Sliding Mode Stabilization of Memristive Neural Networks With Leakage Delays and Control Disturbance.
In this article, we investigate a class of memristive neural networks (MNNs) with time-varying delays and leakage delays via sliding mode control (SMC) with and without control disturbance. SMC is used to ensure MNNs' stability. According to the characteristics of the MNNs, we consider the following three models: the first is the MNNs with time-varying delays, the second is the MNNs with time-varying delays and the control disturbance, and the third is the MNNs with time-varying delays, leakage delays, and the control disturbance. We quote some assumptions and lemmas to ensure that our main results are true. The sliding surface, the corresponding sliding mode controller, and the Lyapunov functions are constructed in different models to ensure MNNs' stability. Finally, some examples and simulations verify the validity of our main results by solving linear matrix inequality (LMI), and the conclusions and analysis of the results are given.


Psychometric properties of acute stress disorder questionnaire for people exposed to Kerman earthquake.
Some people exposed to disasters will suffer from acute stress disorder (ASD) due to the negative consequences of these disasters. Evaluating this disorder at a large scale requires a credible and standardized tool. Therefore, the current study aims to investigate the psychometric properties of the ASD questionnaire for people exposed to Kerman earthquake. This is a descriptive-tooling study, conducted on 435 men and women older than 18 years living in earthquake-affected areas of Kerman Province (Kouh-e-Banan). The study was carried out using the Persian translating of the English version of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ASD questionnaire on accessible individuals living in temporary residence tents in two initial and final stages and different stages of validity and reliability evaluation was carried out. The findings were analyzed using descriptive statistics and Pearson's correlation coefficient. During the evaluation of content validity, no questions were eliminated. To carry out factor analysis, sampling competence, and suitability of sample size were confirmed through Kaiser-Meyer-Olkin and Bartlett's tests. In the factor analysis stage, 14 items in three factors were defined. The factors were included reexperiencing and analysis, arousal (continuous irritability), and avoidance factors which together explained 59.43% of percentage distribution. In the next stage of evaluating divergent validity, the results indicated a significant and inverse correlation between ASD score and quality of life score (r = -0.43, P = 0.002) of the participants, while there was also a positive and significant correlation between ASD score and general health disorder score of the participants (r = 0.47, P < 0.0001). The reliability of the questionnaire was investigated using Cronbach's alpha, and inner class correlation coefficient was calculated to be 0.9. The tool investigated in this study has suitable validity and reliability and is effective for use by psychologists and relief workers for necessary interventions and prevention of ASD in disasters.


The Use of Tools, Modelling Methods, Data Types, and Endpoints in Systems Medicine: A Survey on Projects of the German e:Med-Programme.
Systems medicine is the consequent continuation of research efforts on the road to an individualized medicine. Thereby, systems medicine tries to offer a holistic view on the patient by combining different data sources to highlight different perspectives on the patient's health. Our research question was to identify the main data types, modelling methods, analysis tools, and endpoints currently used and studied in systems medicine. Therefore, we conducted a survey on projects with a systems medicine background. Fifty participants completed this survey. The results of the survey were analyzed using histograms and cross tables, and finally compared to results of a former literature review with the same research focus. The data types reported in this survey were widely diversified. As expected, genomic and phenotype data were used most frequently. In contrast, environmental and behavioral data were rarely used in the projects. Overall, the cross tables of the data types in the survey and the literature review showed overlapping results.


Lamin A/C polymorphisms, type 2 diabetes, and the metabolic syndrome: case-control and quantitative trait studies.
Mutations in the LMNA gene, encoding the nuclear envelope protein lamin A/C, are responsible for a number of distinct disease entities including Dunnigan-type familial partial lipodystrophy. Dunningan-type lipodystrophy is characterized by loss of subcutaneous adipose tissue, insulin resistance, dyslipidemia, and type 2 diabetes and shares many of the features of the metabolic syndrome. Furthermore, several genome-wide linkage scans for type 2 diabetes have found evidence of linkage at chromosome 1q21.2, the region that harbors the LMNA gene. Therefore, LMNA is a biological and positional candidate for type 2 diabetes susceptibility. Previous studies have reported association between a common LMNA variant (1908C>T; rs4641) and adverse metabolic traits in ethnically diverse populations from Asia and North America. In the present study, we characterized the common variation across the LMNA gene (including rs4641) and tested for association with type 2 diabetes in two large case-control studies (n = 2,052) and with features of the metabolic syndrome in a separate cohort study (n = 1,572). Despite our study being sufficiently powered to detect effects similar and even smaller in magnitude than those previously reported, none of the LMNA single nucleotide polymorphisms were statistically significantly associated with type 2 diabetes or the metabolic syndrome. Thus, it appears unlikely that variation at LMNA substantially increases the risk of type 2 diabetes or related traits in U.K. Europids.


Evolution and evaluation of autologous mini punch grafting in vitiligo.
Vitiligo is a result of disrupted epidermal melanization with an undecided etiology and incompletely understood pathogenesis. Various treatment options have resulted in various degrees of success. Various surgical modalities and transplantation techniques have evolved during the last few decades. Of them, miniature punch grafting (PG) has established its place as the easiest, fastest, and least expensive method. Various aspects of this particular procedure have been discussed here. The historical perspective, the instruments, evolution of mini grafting down the ages, and the methodology, advantages, and disadvantages have been discussed. A detailed discussion on the topic along with a review of relevant literature has been provided in this article.


The development of adolescent idiopathic scoliosis.
There are many conflicting actiological theories for adolescent idiopathic scoliosis. We present a simple new model of scoliosis and a mechanism by which it is initiated and progresses. This mechanism provides a final common pathway for the multiple aetiological factors. A simple model of the spine, incorporating its fundamental mechanical features, was constructed. The model consisted of interconnected anterior compression and posterior tension columns. It allowed normal spinal movements, with flexion limited by the posterior column and rotation centered around the anterior column. It also allowed deformities to develop. The ends of the model were fixed in the position of the vertebrae they represented. Overgrowth of the anterior column relative to the posterior column caused the model to take up the shape of an idiopathic scoliosis. The greater the overgrowth, the more marked the deformity. Normally anterior and posterior column growth are coupled. During the growth spurt the thoracic kyphosis flattens indicating that anterior growth temporarily exceeds posterior growth. If this over-growth is marked a scoliosis will develop, as demonstrated by the model. Once this occurs the coupling is lost, anterior growth further outstrips posterior growth and the deformity progresses. Not all scolioses worsen, as the tendency to progress is balanced by neuromuscular factors and remodelling. Factors that increase the growth rate, induce asymmetry or decrease the inherent stability of the spine all encourage the development and progression of a scoliosis. This explains the complex biomechanics of scoliosis and provides a final common pathway by which the multiple aetiological factors can induce idiopathic scoliosis. It has important implications for the understanding and treatment of this condition.


Effects of cognitive impairment and loss of physical capacities on survival of the elderly.
This study investigates the effects of cognitive impairment and loss of physical capacity on the survival rates of the elderly in Taiwan. Data used for this research were obtained from a longitudinal study in northern Taiwan, where 1,434 elderly respondents were randomly selected and were interviewed in 1993 and 1996. Respondents were categorized into four groups: those with physical disability, those with cognitive impairment, those with neither condition and those with both conditions. The survival rates of these four groups were analyzed and compared. The effects of cognitive impairment and physical disability were assessed separately and jointly. Within the study period, we found that elderly persons with both conditions had the lowest survival rate (0.54, 95% confidence interval (CI) 0.35-0. 73), while those with neither condition had the most favorable survival rate (0.92, 95% CI 0.90-0.93). Results from the Cox proportional hazard model showed that physical disability had a significantly adverse effect on the risk of mortality (relative risk 2.5, 95% CI 1.5-4.2), while cognitive impairment did not. Our results are consistent with previous findings which have shown that the decline in physical function affects mortality more than the decline in cognitive function.


