reproductively active adult phase at measured concentrations of <1 (sediment control), 52, 109, 199, 358, and 751 mg tPAH/kg sediment. Throughout the exposure, fish were assessed for growth, survival, and reproduction. Resulting F1 embryos were then collected, incubated, and hatched in clean water to determine if parental full life-cycle exposure to oiled sediment produced trans-generational effects. Larvae experienced significantly reduced standard length (5-13% reduction) and wet weight (13-35% reduction) at concentrations at and above 50 and 103 mg tPAH/kg sediment, respectively. At 92 and 132 days post hatch (dph), standard length was reduced (7-13% reduction) at 199 and 109 mg tPAH/kg dry sediment, respectively, and wet weight for both time periods was reduced at concentrations at and above 109 mg tPAH/kg dry sediment (21-38% reduction). A significant reduction (51-65%) in F0 fecundity occurred at the two highest test concentrations, but no difference was observed in F1 embryo survival. This study is the first to report the effects of chronic laboratory exposure to oiled sediment, and will assist the development of population models for evaluating risk to benthic spawning fish species exposed to oiled sediments. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1627-1639, 2016.


Risk factors and prognosis of hepatic acute GvHD after allogeneic hematopoietic cell transplantation.
Hepatic acute GvHD (aGvHD) is associated with high mortality owing to poor response to immunosuppressive therapy. The pathogenesis of hepatic aGvHD differs from that of other lesions, and specific risk factors related to pre-transplant liver conditions should be determined. We conducted a cohort study by using a Japanese transplant registry database (N=8378). Of these subjects, 1.5% had hepatitis C virus Ab (HCV-Ab) and 9.4% had liver dysfunction (elevated transaminase or bilirubin levels) before hematopoietic cell transplantation (HCT). After HCT, the cumulative incidence of hepatic aGvHD was 6.7%. On multivariate analyses, HCV-Ab positivity (hazard ratio (HR), 1.93; P=0.02) and pre-transplant liver dysfunction (HR, 1.85; P<0.01), as well as advanced HCT risk, unrelated donors, HLA mismatch and cyclosporine as GvHD prophylaxis, were significant risk factors for hepatic aGvHD, whereas hepatitis B virus surface Ag was not. Hepatic aGvHD was a significant risk factor for low overall survival and high transplant-related mortality in all aGvHD grades (P<0.01). This study is the first to show the relationship between pre-transplant liver conditions and hepatic aGvHD. A prospective study is awaited to validate the results of this study and establish a new strategy especially for high-risk patients.


On codon reassignment.
Schultz and Yarus (J. Mol. Biol. 235:1377-1380, 1994) have proposed that reassignment of codons in the genetic code passes through a stage in which the codons are ambiguously translated. In contrast we state that such ambiguity would be deleterious, and that, to be reassigned, a codon, together with the tRNA that translates the codon, must first disappear from coding sequences, after which a tRNA appears with a mutated anticodon, and this enables the codon to reappear with a changed meaning. In the case of a stop codon, the relevant release factor must change so as to recognize it.


[Diabetic foot syndrome-Part 2 : Revascularization, treatment alternatives, care structures, recurrency prophylaxis].
Diabetic foot syndrome (DFS) is the most frequent reason for major amputations in Germany. The majority of foot lesions are triggered by repetitive pressure in diabetic polyneuropathy. Peripheral arterial occlusive disease (PAOD) impairs wound healing and is the main risk factor for amputations. The treatment of wounds and infections as well as timely revascularization are decisive. The use of endovascular and vascular surgical methods depends on the distribution pattern and length of the occlusion processes. Both procedures are complementary. Bypass surgery is of great importance for neuroischemic DFS. Multidisciplinary centers that provide revascularization in DFS can achieve an improvement of arterial blood flow in 90% of the cases and reduce the amputation rate by up to 80%. Due to the high recurrence rate of diabetic foot lesions, measures for secondary prophylaxis are of exceptional importance (podological and orthopedic technical care, foot surgery).


Conjunctival goblet cells: Ocular surface functions, disorders that affect them, and the potential for their regeneration.
Conjunctival goblet cells (CGCs) are specialized cells that produce and secrete soluble mucins to the tear film that bathes the ocular surface. CGC numbers and functions are affected in various ocular surface diseases including dry eye disease with diverse etiologies. In this review we will (i) summarize the important functions of CGCs in ocular surface health, (ii) describe the ocular surface diseases that affect CGC numbers and function, (iii) provide an update on recent research outcomes that elucidate CGC differentiation, gene expression and functions, and (iv) present evidence in support of the prediction that restoring CGC numbers and/or functions is a viable strategy for alleviating ocular surface disorders that impact the CGCs.