Opioid sensitivity in treated and untreated obstructive sleep apnoea: a prospective cohort study.
Opioid administration to patients with obstructive sleep apnoea (OSA) is controversial because they are believed to be more sensitive to opioids. However, objective data on opioid effects in OSA are lacking. We tested the hypothesis that subjects with untreated OSA have increased sensitivity to opioids compared with subjects without OSA, or with OSA treated with continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BIPAP). This was a single-centre, prospective cohort study in subjects without OSA (n=20), with untreated OSA (n=33), or with treated OSA (n=21). OSA diagnosis was verified using type III (in-home) polysomnography. Subjects received a stepped-dose remifentanil infusion (target effect-site concentrations of 0.5, 1, 2, 3, 4 ng ml-1). Primary outcome was miosis (pupil area fractional change), the most sensitive opioid effect. Secondary outcomes were ventilatory rate, end-expired CO2, sedation, and thermal analgesia. There were no differences in miosis between untreated OSA subjects (mean=0.51, 95% confidence interval [CI] 0.41-0.61) and subjects without OSA (mean=0.49, 95% CI 0.36-0.62) (mean difference=0.02, 95% CI -0.18 to 0.22); between treated OSA subjects (mean=0.56, 95% CI 0.43-0.68) and subjects without OSA (difference=0.07, 95% CI -0.16 to 0.29); or between untreated OSA and treated OSA (difference=-0.05, 95% CI -0.25 to 0.16). There were no significant differences between subjects without OSA, untreated OSA, and treated OSA in ventilatory rate, end-expired CO2, sedation, or thermal analgesia responses to remifentanil. There was no relationship between OSA severity and magnitude of opioid effects. Neither obstructive sleep apnoea nor obstructive sleep apnoea treatment affected sensitivity to the miotic, sedative, analgesic, or respiratory depressant effects of the opioid remifentanil in awake adults. These results challenge conventional notions of opioid effects in obstructive sleep apnoea. NCT02898792 (clinicaltrials.gov).


Use of breath sounds to assist difficult intubation of the trachea.
The technique of locating the laryngeal inlet using breath sounds was attempted on six patients referred for appropriate management following a failed intubation at the Eldoret District Hospital. Five of these were successfully intubated. It was still impossible to intubate the sixth patient who subsequently required a tracheostomy.


Seasonal variation of biotic and abiotic parameters in parallel neotropical fishponds.
The present study was carried out to evaluate the phytoplankton community and water quality in four parallel fishponds (FP1 to FP4) during one year. Some abiotic parameters of water column and phytoplankton was sampled in four sites, one in each fishpond. Similarity analysis showed that FP2 fishpond was markedly different for the others ponds with regard to phytoplankton community. Conductivity, orthophosphate, temperature, TSS and hardness parameters were significantly different (p<0.05) between fishponds and all limnological parameters were significantly different (p<0.01) among period (months). Organic matter and phosphorus of the sediment were significantly different (p<0.01) only among fishponds. In current study Chlorophyceae and Bacillariophyceae occurred in most months. Cyanobacteria density in April and May was higher in all fishponds, at FP3 represented 71.4% in April and FP1 represented 78.7% in May of total reported, with chlorophyll-a content lower than 41 mg.L-1. The physical and chemical parameters of fishponds water constituted relations between the parameters and algae occurrence. The present study however, indicated that Cyanobacteria was more frequent in the fishponds after the fish grow-out period (April), and the water quality should be monitored more frequently in this period, due to the high total phosphorus, orthophosphate and chlorophyll-a contents.


Coronary arterial lesions in piglets from sows fed moderate excesses of vitamin D.
Ultrastructural studies were conducted on the coronary arteries of 6 week-old piglets from sows which received diets containing either 25 micrograms or 3.7 micrograms of vitamin D3 per pound of basal ration. The subendothelial space which was rich in mucopolysaccharide and newly formed tiny elastic fibers, contained numerous macrophages, some of which possessed lipid droplets. Degenerated smooth muscle cells with pyknotic nuclei or vesiculated organelles, and mitotic smooth muscle cells were occasionally seen in the coronary artery. Piglets from sows which were fed high doses of vitamin D had more degenerated smooth muscle cells without stainable lipid and lipid containing cells in their coronary arteries than piglets from sows which were fed low doses of vitamin D. These results suggested that an excess dietary intake of vitamin D by pregnant animals may have potential angiotoxic effects on the coronary arteries of their offsprings.


Local production of reactive oxygen species drives vincristine-induced axon degeneration.
Neurological side effects arising from chemotherapy, such as severe pain and cognitive impairment, are a major concern for cancer patients. These major side effects can lead to reduction or termination of chemotherapy medication in patients, negatively impacting their prognoses. With cancer survival rates improving dramatically, addressing side effects of cancer treatment has become pressing. Here, we use iPSC-derived human neurons to investigate the molecular mechanisms that lead to neurotoxicity induced by vincristine, a common chemotherapeutic used to treat solid tumors. Our results uncover a novel mechanism by which vincristine causes a local increase in mitochondrial proteins that produce reactive oxygen species (ROS) in the axon. Vincristine triggers a cascade of axon pathology, causing mitochondrial dysfunction that leads to elevated axonal ROS levels and SARM1-dependent axon degeneration. Importantly, we show that the neurotoxic effect of increased axonal ROS can be mitigated by the small molecule mitochondrial division inhibitor 1 (mdivi-1) and antioxidants glutathione and mitoquinone, identifying a novel therapeutic avenue to treat the neurological effects of chemotherapy.


Peripheral blood Th9 cells are a possible pharmacodynamic biomarker of nivolumab treatment efficacy in metastatic melanoma patients.
Although nivolumab is associated with a significant improvement in overall survival and progression-free survival, only 20 to 40% of patients experience long-term benefit. It is therefore of great interest to identify a predictive marker of clinical benefit for nivolumab. To address this issue, the frequencies of CD4+ T cell subsets (Treg, Th1, Th2, Th9, Th17 and Th22), CD8+ T cells, and serum cytokine levels (IFNγ, IL-4, IL-9, IL-10, TGF-β) were assessed in 46 patients with melanoma. Eighteen patients responded to nivolumab, and the other 28 patients did not. An early increase in Th9 cell counts during the treatment with nivolumab was associated with an improved clinical response. Before the first nivolumab infusion, the responders displayed elevated serum concentrations of TGF-β compared to non-responders. Th9 induction by IL-4 and TGF-β was enhanced by PD-1/PD-L1 blockade in vitro. The role of IL-9 in disease progression was further assessed using a murine melanoma model. In vivo IL-9 blockade promoted melanoma progression in mice using an autochthonous mouse melanoma model, and the cytotoxic ability of murine melanoma-specific CD8+ T cells was enhanced in the presence of IL-9 in vitro. These findings suggest that Th9 cells, which produce IL-9, play an important role in the successful treatment of melanoma patients with nivolumab. Th9 cells therefore represent a valid biomarker to be further developed in the setting of anti-PD-1 therapy.


Phosphonium Salt Displays Cytotoxic Effects Against Human Cancer Cell Lines.
Aims/Objective: Phosphonium salts are compounds whose structural characteristics enable them to cross the plasma and mitochondrial membrane with ease. Cancer cells have higher plasma membrane potentials than normal cells; phosphonium salts selectively accumulate in the mitochondria of neoplastic cells and inhibit mitochondrial function. In the present work, we investigated the cytotoxic activity of lipophilic phosphonium salt (11- methoxy11-oxo-undecyl) triphenylphosphonium bromide (MUTP) as well as of the two new phosphine oxide salts, 3,3'-(methylphosphoryl) dibenzenaminium chloride (SBAMPO) and 3,3' (phenylphosphoryl) dibenzenaminium chloride (SBAPPO) on the proliferation of breast cancer cell line (MCF-7) and human uterin cervix adenocarcinoma cells (HeLa). We showed that only MUTP exhibits antiproliferative effects on both cell lines, without affecting the normal breast epithelial cell proliferation. More specifically, we demonstrated that MUTP treatment of breast cancer cells is associated with impaired cell-cycle progression and metabolically induces mitochondrial damage and triggers apoptotic cell death in MCF-7 and HeLa cells. Taken together, these findings suggest that MUTP may be capable of selectively targeting neoplastic cell growth and therefore has potential applications as anticancer agent.