Tension Pneumocranium Following Transsphenoidal Surgeries-A Case Report and Systematic Review of Literature with Analysis of Predisposing Factors and Treatment Regimens: Is Early Skull Base Repair Better than Conservative Treatment?
Conclusive evidence describing the outcomes following different treatment strategies for tension pneumocranium (TP) is lacking. Impact of predisposing conditions like multiple transnasal transsphenoidal (TNTS) procedures, intraoperative cerebrospinal fluid leak, obstructive sleep apnea, continuous positive airway pressure, violent coughing, nose blowing, positive pressure ventilation on TP outcomes is also unknown. PubMed, Embase, Cochrane, and Google Scholar were searched for articles using Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Multivariate logistic regression analysis was done using STATA/ BE ver 17.0. Thirty-five studies with 49 cases of endoscopic TNTS surgeries were included. Tension pneumocephalus was seen in 77.5% (n = 38), tension pneumosella in 7 (14.28%), and tension pneumoventricle in 4 (8.16%). Nonfunctional pituitary adenomas (40.81%) were most common lesions associated with TP. The need of mechanical ventilation was significantly higher in patients who received conservative management (odds ratio, 1.34; confidence interval, 0.65-2.74) (P < 0.01). However, incidence of meningitis or mortality were not influenced by factors like age, gender, pathological diagnosis, initial conservative management or early skull base repair, use of adjuvant radiation, intraoperative cerebrospinal fluid leak, multiple TNTS explorations, or presence of precipitating factors. Nonfunctional pituitary adenomas were the most common lesions associated with TP. Multiple TNTS procedures did not increase incidence of meningitis or mortality. Conservative management increased the need for mechanical ventilation but did not worsen the mortality outcomes.


Prognostic Significance of the Neutrophil/Lymphocyte Ratio in Patients with Non-Human Papilloma Virus-Related Oropharyngeal Cancer: A Retrospective Cohort Study.
To investigate the effects of the pretreatment neutrophil-to-lymphocyte ratio (N/L) on non-human papilloma virus (HPV)-related oropharyngeal cancer. N/L was calculated by dividing the neutrophil count by the lymphocyte count. Survival outcomes were estimated using the Kaplan-Meier method and compared by the log-rank test. Univariate and multivariate analyses were performed to evaluate the prognostic impact of N/L and other clinical factors on survival outcomes. High/low N/L groups were defined as > 4.7 and ≤4.7, respectively. Data of 57 consecutive patients with non-HPV-related oropharyngeal cancer were analyzed. The 3-year disease-free survival was 79 versus 36.9% in favor of the low N/L group (p = 0.04). The 5-year overall survival was 71.6 versus 53.3% in the low N/L and high N/L group, respectively (p = 0.07). N/L could play an important role in non-HPV-related oropharyngeal cancer progression and indicate prognosis.


Initial experience of use of an articulated external fixator in treating Legg-Calvé-Perthes disease by means of arthrodiastasis during the active phase of the disease.
To present the preliminary results from treating patients with Legg-Calvé-Perthes Disease (LCPD) by means of hip arthrodiastasis using a monolateral external fixator applied to the hip and to succinctly describe the surgical technique used, in a prospective study. Prospective study on 18 patients with LCPD who underwent surgical treatment by means of the hip arthrodiastasis technique using a monolateral external fixator. There were 13 male and five female patients of mean age 8.5 years, ranging from five to 13 years. All the patients presented unilateral hip impairment: nine on the right side and nine on the left. The results were evaluated at maturity using clinical and radiological criteria. All the patients evolved with improvement of joint mobility, and pain relief was achieved in 88.9% of them. Reossification of the femoral epiphysis occurred within the first three months of the treatment. The hips operated at the necrosis stage of the disease did not passed through the fragmentation stage, thus shortening the evolution of the disease. The results were 77.8% satisfactory and 22.2% unsatisfactory. Hip arthrodiastasis with a monolateral external fixator during the active phase of LCPD improved the degree of joint mobility. Use of the arthrodiastasis technique at the necrosis stage or at the fragmentation stage (active phase of the disease) presented satisfactory results from treatment of LCPD.


Tolerance of Organ Transplant Recipients to Physical Activity during a High-Altitude Expedition: Climbing Mount Kilimanjaro.
It is generally unknown to what extent organ transplant recipients can be physically challenged. During an expedition to Mount Kilimanjaro, the tolerance for strenuous physical activity and high-altitude of organ transplant recipients after various types of transplantation was compared to non-transplanted controls. Twelve organ transplant recipients were selected to participate (2 heart-, 2 lung-, 2 kidney-, 4 liver-, 1 allogeneic stem cell- and 1 small bowel-transplantation). Controls comprised the members of the medical team and accompanying family members (n = 14). During the climb, cardiopulmonary parameters and symptoms of acute mountain sickness were recorded twice daily. Capillary blood analyses were performed three times during the climb and once following return. Eleven of the transplant participants and all controls began the final ascent from 4700 meters and reached over 5000 meters. Eight transplant participants (73%) and thirteen controls (93%) reached the summit (5895m). Cardiopulmonary parameters and altitude sickness scores demonstrated no differences between transplant participants and controls. Signs of hyperventilation were more pronounced in transplant participants and adaptation to high-altitude was less effective, which was related to a decreased renal function. This resulted in reduced metabolic compensation. Overall, tolerance to strenuous physical activity and feasibility of a high-altitude expedition in carefully selected organ transplant recipients is comparable to non-transplanted controls.


Microglial Activation Results in Inhibition of TGF-β-Regulated Gene Expression.
Chronic inflammation mediated by persistent microglial activation is associated with the pathogenesis of neurodegenerative diseases. The mechanisms underlying chronic microglial activation are poorly understood. We have previously shown that anti-inflammatory TGF-β signaling is inhibited in LPS-treated microglia. In this study, we assessed whether different disease-related microglial activators could downregulate TGF-β induction of gene expression. We examined the effects of amyloid β (Aβ) (1-42)- or heat-killed Listeria monocytogenes (HKLM) on the TGF-β-regulated gene expression in primary rat microglia. We found that Aβ (1-42) oligomers and HKLM, in addition to LPS, suppressed TGF-β-mediated induction of gene expression in part through reducing expression of TβR1 mRNA encoding the TGF-β receptor 1 in primary microglia. Aβ (1-42) and LPS also prevented induction of TGF-β-induced genes in primary microglia. Additionally, Aβ (1-42) rescued primary microglia from TGF-β-mediated cell death without increasing cell proliferation. Blockage of NFκB signaling, but not the ERK or IRF3 pathways, inhibited Aβ (1-42)- and LPS-mediated reduction of TβR1 mRNA. Finally, LPS and Aβ (1-42) induced transient upregulation of mRNAs encoding SnoN and Bambi, inhibitors of TGF-β signaling. Our data indicate that one mechanism through which activators may prolong microglial stimulation is through direct inhibition of anti-inflammatory signaling. A more detailed understanding of the interaction between inflammatory and anti-inflammatory pathways may reveal potential targets for ameliorating chronic inflammation and hence speed the development of therapeutics to address neurodegenerative diseases.


The metabolic syndrome (MS) in the elderly: considerations on the diagnostic criteria of the International Diabetes Federation (IDF) and some proposed modifications.
This study aimed at verifying the International Diabetes Federation (IDF)-indicated criteria in the elderly, characterized by a decrease of several normal values, the neglected evaluation of those values with aging, and an eventual decision of an obligatory consideration of the visceral obesity as a sign of the metabolic syndrome (MS), the relative prevalence of Acute Myocardial Infarction (AMI) and stroke. The study involved 3038 elderly persons (65-84 years), covered by the Italian Longitudinal Study on Aging (ILSA): they were investigated for the diagnosis of MS, for the prevalence of AMI and stroke at the baseline, and after 3 years. We applied both the IDF-criteria and a new concept considering the age-dependent increase of several parameters in older subjects, the previous cardio-cerebrovascular complications, as well as the presence of other diseases being independent of those complications. The prevalence of AMI and stroke determined according to the IDF-criteria is not different significantly from the results obtained in either the elderly population with "normal" or increased waist circumference (WC), nor in subjects with MS or without MS. After a 3-year-follow-up quite similar results were found. From these results one can conclude that the diagnostic criteria of the IDF for the MS are not valid for the elderly population. We propose some criteria on the basis of which one can reveal systematically significant differences between the MS and the cardiovascular complications. Our conclusion is that it seems to be necessary to verify the validity of our proposed criteria on wider long-term epidemiological studies.


Distinct properties of proteases and nucleases in the gut, salivary gland and saliva of southern green stink bug, Nezara viridula.
Stink bugs negatively impact numerous plant species of agricultural and horticultural importance. While efforts to develop effective control measures are underway, the unique digestive physiology of these pests presents a significant hurdle for either protein- or nucleotide-based management options. Here we report the comparative biochemical and proteomic characterization of proteases and nucleases from the gut, salivary gland and saliva of the southern green stink bug, Nezara viridula. The pH optimum for protease activity was acidic (5 to 6) in the gut with the primary proteases being cysteine proteases, and alkaline (8 to 9) in the saliva and salivary gland with the primary proteases being serine proteases. The serine proteases in saliva differ biochemically from trypsin and chymotrypsin, and the cathepsins in the gut and saliva showed distinct properties in inhibitor assays. Nuclease activity (DNase, RNase, dsRNase) was concentrated in the salivary gland and saliva with negligible activity in the gut. The most abundant proteins of the gut (530) and salivary gland (631) identified by proteomic analysis included four gut proteases along with eight proteases and one nuclease from the salivary gland. Understanding of N. viridula digestive physiology will facilitate the design of new strategies for management of this significant pest.


Molecular characterization and prokaryotic expression of buffalo (Bubalus bubalis) Interleukin-6.
The study describes the characterization of Interleukin-6 cDNA and essential promoter sequences of the Indian Water Buffalo (Bubalus bubalis) and expression of the recombinant IL-6 in Escherichia coli. Buffalo IL-6 shows very high nucleotide level identity of the cDNA (98.7%) and promoter (98%) sequences with the corresponding cattle sequences. All the major regulatory elements of IL-6 promoter like AP-1, Multiple Response Element, NF-IL6, ETS binding domain and NF-kappaB binding sites show absolute conservation. Basal level IL-6 mRNA is detected in organs like liver, lung and spleen. Concanavalin A stimulated splenocytes produced maximum IL-6 mRNA at 8h poststimulation. Recombinant IL-6 production in JM109 (DE3) and BL21 (DE3) pLysS bacterial system is substantially enhanced by supplementation of rare codon tRNAs through co-transformation with a second plasmid. BL21 (DE3) pLysS strain is a more efficient producer of the IL-6 as it expressed two-fold more protein than by JM109 (DE3) cells. The study shows high-level conservation of IL-6 regulatory and coding sequences between cattle and buffalo, and indicates the use of a common reagent for studying the effects of this cytokine in these species.