Endotoxicity of lipopolysaccharide as a determinant of T-cell-mediated colitis induction in mice.
The intestinal microbiota is an important determinant of the mucosal response. In patients with inflammatory bowel diseases, the mucosal immune system has inappropriate interactions with the intestinal microbiota. We investigated how the composition of the intestinal microbiota affects its endotoxicity and development of colitis in mice. Germ-free C57BL/6J-Rag(1tm1Mom) (Rag1(-/-)) mice were colonized with 2 different types of complex intestinal microbiota. Colitis was induced in Rag1(-/-) mice by transfer of CD4(+)CD62L(+) T cells from C57BL/6J mice. Colonic tissues were collected and used for histologic analysis and cell isolation. Activation of lamina propria dendritic cells and T cells was analyzed by flow cytometry. After transfer of CD4(+)CD62L(+) T cells, mice with intestinal Endo(lo) microbiota (a low proportion of Enterobacteriaceae, high proportion of Bacteroidetes, and low endotoxicity) maintained mucosal immune homeostasis, and mice with highly endotoxic Endo(hi) microbiota (a high proportion of Enterobacteriaceae and low proportion of Bacteroidetes) developed colitis. To determine whether the effects of Endo(hi) microbiota were related to the higher endotoxic activity of lipopolysaccharide (LPS), we compared LPS from Enterobacteriaceae with that of Bacteroidetes. Administration of Escherichia coli JM83 (wild-type LPS) to the mice exacerbated colitis, and Escherichia coli JM83 + htrBPG (mutated LPS, with lower endotoxicity, similar to that of Bacteroidetes) prevented development of colitis after transfer of the T cells to mice. The endotoxicity of LPS produced by the intestinal microbiota is a determinant of whether mice develop colitis after transfer of CD4(+)CD62L(+) T cells. This finding might aid the design of novel biologics or probiotics to treat inflammatory bowel disease.


Online vs. face-to-face discussion in a Web-based research methods course for postgraduate nursing students: a quasi-experimental study.
Web-based technologies are increasingly being used to create modes of online learning for nurses but their effect has not been assessed in nurse education. Assess whether participation in face-to-face discussion seminars or online asynchronous discussion groups had different effects on educational attainment in a web-based course. Non-randomised or quasi-experimental design with two groups-students choosing to have face-to-face discussion seminars and students choosing to have online discussions. The Core Methods module of a postgraduate research methods course. All 114 students participating in the first 2 yr during which the course teaching material was delivered online. Assignment mark for Core Methods course module. Background details of the students, their choices of modules and assignment marks were collected as part of the routine course administration. Students' online activities were identified using the student tracking facility within WebCT. Regression models were fitted to explore the association between available explanatory variables and assignment mark. Students choosing online discussions had a higher Core Methods assignment mark (mean 60.8/100) than students choosing face-to-face discussions (54.4); the difference was statistically significant (t=3.13, df=102, p=0.002), although this ignores confounding variables. Among online discussion students, assignment mark was significantly correlated with the numbers of discussion messages read (Kendall's tau(b)=0.22, p=0.050) and posted (Kendall's tau(b)=0.27, p=0.017); among face-to-face discussion students, it was significantly associated with the number of non-discussion hits in WebCT (Kendall's tau(b)=0.19, p=0.036). In regression analysis, choice of discussion method, whether an M.Phil./Ph.D. student, number of non-discussion hits in WebCT, number of online discussion messages read and number posted were associated with assignment mark at the 5% level of significance when taken singly; in combination, only whether an M.Phil./Ph.D. student (p=0.024) and number of non-discussion hits (p=0.045) retained significance. This study demonstrates that a research methods course can be delivered to postgraduate healthcare students at least as successfully by an entirely online method in which students participate in online discussion as by a blended method in which students accessing web-based teaching material attend face-to-face seminar discussions. Increased online activity was associated with higher assignment marks. The study highlights new opportunities for educational research that arise from the use of virtual learning environments that routinely record the activities of learners and tutors.


Environmental stiffness restores mechanical homeostasis in vimentin-depleted cells.
Recent experimental evidence indicates a role for the intermediate filament vimentin in regulating cellular mechanical homeostasis, but its precise contribution remains to be discovered. Mechanical homeostasis requires a balanced bi-directional interplay between the cell's microenvironment and the cellular morphological and mechanical state-this balance being regulated via processes of mechanotransduction and mechanoresponse, commonly referred to as mechanoreciprocity. Here, we systematically analyze vimentin-expressing and vimentin-depleted cells in a swatch of in vitro cellular microenvironments varying in stiffness and/or ECM density. We find that vimentin-expressing cells maintain mechanical homeostasis by adapting cellular morphology and mechanics to micromechanical changes in the microenvironment. However, vimentin-depleted cells lose this mechanoresponse ability on short timescales, only to reacquire it on longer time scales. Indeed, we find that the morphology and mechanics of vimentin-depleted cell in stiffened microenvironmental conditions can get restored to the homeostatic levels of vimentin-expressing cells. Additionally, we observed vimentin-depleted cells increasing collagen matrix synthesis and its crosslinking, a phenomenon which is known to increase matrix stiffness, and which we now hypothesize to be a cellular compensation mechanism for the loss of vimentin. Taken together, our findings provide further insight in the regulating role of intermediate filament vimentin in mediating mechanoreciprocity and mechanical homeostasis.


Synthesis and partial maturation of the alpha- and gamma-subunits of the mouse submaxillary gland nerve growth factor in Xenopus laevis oocytes.
Sera raised against the alpha-, beta- and gamma-subunits of the mouse 7 S NGF were used to characterize translation products coded by submaxillary gland mRNAs microinjected into Xenopus oocytes. Anti-beta NGF sera did not cross-react with any material. In contrast, the precursors of the alpha- and gamma-subunits, as well as that of renin were identified. Use of tunicamycin, and a comparison of the translation products obtained in oocytes or in the reticulocyte lysate indicated that oocytes achieved the cleavage of signal sequences, the glycosylation of the alpha- and gamma-precursors, and the subsequent secretion of the 3 proteins. In the submaxillary gland, however, the mature forms of alpha NGF, gamma NGF and renin are composed of peptides of smaller size than those produced by the oocytes. These latter appear to lack specific proteases involved in the terminal processing of the submaxillary gland proteins.


Early to mid-term results after total cavopulmonary connection performed in the second decade of life.
Total cavopulmonary connection (TCPC) performed in the second decade of life has rarely been studied. Thus, we investigated (bicentric study) early and late morbidity and mortality following completion of TCPC in these patients. From January 1999 to June 2014, 63 patients (14.5 ± 2.9 years) underwent TCPC (extracardiac conduit). Palliation before completion was an isolated bidirectional cavopulmonary shunt (BCPS) in 3 patients or BCPS associated with additional pulmonary blood flow (APBF) that was either antegrade (Group 1) in 38 (63%) or retrograde (Group 2) in 22 (37%). Preoperative and perioperative data were reviewed retrospectively. Mean pulmonary arterial and ventricular end-diastolic pressures were 12.2 and 9.2 mmHg, respectively. Mean Nakata index was 279 ± 123 and 228 ± 87 mm 2 /m 2 in Groups 1 and 2, respectively ( P = 0.01). Aortic cross-clamping was performed in 22 from Group 1 and 8 from Group 2 ( P = 0.04). Mean follow-up was 4.57 years [0.8-15]. Nine patients had prolonged stays in the intensive care unit (>6 days). There were 1 early and 2 late deaths (non-cardiac related). Actuarial survival was 96% at 4 years. At last follow-up, single-ventricle function remained normal or improved in all patients (Group 1) compared to 82% in Group 2 ( P = 0.02). New York Heart Association (NYHA) class had improved in both groups: 47 patients were NYHA class II and 16 class III preoperatively vs 50 class I and 10 class II postoperatively ( P < 0.001). Single-ventricle palliation with BCPS and APBF allowed completion of TCPC in the second decade of life, with encouraging mid-term results. However, BCPS with retrograde APBF was associated with single-ventricle dysfunction: thus, this technique needs to be used cautiously as long-lasting palliation.


Silicate fiber-based 3D cell culture system for anticancer drug screening.
Three-dimensional (3D) in vitro cultures can recapitulate the physiological in vivo microenvironment. 3D Modeling techniques have been investigated and applied in anticancer drug screening. A silicate fiber scaffold was used for 3D cell cultures, and used to model the efficacy of anticancer drugs, such as mytomicin C and doxorubicin. A unique 3D structure was observed in 13 human tumor cell lines on scaffold, and these cells exhibited higher drug resistance than cells in two-dimensional (2D) cultures. Furthermore, the production of lactate and expression of the nuclear factor-kappa B (NF-κB)-regulated genes B cell lymphoma-2 (BCL2), cyclooxygenase-2 (COX2), and vascular endothelial growth factor (VEGF) were higher in 3D cultures than in 2D cultures. These findings suggest that a 3D model using a silicate fiber scaffold can mimic features of cancer, and is also a suitable model for the evaluation of anticancer drugs in vitro.