[A rare cause of stridor in a 59 year old woman in intensive care].
Stridor in the post extubation period occurs frequently and is most commonly caused by laryngeal oedema. During this period, the trachea can also be obstructed by pseudomembranes. We report the case of a 59 year old woman who required re-intubation, 15 days after extubation because of the acute onset of severe respiratory distress secondary to pseudomembranes in her trachea. It is essential that physicians who care for patients during the post extubation period are aware of this severe and life threatening cause of stridor. Definitive treatment with the rigid bronchoscope allows for rapid recanalisation of the airway.


Customized palatal guide and splint for maxillary expansion.
Customization in orthognathic surgery allows better precision and a reduced surgical time. In Le Fort I osteotomy surgery, the maxillary segmentation is considered one of the most unstable procedures due to transverse instability. Various different types of palatal device have been proposed to address this instability. This note describes a customized bone-borne palatal guide and splint that may help surgeons shorten the surgical time and achieve better three-dimensional repositioning, with more postoperative comfort for the patient and occlusal control for the surgeon.


Evaluation of the lysis-centrifugation system for culturing dialysates from continuous ambulatory peritoneal dialysis patients with peritonitis.
Recovery of organisms from continuous ambulatory peritoneal dialysis (CAPD) patients with peritonitis presents special problems to the laboratory. The Isolator (Dupont Co, Wilmington, DE), based on lysis and centrifugation, is generally used for the recovery of blood isolates. This study determined the efficacy of the Isolator relative to the Bactec System (Johnston Laboratories, Inc, Towson, MD) for the culture of dialysates from CAPD patients with peritonitis. On the basis of clinical criteria, 31 episodes of peritonitis were included for our study. Dialysate was inoculated into an Isolator and Bactec 6B and 7D bottles. A causative agent was isolated by the Isolator in 29 of 31 episodes, by the Bactec in 29 of 31, and by one or both techniques in 30 of 31 episodes (overall sensitivity 97%). The Isolator failed to detect a Pseudomonas luteola and the Bactec failed to detect a coagulase-negative staphylococcus. Coagulase-positive and negative staphylococci represented 58.1% of the isolates. The Isolator detected 21.4% (six of 28) of the isolates 24 to 72 hours earlier than the Bactec; the Bactec was faster in this regard in 3.6% (one of 28). Time to positivity for the remaining 21 cultures was the same in both systems. Isolate identification and antimicrobial sensitivity was available 24 hours earlier using the Isolator in 96.4% (27 of 28). The Isolator was more rapid and as sensitive as the Bactec system in detecting causative organisms of peritonitis in CAPD patients.


Separation of human apolipoproteins A-IV, A-I and E by reversed-phase high-performance liquid chromatography on a TSK Phenyl-5PW column.
A method has been developed for the rapid separation of the medium-molecular-weight apolipoproteins A-IV, A-I and E by high-performance liquid chromatography. Separations were achieved using a commercially available column of very low hydrophobicity (TSK Phenyl-5PW) in the reversed-phase mode rather than the conventional mode of hydrophobic interaction. Delipidated apolipoproteins were dissolved in 20 mM orthophosphoric acid (pH 2.3), applied to the column which was pre-equilibrated with the same buffer, and eluted with an increasing gradient of acetonitrile. Purified apolipoproteins were identified by a combination of sodium dodecyl sulphate-polyacrylamide gel electrophoresis, amino acid analysis and N-terminal sequence analysis. In one step the method can be used to separate the major human chylomicron apolipoproteins A-IV, A-I and E, following preliminary removal of apolipoprotein A-II and the C apolipoproteins by size-exclusion chromatography.


New distribution records for Cassidinae gyllenhal (Coleoptera: Chrysomelidae).
Range extensions are provided for four Neotropical tortoise beetle species. A new host plant for a potentially new species of Delocrania Guérin-Méneville is also provided.


Rutin determination in pharmaceutical formulations using a carbon paste electrode modified with poly(vinylpyrrolidone).
A carbon paste electrode modified with poly(vinylpyrrolidone) (PVP) was developed for the determination of rutin. PVP enhances the adsorption of rutin on the electrode surface due to the presence of hydrogen bonding between the imide group in PVP and the hydroxyl group in rutin. The current responses in cyclic and linear sweep voltammetric experiments were investigated and an oxidation peak was observed at +0.87 V vs. Ag/AgCl. Several parameters were investigated to evaluate the performance of the modified electrode. The best analytical response was obtained employing (75:15:10%, w/w/w) graphite powder:Nujol:PVP, with an accumulation time of 10 min, scan rate of 100 mV s(-1) and 0.1M phosphate buffer solution (pH 6.0) as supporting electrolyte. The analytical curve was linear for rutin concentrations of 3.9 x 10(-7) to 1.3 x 10(-5)M (r=0.9991) and the detection limit was 1.5 x 10(-7)M. The recovery of rutin from pharmaceutical samples ranged from 98.3 to 101.7% and the relative standard deviation was 3.3% for a solution containing 7.7 x 10(-6)M rutin (n=5). This electrode was successfully applied to the determination of rutin in pharmaceutical formulations. The results obtained using the proposed modified carbon paste electrode and those obtained by the standard method are in agreement at the 95% confidence level.