Selenopeptides and elemental selenium in Thunbergia alata after exposure to selenite: quantification method for elemental selenium.
Three month old Thunbergia alata were exposed for 13 days to 10 μM selenite to determine the biotransformation of selenite in their roots. Selenium in formic acid extracts (80 ± 3%) was present as selenopeptides with Se-S bonds and selenium-PC complexes (selenocysteinyl-2-3-dihydroxypropionyl-glutathione, seleno-phytochelatin2, seleno-di-glutathione). An analytical method using HPLC-ICPMS to detect and quantify elemental selenium in roots of T. alata plants using sodium sulfite to quantitatively transform elemental selenium to selenosulfate was also developed. Elemental selenium was determined as 18 ± 4% of the total selenium in the roots which was equivalent to the selenium not extracted using formic acid extraction. The results are in an agreement with the XAS measurements of the exposed roots which showed no occurrence of selenite or selenate but a mixture of selenocysteine and elemental selenium.


Psychological significance of the irritable colon syndrome.
Sixty-seven patients with the irritable colon syndrome are reported. The symptom complex is considered to be a concomitant of an affective disorder, and the psychological factors associated with the genesis of the illness are discussed. Fifty-six patients received treatment with anti-depressant therapy, of whom 80% reported significant improvement.


[Role of biochemical methods in follow-up and treatment of patients with urolithiasis].
4-6-year follow-up using different tests covered 15 patients with urolithiasis and 11 control subjects aged 25 to 66 years. All the patients underwent 1 to 5 sessions of extracorporeal lithotripsy and one patient underwent open surgery. Clinical and biochemical findings on the groups were compared to the evidence of Litos test. Initiation of antirecurrence therapy should be based on the information gained with different methods, primarily, biochemical. Follow-up of the patients including biochemical control over their metabolic condition must be conducted for at least 5 years.


Martyrs' last letters: are they the same as suicide notes?
Of the 800,000 suicides worldwide every year, a small number fall under Emile Durkheim's term of altruistic suicides. Study on martyrdom has been limited. There has to date, for example, been no systematic empirical study of martyr letters. We examined 33 letters of Korean self-immolators, compared with 33 suicide notes of a matched sample of more common suicides. An analysis of intrapsychic factors (suicide as unbearable pain, psychopathology) and interpersonal factors (suicide as murderous impulses and need to escape) revealed that, although one can use the same psychological characteristics or dynamics to understand the deaths, the state of mind of martyrs is more extreme, such that the pain is reported to be even more unbearable. Yet, there are differences, such as there was no ambivalence in the altruistic notes. It is concluded that intrapsychic and interpersonal characteristics are central in understanding martyrs, probably equal to community or societal factors. More forensic study is, however, warranted.


Occupational and environmental toxicology of mercury and its compounds.
Mercury exists in various chemical forms. The important forms from a toxicological viewpoint are the metallic form, also called the elemental form, the divalent inorganic forms and methylmercury compounds. Elemental (Hg0) mercury has a high vapor pressure and the vapor causes a number of cases of poisoning via inhalation. Classical mercury poisoning is characterized by a triad of signs, namely tremors, erethism and gingivitis. Mercurial erethism, which is characterized by behavioral and personality changes such as extreme shyness, excitability, loss of memory, and insomnia are also observed. Recently, the effects of mercury exposure at levels around 0.05 mg/m3 or lower have been of concern and may include minor renal tubular damage, increased complaints of tiredness, memory disturbance and other symptoms, subclinical finger tremor, abnormal EEG by computerized analysis and impaired performance in neurobehavioral or neuropsychological tests. Abnormal gait, dysarthria, ataxia, deafness and constriction of the visual field are typical of the symptoms of methylmercury poisoning observed in Minamata and Iraqi outbreaks, as well as in occupational methylmercury poisoning cases. Furthermore, an infant born to a mother with excessive methylmercury consumption showed various neurological disturbances and delayed development. Since several populations are believed to be still exposed to methylmercury through the consumption of fish and sea mammals, neurobehavioral deviations in children of these populations have recently been investigated.


Increasing Nature Connection in Children: A Mini Review of Interventions.
Half of the world's population live in the urban environment. Lifestyle changes in the 20th century have led to spending more time indoors and less in nature. Due to safety concerns, longer hours in formal education, as well as lack of suitable outdoor environments, children in particular have been found to spend very little time outdoors. We have an opportunity, both timely and unique to have our children (re)connect with nature. Nature connection is a subjective state and trait that encompasses affective, cognitive, and experiential aspects in addition to being positively associated with wellbeing, and strong predictor of pro-environmental attitudes and behaviors. This mini-review brings together recent studies that report on interventions to increase nature connection in children. Fourteen studies were identified through electronic searches of Web of Science, Scopus, PsychInfo, ERIC, and Google Scholar. The review aims to offer an overview of the interventions identified, provide a snapshot of the current state of the literature, briefly present themes and trends in the studies identified in relation to nature connection in young people, and propose potential guidelines for future work.


Case Report: Surgical Management in Acute Subdural Hematoma Induced by Chronic Myelogenous Leukemia.
BACKGROUND Chronic subdural hematoma is defined as collection in the subdural space for more than 3 weeks. The incidence ranges from 1 to 20 per 100 000/year, with increased prevalence in the elderly, in males, and with use of anticoagulants or antiplatelets. Chronic myeloid leukemia has been linked to spontaneous subdural hematoma, with the highest reported cases of 39 patients in Korea, but no management is mentioned in that paper. There are few reported cases of patients who are medically free with no use of anticoagulants, diagnosed as having a subdural hematoma and then later discovered to have chronic myelogenous leukemia. CASE REPORT We report the case of a 45-year-old man, with known hypertension and diabetes mellitus type 2, on aspirin weekly, who was referred from another hospital with a history of sudden-onset severe headache not related to trauma. Computed tomography (CT) of the brain done in the other hospital showed a left-side subdural hematoma with midline shift. He underwent left-sided acute subdural hematoma evacuation and decompressive hemicraniectomy. He was started on hydroxyurea for chronic myelogenous leukemia. CONCLUSIONS A lesson from this rare case is to look for a differential diagnosis and to keep chronic myelogenous leukemia in mind in patients with leukocytosis. Also, we recommend sending a hematology referral in nontraumatic subdural hematoma. There is no specific treatment or algorithm based on previous research, although from observed data and based on information from the American Heart Association, it is reasonable to perform craniectomy in extra-axial collections of more than 1 cm with midline shift to avoid mortality, as reaching a diagnosis would take too much time.


Proteolytic processing of von Willebrand factor by adamts13 and leukocyte proteases.
ADAMTS13 is a 190 kDa zinc protease encoded by a gene located on chromosome 9q34. This protease specifically hydrolyzes von Willebrand factor (VWF) multimers, thus causing VWF size reduction. ADAMTS13 belongs to the A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats (ADAMTS) family, involved in proteolytic processing of many matrix proteins. ADAMTS13 consists of numerous domains including a metalloprotease domain, a disintegrin domain, several thrombospondin type 1 (TSP1) repeats, a cysteine-rich domain, a spacer domain and 2 CUB (Complement c1r/c1s, sea Urchin epidermal growth factor, and Bone morphogenetic protein) domains. ADAMTS13 cleaves a single peptide bond (Tyr1605-Met1606) in the central A2 domain of the VWF molecule. This proteolytic cleavage is essential to reduce the size of ultra-large VWF polymers, which, when exposed to high shear stress in the microcirculation, are prone to form with platelets clumps, which cause severe syndromes called thrombotic microangiopathies (TMAs). In this review, we a) discuss the current knowledge of structure-function aspects of ADAMTS13 and its involvement in the pathogenesis of TMAs, b) address the recent findings concerning proteolytic processing of VWF multimers by different proteases, such as the leukocyte-derived serine and metallo-proteases and c) indicate the direction of future investigations.


Molecular cloning and functional analysis of three type D endogenous retroviruses of sheep reveal a different cell tropism from that of the highly related exogenous jaagsiekte sheep retrovirus.
Integrated into the sheep genome are 15 to 20 copies of type D endogenous loci that are highly related to two exogenous oncogenic viruses, jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV). The exogenous viruses cause infectious neoplasms of the respiratory tract in small ruminants. In this study, we molecularly cloned three intact type D endogenous retroviruses of sheep (enJS56A1, enJS5F16, and enJS59A1; collectively called enJRSVs) and analyzed their genomic structures, their phylogenies with respect to their exogenous counterparts, their capacity to form viral particles, and the expression specificities of their long terminal repeats (LTRs). In addition, the pattern of expression of enJSRVs in vivo was studied by in situ hybridization. All of the three enJSRV proviruses had open reading frames for at least one of the structural genes. In particular, enJS56A1 had open reading frames for all structural genes, but it could not assemble viral particles when highly expressed in human 293T cells. We localized the defect for viral assembly in the first two-thirds of the gag gene by making a series of chimeras between enJS56A1 and the exogenous infectious molecular clone JSRV(21). Phylogenetic analysis distinguished five ovine type D retroviruses: enJSRV groups A and B, ENTV, and two exogenous JSRV groups (African versus United Kingdom/North America isolates). Transient transfection assays indicated that the LTRs of the three enJSRVs were not preferentially active in differentiated lung epithelial cells. This suggests that the pulmonary tropic JSRV developed from a type D retrovirus that did not have lung specificity. Consistent with this, in situ hybridization of a panel of normal ovine tissues revealed high expression of enJSRV mRNA in the luminal epithelium and glandular epithelium of the uterus; lower expression was localized in the lamina propria of the gut and in the bronchiolar epithelium of the lungs.


[Familial deficiency of thyroxine-binding globulin].
A family with congenital athyropexinemia is reported. By reconstruction of the family tree over seven generations, a heterozygous woman born in 1842 was identified as the first carrier of the anomaly who introduced the disorder into two family branches by marrying twice. 24 descendants examined included 6 heterozygous females and 8 hemizygous males. All were euthyroid. The mode of inheritance was obviously linked to the X-chromosome. An interesting fact was that in one family thyroxine binding globulin was absent or measured only in traces in hemizygous patients.


Removable Partial Denture - Functional Impression Techniques: Review.
The objective of this article is to concisely review the main clinical techniques used to make the functional impression to manufacture a removable partial denture. Through this review, the dentist can develop his clinical knowledge.


Role of capecitabine and irinotecan combination therapy in advanced or metastatic gastric cancer.
Gastric cancer is one of the most common cancers and the second leading cause of cancer-related death. So far, the only curative treatment for gastric cancer is surgery. However, approximately half of all patients present with nonoperable tumors. Therefore, combination chemotherapy regimens are being accepted nowadays as first-line treatment for this disease. Despite the numerous efforts of randomized trials on advanced gastric cancer, no globally accepted regimen has yet been established. Historically, the most widely adopted protocols use 5-fluorouracil or platinum-based therapy with a response rate not exceeding 50% in combination therapy with a high rate of toxicity. Recently, many new drugs have emerged on the market and have been used in treating advanced or metastatic gastric cancer allowing the creation of new combination regimens with better clinical benefit. The combination of irinotecan plus capecitabine is one of these new combinations that seem to provide an acceptable response rate and good toxicity profile. In this article, we review the efficacy, tolerability, and feasibility of this combination for the treatment of advanced or metastatic gastric cancer and we summarize the clinical trials using this regimen.


Mass Customized Outlook for Regenerative Heart Failure Care.
Heart failure pathobiology is permissive to reparative intent. Regenerative therapies exemplify an emerging disruptive innovation aimed at achieving structural and functional organ restitution. However, mixed outcomes, complexity in use, and unsustainable cost have curtailed broader adoption, mandating the development of novel cardio-regenerative approaches. Lineage guidance offers a standardized path to customize stem cell fitness for therapy. A case in point is the molecular induction of the cardiopoiesis program in adult stem cells to yield cardiopoietic cell derivatives designed for heart failure treatment. Tested in early and advanced clinical trials in patients with ischemic heart failure, clinical grade cardiopoietic cells were safe and revealed therapeutic improvement within a window of treatment intensity and pre-treatment disease severity. With the prospect of mass customization, cardiopoietic guidance has been streamlined from the demanding, recombinant protein cocktail-based to a protein-free, messenger RNA-based single gene protocol to engineer affordable cardiac repair competent cells. Clinical trial biobanked stem cells enabled a systems biology deconvolution of the cardiopoietic cell secretome linked to therapeutic benefit, exposing a paracrine mode of action. Collectively, this new knowledge informs next generation regenerative therapeutics manufactured as engineered cellular or secretome mimicking cell-free platforms. Launching biotherapeutics tailored for optimal outcome and offered at mass production cost would contribute to advancing equitable regenerative care that addresses population health needs.


Capreomycin and hygromycin B modulate the catalytic activity of the delta ribozyme in a manner that depends on the protonation and complexation with Cu2+ ions of these antibiotics.
Catalytic RNA molecules (ribozymes) have often been used for the testing of interactions of antibiotics with ribonucleic acids. We showed that the impact of capreomycin and hygromycin B on delta ribozyme catalysis might change dramatically, from stimulation to inhibition, depending on conditions. In order to evaluate possible mechanisms of modulation of the ribozyme catalytic activity we used our earlier data on species distribution for protonated forms of capreomycin and hygromycin B and their complexes with Cu(2+) ions at different pH values. We proposed that, upon inhibition, the protonated amino group of capreomycin was located in the ribozyme catalytic cleft interfering with binding catalytic Mg(2+). Such a mechanism was also supported by the results of ribozyme inhibition with capreomycin complexed with Cu(2+). The effects of stimulation of the delta ribozyme activity by capreomycin and hygromycin B were less pronounced than inhibition. Possibly, the amino functions of these antibiotics might be involved in a general acid-base catalysis performed by the ribozyme, acting as proton acceptors/donors.


11 beta-hydroxyandrostenedione in human amniotic fluid.
11 beta-Hydroxyandrostene-3,17-dione (11 beta-hydroxyandrostenedione), a potential marker for prenatal diagnosis of CAH, has been for the first time determined in amniotic fluid obtained from 68 women who later delivered children without endocrine disorders. Its concentration averaged 0.96 +/- 0.31 (S.D.) (range 0.48-1.85) nmol/l and did not depend on the fetal sex. There was mild, insignificant increase of these values along with duration of pregnancy.


Contrast-enhanced ultrasound: The evolving applications.
Contrast-enhanced ultrasound (CEUS) is a major breakthrough for ultrasound imaging in recent years. By using a microbubble contrast agent and contrast-specific imaging software, CEUS is able to depict the micro- and macro-circulation of the targeted organ, which in turn leads to improved performance in diagnosis. Due to the special dual blood supply system in the liver, CEUS is particularly suitable for liver imaging. It is evident that CEUS facilitates improvement for characterization of focal liver lesions (FLLs), detection of liver malignancy, guidance for interventional procedures, and evaluation of treatment response after local therapies. CEUS has been demonstrated to be equal to contrast-enhanced computed tomography or magnetic resonance imaging for the characterization of FLLs. In addition, the applicability of CEUS has expanded to non-liver structures such as gallbladder, bile duct, pancreas, kidney, spleen, breast, thyroid, and prostate. The usefulness of CEUS in these applications is confirmed by extensive literature production. Novel applications include detecting bleeding sites and hematomas in patients with abdominal trauma, guiding percutaneous injection therapy and therefore achieving the goal of using interventional ultrasonography in managing splenic trauma, assessing the activity of Crohn's disease, and detecting suspected endoleaks after endovascular abdominal aneurysm repair. Contrast-enhanced intraoperative ultrasound (US) and intracavitary use of CEUS have been developed and clinically studied. The potential use of CEUS involves sentinel lymph node detection, drug or gene delivery, and molecular imaging. In conclusion, the advent of CEUS has greatly enhanced the usefulness of US and even changed the status of US in clinical practice. The application of CEUS in the clinic is continuously evolving and it is expected that its use will be expanded further in the future.


[Hemorrhage and blood replacement. 2. Hemorrhage prevention and hemostasis, volume replacement].
Reviewed are the causes of hemorrhagic shock, pathophysiology of blood loss as well as clinical signs and diagnostic measures. The problematic nature of determination and judgement of blood loss, especially at internal bleeding and during operations is pointed out. Measures for prevention and stanching of bleeding are touched. Blood, blood plasma and colloids (dextran, gelatine and hydroxyethyl starch) for volume replacement and their side effects are discussed briefly.


The federal governments's role in management of end-stage renal disease.
This presentation traces the history of the Federal government's support of research and development related to the therapeutic modalities dialysis and renal transplantation. A description is presented of the Federal government's role in introduction of these new treatment methods into medical practice and of the gradual assumption by the government of responsibility for funding of the cost of dialysis and transplantation in the United States. Current issues and problems related to the federally subsidized End-State Renal Disease Program are discussed. The concept of "technology assessment" is introduced followed by discussion of the vital role it must play in any future federal development and support of new medical treatment technologies which must be paid for with public moneys because of their high cost.