Ribonucleotide reductase large subunit (RRM1) gene expression may predict efficacy of adjuvant mitotane in adrenocortical cancer.
Mitotane is the most broadly used systemic therapy for adrenocortical carcinoma (ACC), but its mechanism of action and possible predictors of treatment response are currently poorly defined. Our aim was to evaluate the gene expression of ribonucleotide reductase large subunit 1 (RRM1) and excision repair cross-complementation group 1 (ERCC1) in ACC as potential biomarkers for clinical outcome and response to mitotane. Forty-five and 47 tissue samples from two cohorts (Orbassano, Italy; Wuerzburg, Germany) of completely resected ACC were centrally analyzed using real-time PCR for RRM1 and ERCC1 expression. Fifty-four patients received surgery alone and 38 received adjuvant mitotane after surgery. Clinical and pathologic features were highly comparable in the two series. H295R and SW-13 ACC cell lines were also used for pharmacologic tests. ERCC1 gene expression was not associated to clinical outcome. In contrast, high RRM1 gene expression was associated to shorter disease-free survival (DFS) and overall survival at both univariate and multivariate analysis. In patients with low RRM1 gene expression, adjuvant mitotane was associated with improved DFS, whereas this effect was lost in cases with high RMM1 expression. In vitro mitotane induced strong up regulation of RRM1 transcription (up to 25-fold increase) in mitotane-insensitive SW-13 but not in mitotane-sensitive H295R cells. Furthermore, RRM1 silencing in SW-13 cells induced sensitivity to mitotane. Our in vitro and in vivo data indicate that RRM1 gene expression is functionally associated to mitotane sensitivity and support a possible role of RRM1 determination as a novel molecular biomarker predicting response to adjuvant mitotane in ACC.


Immune checkpoint therapy for solid tumours: clinical dilemmas and future trends.
Immune-checkpoint inhibitors (ICBs), in addition to targeting CTLA-4, PD-1, and PD-L1, novel targeting LAG-3 drugs have also been approved in clinical application. With the widespread use of the drug, we must deeply analyze the dilemma of the agents and seek a breakthrough in the treatment prospect. Over the past decades, these agents have demonstrated dramatic efficacy, especially in patients with melanoma and non-small cell lung cancer (NSCLC). Nonetheless, in the field of a broad concept of solid tumours, non-specific indications, inseparable immune response and side effects, unconfirmed progressive disease, and complex regulatory networks of immune resistance are four barriers that limit its widespread application. Fortunately, the successful clinical trials of novel ICB agents and combination therapies, the advent of the era of oncolytic virus gene editing, and the breakthrough of the technical barriers of mRNA vaccines and nano-delivery systems have made remarkable breakthroughs currently. In this review, we enumerate the mechanisms of each immune checkpoint targets, associations between ICB with tumour mutation burden, key immune regulatory or resistance signalling pathways, the specific clinical evidence of the efficacy of classical targets and new targets among different tumour types and put forward dialectical thoughts on drug safety. Finally, we discuss the importance of accurate triage of ICB based on recent advances in predictive biomarkers and diagnostic testing techniques.


Chronic renal disease progression: treatment strategies and potassium intake.
Disordered potassium homeostasis is a common complication of chronic kidney disease and traditional management focuses on restricting potassium intake to avoid hyperkalemia. Permissive potassium intake carries the risk of hyperkalemia and hyperphosphatemia, and possibly may contribute to the development of uremic neuropathy. Excessive potassium restriction and removal by dialysis carries the risk of worsened chronic hypertension, intradialytic hypotension, renal fibrosis and cyst formation, and ventricular arrhythmias. Cohort studies have associated both hypokalemia and hyperkalemia with increased mortality in CKD. A single study of potassium intake in hemodialysis patients found increased intake associated with increased mortality despite adjustment for serum potassium concentration. We recommend avoiding mandatory potassium restriction in early chronic kidney disease. We endorse routine potassium restriction in advanced chronic kidney disease requiring hemodialysis and close monitoring of serum potassium concentration in any patients receiving renin-angiotensin-aldosterone system blockers.


Impact of abiraterone acetate plus prednisone in patients with castration-sensitive prostate cancer and visceral metastases over four years of follow-up: A post-hoc exploratory analysis of the LATITUDE study.
A post-hoc analysis of the phase-3 LATITUDE study assessed the impact of abiraterone acetate plus prednisone (AA+P) on overall survival (OS) and radiographic progression-free survival (rPFS) in men with metastatic castration-sensitive prostate cancer (mCSPC) and visceral metastases (VM). Newly diagnosed mCSPC patients were randomized (1:1) to AA+P and androgen deprivation therapy (ADT) or placebo+ADT. Patients with VM in liver or lungs with or without other soft tissue and bone metastases (based on CT/MRI) at baseline were analyzed, after 51.8 months' median follow-up. Co-primary endpoints, OS and rPFS, were analyzed. Among 1199 patients enrolled, 228 (19%) had VM at baseline (114 each in AA+P and placebo groups), of which 53 (23.2%; AA+P = 29, Placebo = 24) had liver metastases and 117 (51.3%; AA+P = 60, Placebo = 57) had lung metastases. In patients with VM, treatment with AA+P versus placebo showed an improvement in OS (median 55.4 vs 33.0 months; HR = 0.582; 95%CI = 0.406-0.835;P = 0.0029) and rPFS (median 30.7 vs 18.3 months; HR = 0.527; 95%CI = 0.366-0.759;P = 0.0005), comparable to that of patients without VM. AA+P versus placebo in lung metastases patients was associated with greater improvement in OS (HR = 0.60; 95%CI = 0.35-1.04;P = 0.0678) than in liver metastases patients (HR = 0.82; 95%CI = 0.41-1.66;P = 0.5814). AA+P versus placebo showed improvement in rPFS in lung metastases patients (HR = 0.50; 95%CI = 0.29-0.89;P = 0.0157), but not in liver metastases patients (HR = 1.05; 95%CI = 0.53-2.09; P = 0.8970). AA+P treatment improved both rPFS and OS in men with mCSPC and visceral disease, especially those with lung metastases. Men with liver metastases had a poorer prognosis and their optimal treatment remains to be defined. ClinicalTrials.gov, number NCT01715285.