The cognitive abnormalities underlying the symptomatology and the disability of patients with schizophrenia.
A variety of cognitive impairments can be observed in patients with schizophrenia, including substantial reductions in the intelligence quotient (IQ). I propose that these impairments can be best understood in terms of the abnormal processes underlying the signs and symptoms manifested by the patient at the time of the cognitive assessment. Negative signs such as poverty of speech are associated with defects of willed action, while positive symptoms such as hallucinations are associated with defects of self-monitoring. Hypotheses about the brain systems underlying these processes can be examined using functional brain imaging.


A mathematical model of spontaneous calcium release in cardiac myocytes.
In cardiac myocytes, calcium (Ca) can be released from the sarcoplasmic reticulum independently of Ca influx from voltage-dependent membrane channels. This efflux of Ca, referred to as spontaneous Ca release (SCR), is due to Ryanodine receptor fluctuations, which can induce spontaneous Ca sparks, which propagate to form Ca waves. This release of Ca can then induce delayed after-depolarizations (DADs), which can lead to arrhythmogenic-triggered activity in the heart. However, despite its importance, to date there is no mathematical model of SCR that accounts for experimentally observed features of subcellular Ca. In this article, we present an experimentally based model of SCR that reproduces the timing distribution of spontaneous Ca sparks and key features of the propagation of Ca waves emanating from these spontaneous sparks. We have coupled this model to an ionic model for the rabbit ventricular action potential to simulate SCR within several thousand cells in cardiac tissue. We implement this model to study the formation of an ectopic beat on a cable of cells that exhibit SCR-induced DADs.


Non-steroidal anti-inflammatory drugs and the risk of out-of-hospital cardiac arrest: a case-control study.
Non-steroidal anti-inflammatory drugs (NSAIDs), particularly selective COX-2 inhibitors, are associated with an increased risk of cardiovascular adverse events. However, the association between these drugs and out-of-hospital cardiac arrest with electrocardiogram-documented ventricular tachycardia/ventricular fibrillation (VT/VF-OHCA) has not been studied yet. This study was aimed to evaluate the association between the use of selective COX-2 inhibitors or conventional NSAIDs and VT/VF-OHCA compared with non-use. A case-control study was conducted among 2483 cases with VT/VF-OHCA from the AmsteRdam REsuscitation STudies (ARREST) registry, an ongoing Dutch registry of OHCA, and 10 441 non-VT/VF-OHCA-controls from the Dutch PHARMO Database Network, containing drug dispensing records of community pharmacies, over the period July 2005-December 2011. Up to five controls were matched for age and sex to one case at the date of VT/VF-OHCA (index date). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by conditional logistic regression analysis. Of the cases, 0.5% was currently exposed at the index date to selective COX-2 inhibitors and 2.5% to conventional NSAIDs. Neither current use of selective COX-2 inhibitors nor conventional NSAIDs were associated with an increased risk of VT/VF-OHCA (adjusted OR 1.11, 95% CI: 0.79-1.56 and adjusted OR 0.97, 95% CI: 0.86-1.10, respectively) compared with non-use. Stratification for VT/VF-OHCA with presence/absence of acute myocardial infarction did not change these results. Exposure to selective COX-2 inhibitors or conventional NSAIDs was not associated with an increased risk of VT/VF-OHCA compared with non-use.


Application of a FLAP-consensus docking mixed strategy for the identification of new fatty acid amide hydrolase inhibitors.
Fatty acid amide hydrolase (FAAH) is the principal responsible for the termination of anandamide signaling, a major actor of the endocannabinoid system. The indirect stimulation of endocannabinoid responses achieved through FAAH inhibition can represent a valid pharmacological strategy for the treatment of neurodegenerative and neuroinflammatory diseases such as multiple sclerosis, Alzheimer's, Huntington's, and Parkinson's diseases, as well as rheumatoid arthritis, gastrointestinal inflammatory states, anxiety, and other pathologies. With the aim of identifying new noncovalent FAAH inhibitors and also experimentally validating the reliability of the recently reported consensus docking approach, we filtered a commercial database of about 1 million compounds by using a mixed FLAP (fingerprints for ligands and proteins) consensus docking approach. Enzymatic assays showed FAAH inhibitory activity and selectivity versus MAGL for 8 out of the 10 top ranked compounds, with IC50 values in the low micromolar range for the two most active compounds. These results demonstrate the reliability of the virtual screening strategy and constitute an experimental validation of the consensus docking approach. Moreover, the two most active compounds described could represent promising leads for the development of high potent noncovalent FAAH inhibitors.


Resistance and inertia of endotracheal tubes used in infants during periodic flow.
To study the effects of a periodic pattern of gas flow on the dynamic behavior of infant endotracheal tubes, we measured the resistance (expressed as a function of gas flow) and inertia of endotracheal tubes of 2.5, 3.0, and 3.5-mm internal diameter under conditions of both periodic and quasisteady gas flow. We examined how resistance and inertia are affected by ventilatory rate, the direction of gas flow through the tube, and the expansion of the airway caliber at the junction of the tube and the trachea. The resistance of the endotracheal tubes was proportional to gas flow for ventilatory rates of 60, 90, and 120 breath/min and for quasisteady flow, indicating turbulence even at low flow rates. The resistance of the tubes was less sensitive to ventilatory rate, direction of flow, and expansion of the airway caliber than that of larger endotracheal tubes, a finding explained by the flow conditions defined by the Womersley and Reynolds numbers in these tubes. All tubes exhibited measureable inertia, as predicted from their small diameter. The resistive and inertial properties of the endotracheal tubes described in this report can be used to evaluate the contribution of the endotracheal tube to the dynamics of breathing in intubated infants.


Surgical modifications to the Brånemark zygomaticus protocol in the treatment of the severely resorbed maxilla: a clinical report.
The Zygomaticus dental implant, designed by Nobel Blocare, was developed for the treatment of the severely resorbed maxilla. Brånemark has reported an overall success rate of 97.6% with the placement of 183 implants over the last 12 years. The purpose of this article was to present a modification to the original Brånemark surgical approach to achieve better access and optimal Implant placement. There are parameters within the patient's resorbed skeletal frame that guide the surgical placement of the currently used Implant However, there are shortcomings in the current surgical protocol. This report describes a simplified surgical approach in 45 patients (77 implants) using an Implant with a modified head angulation of 55 degrees and a placement appliance to assist the surgeon in placing the implant as close to the crest of the edentulous ridge as possible. The placement appliance identifies accurately the anatomic constraints of the resorbed skeletal frame that limit implant placement. This, together with the modified surgical protocol, has resulted in improved access and in ideal positioning of the restorative head. The present technique allows restorative clinicians to achieve a more ideal restorative result In the posterior maxillary alveolus using the zygomatic implant, while reducing the buccal cantilever, improving tongue space, and access for maintenance. By placing the implant closer to the crest of the alveolar ridge using the placement appliance and an implant with a 55-degree head, the emergence of the restorative head and resultant buccal cantilever can be reduced by as much as 20%.


Parametric merging of MEG and fMRI reveals spatiotemporal differences in cortical processing of spoken words and environmental sounds in background noise.
There is an increasing interest to integrate electrophysiological and hemodynamic measures for characterizing spatial and temporal aspects of cortical processing. However, an informative combination of responses that have markedly different sensitivities to the underlying neural activity is not straightforward, especially in complex cognitive tasks. Here, we used parametric stimulus manipulation in magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) recordings on the same subjects, to study effects of noise on processing of spoken words and environmental sounds. The added noise influenced MEG response strengths in the bilateral supratemporal auditory cortex, at different times for the different stimulus types. Specifically for spoken words, the effect of noise on the electrophysiological response was remarkably nonlinear. Therefore, we used the single-subject MEG responses to construct parametrization for fMRI data analysis and obtained notably higher sensitivity than with conventional stimulus-based parametrization. fMRI results showed that partly different temporal areas were involved in noise-sensitive processing of words and environmental sounds. These results indicate that cortical processing of sounds in background noise is stimulus specific in both timing and location and provide a new functionally meaningful platform for combining information obtained with electrophysiological and hemodynamic measures of brain function.