Ischemia detection using Isoelectric Energy Function.
A novel method has been proposed for the detection of ischemia using an isoelectric energy function (IEEF) resulting from ST segment deviations in ECG signals. The method consists of five stages: pre-processing, delineation, measurement of isoelectric energy, a beat characterization algorithm and detection of ischemia. The isoelectric energy threshold is used to differentiate ischemic beats from normal beats for ischemic episode detection. Then, ischemic episodes are classified as transmural or subendocardial. The method is validated for recordings of the annotated European ST-T database (EDB). The results show 98.12% average sensitivity (SE) and 98.16% average specificity (SP). These results are significantly better than those of existing methods cited in the literature. The advantage of the proposed method includes simplicity, ruggedness and automatic discarding of noisy beats.


Nucleotide binding and conformational switching in the hexameric ring of a AAA+ machine.
ClpX, a AAA+ ring homohexamer, uses the energy of ATP binding and hydrolysis to power conformational changes that unfold and translocate target proteins into the ClpP peptidase for degradation. In multiple crystal structures, some ClpX subunits adopt nucleotide-loadable conformations, others adopt unloadable conformations, and each conformational class exhibits substantial variability. Using mutagenesis of individual subunits in covalently tethered hexamers together with fluorescence methods to assay the conformations and nucleotide-binding properties of these subunits, we demonstrate that dynamic interconversion between loadable and unloadable conformations is required to couple ATP hydrolysis by ClpX to mechanical work. ATP binding to different classes of subunits initially drives staged allosteric changes, which set the conformation of the ring to allow hydrolysis and linked mechanical steps. Subunit switching between loadable and unloadable conformations subsequently isomerizes or resets the configuration of the nucleotide-loaded ring and is required for mechanical function.


Variable Selection for Time-to-Event Data.
With the increasing availability of large scale biomedical and -omics data, researchers are offered with unprecedented opportunities to discover novel biomarkers for clinical outcomes. At the same time, they are also faced with great challenges to accurately identify important biomarkers from numerous candidates. Many novel statistical methodologies have been developed to tackle these challenges in the last couple of decades. When the clinical outcome is time-to-event data, special statistical methods are needed to analyze this type of data due to the presence of censoring. In this article, we review some of the most commonly used modern statistical methodologies for variable selection for time-to-event data. The reviewed methods are classified into three large categories: filter-test based method, penalized regression method, and machine learning method.


Regional variation in T1ρ and T2 times in osteoarthritic human menisci: correlation with mechanical properties and matrix composition.
Changes in T1ρ and T2 magnetic resonance relaxation times have been associated with articular cartilage degeneration, but similar relationships for meniscal tissue have not been extensively investigated. This work examined relationships between T1ρ and T2 measurements and biochemical and mechanical properties across regions of degenerate human menisci. Average T1ρ and T2 relaxation times were determined for nine regions each of seven medial and 13 lateral menisci from 14 total knee replacement patients. Sulfated glycosaminoglycan (sGAG), collagen and water contents were measured for each region. Biomechanical measurements of equilibrium compressive, dynamic compressive and dynamic shear moduli were made for anterior, central and posterior regions. T1ρ and T2 times showed similar regional patterns, with longer relaxation times in the (radially) middle region compared to the inner and outer regions. Pooled over all regions, T1ρ and T2 times showed strong correlations both with one another and with water content. Correlations with biochemical content varied depending on normalization to wet or dry mass, and both imaging parameters showed stronger correlations with collagen compared to sGAG content. Mechanical properties displayed moderate inverse correlations with increasing T1ρ and T2 times and water content. Both T1ρ and T2 relaxation times correlated strongly with water content and moderately with mechanical properties in osteoarthritic menisci, but not as strongly with sGAG or collagen contents alone. While the ability of magnetic resonance imaging (MRI) to detect early osteoarthritic changes remains the subject of investigation, these results suggest that T1ρ and T2 relaxation times have limited ability to detect compositional variations in degenerate menisci.


Autonomous fuelled directional rotation about a covalent single bond.
Biology operates through autonomous chemically fuelled molecular machinery1, including rotary motors such as adenosine triphosphate synthase2 and the bacterial flagellar motor3. Chemists have long sought to create analogous molecular structures with chemically powered, directionally rotating, components4-17. However, synthetic motor molecules capable of autonomous 360° directional rotation about a single bond have proved elusive, with previous designs lacking either autonomous fuelling7,10,12 or directionality6. Here we show that 1-phenylpyrrole 2,2'-dicarboxylic acid18,19 (1a) is a catalysis-driven20,21 motor that can continuously transduce energy from a chemical fuel9,20-27 to induce repetitive 360° directional rotation of the two aromatic rings around the covalent N-C bond that connects them. On treatment of 1a with a carbodiimide21,25-27, intramolecular anhydride formation between the rings and the anhydride's hydrolysis both occur incessantly. Both reactions are kinetically gated28-30 causing directional bias. Accordingly, catalysis of carbodiimide hydration by the motor molecule continuously drives net directional rotation around the N-C bond. The directionality is determined by the handedness of both an additive that accelerates anhydride hydrolysis and that of the fuel, and is easily reversed additive31. More than 97% of fuel molecules are consumed through the chemical engine cycle24 with a directional bias of up to 71:29 with a chirality-matched fuel and additive. In other words, the motor makes a 'mistake' in direction every three to four turns. The 26-atom motor molecule's simplicity augurs well for its structural optimization and the development of derivatives that can be interfaced with other components for the performance of work and tasks32-36.


Keratoacanthoma with perineural invasion: an indicator for aggressive behavior?
Neurotropic invasion of keratoacanthoma (KA) is rare and can easily be missed histologically. A 36-year-old woman developed a KA on the upper lip four weeks after CO(2) laser skin resurfacing; it showed microscopic evidence of perineural invasion. Despite repeated treatment with intralesional methotrexate, the KA recurred after 6 months. She was then treated with ionizing radiation (56 Gy) and has been tumor-free for more than 3 years. Immunohistochemistry showed decreased expression of desmoglein 1 as it is seen in squamous cell carcinomas. In most cases not much importance is attached to perineural invasion which is frequently seen in KA because of the high rate of spontaneous regression. Our case suggests that perineural invasion may be an indicator for aggressive growth of head-and-neck KAs so that histologically-controlled excision is recommended.


Monocyte phagocytosis of viable Staphylococcus aureus is impaired by barbiturates, but not by propofol.
Barbiturates and propofol are used for deep sedation of patients with elevated intracranial pressure refractory to standard therapeutic regimens. Such patients often suffer from bacterial infections, which are most commonly caused by Staphylococcus aureus. Various interactions of anesthetics with components of the host defense have been documented, but very little is known about the influence on monocytes, which are a first-line defense against bacterial invasion. Therefore, we studied the effects of thiopental, methohexital, and propofol on monocyte phagocytosis using an in vitro whole blood model of viable S. aureus. Whole blood samples were preincubated with different concentrations of thiopental, methohexital, and propofol. Phagocytosis was stopped at different time points after addition of viable S. aureus. Monocytes then were stained with monoclonal antibodies for flow cytometric analysis of monocyte recruitment (ratio of ingesting monocytes). Furthermore, the fluorescence intensity of ingested bacteria served as semiquantitative measurement of phagocytosis activity. Both barbiturates inhibited monocyte recruitment and phagocytosis activity concentration-dependently, whereas propofol did not affect any of the investigated parameters. At concentrations of 7.6 x10(-3) M thiopental or 1.1 x 10(-3) M methohexital and greater, monocyte recruitment and phagocytosis activity were significantly inhibited. The calculated half-maximum inhibitory concentration (IC50) of thiopental was 8.4 x 10(-3) M for monocyte recruitment and 8.6 x 10(-3) M for phagocytosis activity. The corresponding values for methohexital were 4.1 x 10(-3) M and 1.1 x 10(-3) M, respectively. The two barbiturates induce concentration-dependent inhibition of monocyte phagocytosis, whereas propofol is without effect. In combination with previously described effects on granulocyte function, these findings suggest that defense against bacterial infection might be reduced by barbiturates.


Safety and efficacy of lobeglitazone monotherapy in patients with type 2 diabetes mellitus over 52 weeks: An open-label extension study.
We aimed to assess the safety and efficacy of lobeglitazone in patients with type 2 diabetes over 52 weeks through 28-week extension study. Clinical benefits in terms of glycemic and lipid control were maintained for 52 weeks. Lobeglitazone showed a favorable balance of efficacy and safety during the extension study.


[Endovascular therapy of chronic mesenteric ischemia].
Arteriosclerosis is the most common cause of chronic mesenteric ischemia, which is characterized by postprandial pain, unintentional weight loss and food avoidance. The use of endovascular techniques for revascularization of chronic stenoses and occlusions of the mesenteric arteries has rapidly increased over the last 10 years. The results of endovascular therapy have shown less morbidity and mortality compared to open surgical procedures, such as bypass and thrombendarterectomy. Early publications have reported higher rates of restenosis, symptomatic recurrence and reinterventions but recent case series show comparable patency rates. This article reviews visceral arterial anatomy and anomalies and endovascular techniques for the revascularization of mesenteric arteries.