Occult tumor cells in bone marrow of patients with locoregionally restricted ovarian cancer predict early distant metastatic relapse.
Based on conventional tumor staging, primary ovarian cancer is viewed as an intraperitoneal disease that rarely spreads to extraperitoneal organs. However, autopsy studies reveal a much higher rate of occult metastasis, indicating that extraperitoneal spread occurs with much greater frequency than previously appreciated. Consequently, we investigated the incidence of early hematogenous dissemination and its association with distant disease-free and overall survival. Bone marrow aspirates from 108 patients newly diagnosed with International Federation of Gynecology and Obstetrics stage I to III ovarian cancer were prospectively analyzed with the novel anti-cytokeratin (CK) antibody A45-B/B3. We investigated the frequency of CK-positive tumor cells in bone marrow and their effect on prognosis in relation to established risk factors for tumor progression. Tumor cells in bone marrow were detected in 32 (30%) of 108 patients. A CK-positive finding was unrelated to established risk parameters, except for poor nuclear grading of the primary tumor. At a median follow-up of 45 months (range, 12 to 77 months), the presence of occult metastatic cells in bone marrow was associated with the occurrence of clinically overt, extraperitoneal (predominantly extraskeletal) distant metastasis (relative risk [RR], 16.5; 95% confidence interval [CI], 6.2 to 56.9; P < .0001) and death from cancer-related causes (RR, 2.3; 95% CI, 1.2 to 4.3; P = .01). Multivariate analysis identified a positive bone marrow finding as an independent prognostic factor of reduced distant disease-free survival for all patients (RR, 13.8; 95% CI, 5.4 to 52.9; P < .0001) and for the 64 stage R0-1 patients (RR, 7.3; 95% CI, 1.5 to 56.8; P = .0021). Our data signal that hematogenous dissemination of tumor cells occurs early and throughout all stages of ovarian cancer. The clinical significance of our findings is supported by the unfavorable prognosis in association with the presence of occult metastatic cells, especially in those patients who received an effective locoregional therapy.


Spectral Analysis of Hypernasality in Cleft Palate Children: A Pre-Post Surgery Comparison.
Change in resonance is the most commonly experienced speech problems in children diagnosed with cleft lip and palate. The degree of nasality during normal speech production is maintained by the changes in velopharyngeal port. These variations in speech signal are reported to be successfully captured using acoustical tools like spectral analysis. The present study investigated to note voice low tone to high tone ratio (VLHR) values for phonation samples of individuals with cleft palate before and after surgery. Thirty children with congenital cleft of palate within 8 to 15 years of age participated in the study. Three trials of sustained vowels (/a/,/i/ and /u/) were recorded at their comfortable pitch and loudness level in a noise free room using a hand held dynamic microphone. Praat software that utilized Hillenbrand algorithm was used to extract the VLHR values for samples recorded before and after recovery from the surgery. Statistical analysis revealed significant decrease in VLHR values after surgery in comparison to before the surgery. Analysis of Variance revealed statistical significant difference at 95% confidence level. It is concluded that VLHR parameter could be used as an index to measure nasality and can be included in the routine tool assessment protocol.


Inactivation of LLC1 gene in nonsmall cell lung cancer.
Serial analysis of gene expression studies led us to identify a previously unknown gene, c20orf85, that is present in the normal lung epithelium but absent or downregulated in most primary nonsmall cell lung cancers and lung cancer cell lines. We named this gene LLC1 for Low in Lung Cancer 1. LLC1 is located on chromosome 20q13.3 and has a 70% GC content in the promoter region. It has 4 exons and encodes a protein containing 137 amino acids. By in situ hybridization, we observed that LLC1 message is localized in normal lung bronchial epithelial cells but absent in 13 of 14 lung adenocarcinoma and 9 out of 10 lung squamous carcinoma samples. Methylation at CpG sites of the LLC1 promoter was frequently observed in lung cancer cell lines and in a fraction of primary lung cancer tissues. Treatment with 5-aza deoxycytidine resulted in a reduced methylation of the LLC1 promoter concomitant with the increase of LLC1 expression. These results suggest that inactivation of LLC1 by means of promoter methylation is a frequent event in nonsmall cell lung cancer and may play a role in lung tumorigenesis.


Elevated UV-B radiation reduces genome stability in plants.
Long-term depletion of the stratospheric ozone layer contributes to an increase in terrestrial solar ultraviolet-B radiation. This has deleterious effects on living organisms, such as DNA damage. When exposed to elevated ultraviolet-B radiation (UV-B; 280-315 nm), plants display a wide variety of physiological and morphological responses characterized as acclimation and adaptation. Here we show, using special sun simulators, that elevated solar UV-B doses increase the frequency of somatic homologous DNA rearrangements in Arabidopsis and tobacco plants. Increases in recombination are accompanied by a strong induction of photolyase and Rad51 gene expression. These genes are putatively involved in major DNA repair pathways, photoreactivation and recombination repair. In mutant Arabidopsis plants that are deficient in photoreactivating ultraviolet-induced cyclobutane pyrimidine dimers, recombination under elevated UV-B regimes greatly exceeds wild-type levels. Our results show that homologous recombination repair pathways might be involved in eliminating UV-B-induced DNA lesions in plants. Thus, increases in terrestrial solar UV-B radiation as forecasted for the early 21st century may affect genome stability in plants.


High-power laser diodes emitting light above 1100 nm with a small vertical divergence angle of 13 degrees.
Laser diodes with highly strained InGaAs quantum wells, emitting at 1130 nm, embedded in a GaAs waveguide were investigated. This Letter reviews the design of the vertical structure for enclosing high output power in angles smaller than 18 degrees . Example designs were processed to 200 microm stripe-width lasers with an 8-mm-long optical cavity. When these are mounted on C mounts, they give an output power of 38 W under quasi-cw operation from a single emitter.


Vasoactive peptides and phenylephrine actions in isolated teleost hepatocytes.
The metabolic actions of the vasoactive peptides vasotocin and isotocin and the alpha-agonist phenylephrine are examined in hepatocytes isolated from three teleost species: brown bullhead, rainbow trout, and American eel. These three compounds influenced hepatic gluconeogenesis and glycogenolysis with significant species differences. Vasotocin and isotocin affected only eel hepatocytes activating gluconeogenesis by 1.7-fold and glycogenolysis by 3-fold. Phenylephrine increased glycogenolysis by 7-fold in bullhead hepatocytes and gluconeogenesis by 1.4-fold in trout cells. Vasotocin and phenylephrine actions were correlated with increases in adenosine 3',5'-cyclic monophosphate (cAMP). The vasotocin effects were unaffected by beta- and alpha-antagonists supporting a V2-type receptor on eel hepatocytes. Phenylephrine effects were abolished by propranolol and reduced by prazosin and yohimbine (alpha 1- and alpha 2-antagonists, respectively). Phenylephrine, therefore, affected fish hepatocyte metabolism either by a mixed alpha/beta-receptor mechanism emphasizing beta-adrenoceptors or the classic alpha/beta agonist/antagonist scheme defined for mammals is not appropriate for these fish preparations.


Responsiveness and minimal important changes for the Neck Disability Index and the Neck Pain Disability Scale in Italian subjects with chronic neck pain.
To evaluate the responsiveness and minimal important changes (MICs) for the Italian Neck Disability Index (NDI) and Neck Pain Disability Scale (NPDS) as well as which questionnaire was the most responsive in subjects with chronic neck pain (NP). At the beginning and end of an 8-week rehabilitation programme, 200 patients completed the NDI and NPDS. After the programme, the global perceived effect (GPE) was also evaluated and collapsed to produce a dichotomous outcome (improved vs. stable). Responsiveness was calculated by distribution [effect size (ES); standardised response mean (SRM)] and anchor-based methods (ROC curves; correlations between change scores of NPDS and NDI, and GPE). ROC curves were also used to compute the best cutoff levels between improved and stable subjects (MICs). The ES was 0.66 and 0.73, and the SRM was 1.09-1.26 for the NDI and NPDS, respectively. The ROC analyses revealed AUCs of 0.96 and 0.91 for the NDI and NPDS, respectively; the MICs were 7-percentage points for the NDI (sensitivity: 98%; specificity: 81%) and 10 for NPDS (93; 83%), showing equivalent responsiveness properties. Baseline NPDS scores did not affect MIC estimate for the NPDS, while, for the NDI, higher MICs were found for patients with worst disability levels. Correlations between change scores of the NDI and NPDS and GPE were, respectively, high (0.71) and moderate (0.59). The Italian NDI and NPDS were equally sensitive in detecting clinical changes in subjects with chronic NP undergoing rehabilitation. We recommend taking the MICs into account when assessing patient improvement or planning studies in this clinical context.