Altitude and birth weight.
The effect of altitude on birth weight was measured with data in U.S. natality records from 1978 to 1981 after correlation with the mean altitude of the mother's resident county. For comparison of the low birth weight (LBW) rate at different altitudes, certain socioeconomic risk factors known to affect birth weight were controlled by the selection of an idealized subpopulation of singleton births. With 500 m gradations for altitude, a curvilinear dose-response relationship of birth weight reduction with increasing altitude was demonstrated (P less than 0.001). In comparison with neonates born at sea level, neonates born at higher altitudes (greater than 2000 m) had a twofold to threefold increase in LBW rate, mainly related to a higher incidence of intrauterine growth retardation. Comparison of the LBW rate on the basis of small geographic divisions in the mountain states showed a positive correlation between the LBW rate and the high altitude. The birth weight frequency distribution curves of the idealized subpopulation at each altitude approximate normal distributions and parallel one another, indicating that altitude has a general effect on all births. Such nearly normal birth weight distributions allowed the determination of altitude-specific LBW cutoff limits that can be used to detect areas of greater risk for LBW but independent of the altitude effect.


Prediction and Estimation of Parkinson's Disease Severity Based on Voice Signal.
This paper presents the possibilities of using speech signal processing, analysis and regression methods in the context of assessment of neurological state in Parkinson's disease patients up to 3 hours after taking medication which alleviates symptoms of the disease. The obtained results were used to create a system whose goals were the prognosis of values of selected acoustic parameters based on which it will be possible to further estimate a unified Parkinson's disease rating scale score. For the experiment, we used the recordings of the vowel /a/ of 27 patients who were recorded 5 times each at a certain time after levodopa intake. The speech signal was parameterized, where in the acoustic parameters describing the signal were extracted and constituted input vectors to machine learning regression methods to search for characteristic diagnostic symptoms enabling automatic monitoring of the course of Parkinson's disease. The results of the acoustic analysis were correlated with the clinical description and disease severity was assessed using the unified Parkinson's disease rating scale. As a result, it was possible to create software which will support the work of the clinician in the field of therapy monitoring and provide a quantitative assessment of treatment results and a forecast of the effects of the therapy in short-term monitoring.


Efficacy of Lecture cum demonstration versus video-based teaching regarding active management of third stage of labor in terms of knowledge and skills of GNM students: An interventional study.
Educational interventions have been associated with improved performance and significant changes, especially in perinatal outcomes. Teaching is one of the main components in educational planning which is a key factor in conducting educational plans through various teaching strategies such as simulation, demonstration and video teaching. The study aimed to assess lecture cum demonstration (LCD) versus video-based teaching (VBT) regarding active management of the third stage of labor (AMTSL) in terms of knowledge and skills of General Nursing Midwifery (GNM) students. This was a quasi-experimental study conducted on 100 GNM third-year students selected by purposive sampling and randomly assigned to LCD (n = 50) and VBT (n = 50) groups. Sample characteristics performa, Structured Knowledge Questionnaire, and observational checklist were used to collect data from GNM students through self-report and observational technique. The study results showed that the mean posttest knowledge scores of LCD (17.32 ± 2.14) and VBT group (16.90 ± 2.41) were nearly equal and mean rank posttest skills score of LCD group (54.40) was slightly higher than VBT group (49.51), but computed " t " value of mean posttest knowledge and computed " Z " value of skill score of both LCD and VBT group (0.47, 0.54) were found to be statistically non-significant at 0.05 level of significance. It can be concluded that both LCD and VBT were found to be effective in improving knowledge and skills of GNM students regarding AMTSL.


Plus and minus strand leader RNAs in negative strand virus-infected cells.
Sendai virus and VSV minus strand genome RNAs, labeled specifically at their 3' ends with RNA ligase, were used as probes to detect leader RNA--that is, short transcripts (approximately 50 nucleotides) complementary to the exact 3' end of the minus strand genome. These probes have allowed the detection of plus strand leader RNAs in both Sendai virus and VSV-infected cells as well as in the virion transcriptase reactions. The use of a similar probe, prepared from the self-complementary ends of DI genome RNA and containing the 3' end of the plus strand antigenome RNA, has allowed the detection of a minus strand leader RNA of identical size in VSV-infected cells. Since the presence of DI genomes could not be detected by analytical sucrose gradient centrifugation in these VSV-infected cells, this minus strand leader RNA is apparently synthesized on the template formed by the exact 3' end of the antigenome RNA.


Increased expression of intracystic matrix metalloproteinases in brain tumors: relationship to the pathogenesis of brain tumor-associated cysts and peritumoral edema.
Although several types of brain tumors are commonly associated with cyst formation, the pathogenesis of tumor-associated cysts (TAC) is unknown. We investigated the matrix metalloproteinase (MMP) expression of cyst fluids to elucidate the pathogenesis of TAC in brain tumors. We also examined the relationship between the severity of peritumoral edema and the expression of intracystic MMP. We collected 40 cyst fluid samples from 34 patients with TAC and studied the expression of MMP-2 and -9 in the cyst fluid using gelatin zymography. Radiological studies were used to estimate the severity of the peritumoral edema and to determine the presence of TAC. Although gelatin zymography of the cyst fluid showed high levels of MMPs, there was no correlation between the expression of MMPs in the cyst fluid and that in the tumor tissue. The level of MMP expression in the cyst fluid did not reflect the pathologic grade of the individual tumors. However, the total and activated MMP-9 levels were significantly associated with the severity of the peritumoral edema (p<0.05). These results suggest that MMPs may be partly involved in the pathogenesis of TAC and peritumoral edema in brain tumors.