[Physiopathologic aspects of anemia and thrombocytopenia in children with cancers: the roles of erythropoietin and thrombopoietin].
Physiopathology of anaemia and thrombocytopaenia in children with malignancy: the role of erythropoietin and thrombopoietin. The aim of our work was to determine the role of an impaired erythropoietin (EPO) and thrombopoietin (TPO) production in development of, respectively, the anaemia and thrombocytopaenia in children with malignancy. Simultaneous dosage of EPO and of serum transferrin receptor have shown that anaemia in these patients is of central origin but related to a blunted EPO production. The same observation has been made in children at diagnosis either with acute leukaemia or solid tumour as well as during chemotherapy. In patients under maintenance chemotherapy for acute leukaemia, using long-term bone marrow cultures, we could detect an impaired supportive capacity of bone marrow micro-environment for erythropoiesis. The last part of this work has shown that thrombocytopaenia associated with acute leukaemia in children is accompanied by very high TPO levels as observed in other thrombocytopaenia of central origin, excepted in patients with acute leukaemia of myeloid origin. In these patients, TPO levels are inappropriately low in most cases. The low TPO levels are related to the presence of TPO receptor-expressing myeloid leukaemic cells, suggesting that TPO is "consumed" by blast cells expressing a functional TPO receptor.


A neutral molecule in a cation-binding site: specific binding of a PEG-SH to acetylcholinesterase from Torpedo californica.
The crystal structure of acetylcholinesterase from Torpedo californica complexed with the uncharged inhibitor, PEG-SH-350 (containing mainly heptameric polyethylene glycol with a terminal thiol group) is determined at 2.3 A resolution. This is an untypical acetylcholinesterase inhibitor, since it lacks the cationic moiety typical of the substrate (acetylcholine). In the crystal structure, the elongated ligand extends along the whole of the deep and narrow active-site gorge, with the terminal thiol group bound near the bottom, close to the catalytic site. Unexpectedly, the cation-binding site (formed by the faces of aromatic side-chains) is occupied by CH(2) groups of the inhibitor, which are engaged in C-H...pi interactions that structurally mimic the cation-pi interactions made by the choline moiety of acetylcholine. In addition, the PEG-SH molecule makes numerous other weak but specific interactions of the C-H...O and C-H...pi types.


Significance of overexpression of alpha methylacyl-coenzyme A racemase in hepatocellular carcinoma.
alpha-Methylacyl-CoA racemase (AMACR), an immunomarker for prostatic adenocarcinoma, has been shown to be expressed in a variety of other neoplasms. This study aims to evaluate immunohistochemical expression of the AMACR in neoplastic and nonneoplastic liver lesions, and assess its value in the diagnosis of hepatocellular carcinoma (HCC). Formalin-fixed paraffin-embedded tissue sections of 51 HCC (14 well, 22 moderately and 15 poorly differentiated), 9 hepatocellular adenoma (HCA), 48 cirrhotic nodules (CN) and 16 normal liver tissues (NLT) were immunostained for AMACR. Expression of AMACR is significantly enhanced in HCC tissue compared with non-HCC tissue. High expression of AMACR was found in 82% of HCC including 86% of well-differentiated HCC. In contrast, only 11% of HCA, 13% of CN and 6% of NLT showed high expression for AMACR. Clinicopathological evaluation showed a significant correlation between AMACR expression and venous invasion and capsular invasion by HCC. Our results suggest that AMACR staining may serve as a useful marker for the differential diagnosis of well-differentiated HCC from HCA. Increased AMACR expression and its association with tumor venous invasion suggest that AMACR may play a role in HCC development and progression.


Forecasting seasonal influenza with a state-space SIR model.
Seasonal influenza is a serious public health and societal problem due to its consequences resulting from absenteeism, hospitalizations, and deaths. The overall burden of influenza is captured by the Centers for Disease Control and Prevention's influenza-like illness network, which provides invaluable information about the current incidence. This information is used to provide decision support regarding prevention and response efforts. Despite the relatively rich surveillance data and the recurrent nature of seasonal influenza, forecasting the timing and intensity of seasonal influenza in the U.S. remains challenging because the form of the disease transmission process is uncertain, the disease dynamics are only partially observed, and the public health observations are noisy. Fitting a probabilistic state-space model motivated by a deterministic mathematical model [a susceptible-infectious-recovered (SIR) model] is a promising approach for forecasting seasonal influenza while simultaneously accounting for multiple sources of uncertainty. A significant finding of this work is the importance of thoughtfully specifying the prior, as results critically depend on its specification. Our conditionally specified prior allows us to exploit known relationships between latent SIR initial conditions and parameters and functions of surveillance data. We demonstrate advantages of our approach relative to alternatives via a forecasting comparison using several forecast accuracy metrics.


Regulation and interaction of intracellular calcium, sodium and hydrogen ions in cardiac muscle.
The contractility of heart muscle is sensitive to the relative cytoplasmic concentrations of Na+, H+ and Ca++. The concentration of Na+ is mainly controlled by the Na+/K(+)-ATPase while the concentration of H+ is regulated by the Na+/H+ and Cl-/HCO3- exchanges. Cytoplasmic Ca++ concentration is mainly under the control of the sarcolemmal Na+/Ca++ exchange and Ca(++)-ATPase and sarcoplasmic reticular Ca(++)-ATPase. However, in heart muscle there is also a complex interaction between these ions such that altering the main regulation of one will affect the intracellular levels of the other two. Such interaction may thus enhance or attenuate the contractile response to the initial change. This review briefly describes the properties of the main regulatory mechanisms and focuses on their interactions and what consequences these have for contraction.


Persistent racial disparities in survival after heart transplantation.
Racial and ethnic disparities are well documented in many areas of health care, but have not been comprehensively evaluated among recipients of heart transplants. We performed a retrospective cohort study of 39075 adult primary heart transplant recipients from 1987 to 2009 using national data from the United Network of Organ Sharing and compared mortality for nonwhite and white patients using the Cox proportional hazards model. During the study period, 8082 nonwhite and 30 993 white patients underwent heart transplantation. Nonwhite heart transplant recipients increased over time, comprising nearly 30% of transplantations since 2005. Nonwhite recipients had a higher clinical risk profile than white recipients at the time of transplantation, but had significantly higher posttransplantation mortality even after adjustment for baseline risk. Among the nonwhite group, only black recipients had an increased risk of death compared with white recipients after multivariable adjustment for recipient, transplant, and socioeconomic factors (hazard ratio, 1.34; 95% confidence interval, 1.21 to 1.47; P<0.001). Five-year mortality was 35.7% (95% confidence interval, 35.2 to 38.3) among black and 26.5% (95% confidence interval, 26.0 to 27.0) among white recipients. Black patients were more likely to die of graft failure or a cardiovascular cause than white patients, but less likely to die of infection or malignancy. Although mortality decreased over time for all transplant recipients, the disparity in mortality between blacks and whites remained essentially unchanged. Black heart transplant recipients have had persistently higher mortality than whites recipients over the past 2 decades, perhaps because of a higher rate of graft failure.


Serum microRNA profile enables preoperative diagnosis of uterine leiomyosarcoma.
Uterine leiomyosarcoma (ULMS) is the major subtype of uterine sarcoma (US) and contributes to uterine cancer deaths. Although preoperative diagnosis of US remains challenging, frequent application of laparoscopic surgery for benign uterine leiomyomas (ULM) requires precise exclusion of US. MicroRNAs are stably present in the bloodstream, and the application of circulating miRNAs as disease biomarkers has been recognized. In the present study, we aimed to identify diagnostic biomarkers for distinguishing US from ULM by focusing on circulating miRNAs. All serum samples were collected preoperatively between 2009 and 2017, and all cases were histopathologically diagnosed. Whole miRNA profiles were obtained using a miRNA microarray. By analyzing expression levels of the miRNAs, candidate miRNAs were selected based on diagnostic performance in discriminating US from ULM, and a diagnostic model was then constructed. A total of 90 serum samples were analyzed, and clustering analyses revealed that the profiles of ULMS were distinct from those of controls. Based on leave-one-out cross-validation, seven miRNAs were selected as biomarker candidates. Based on model construction, the optimal model consisted of two miRNAs (miR-1246 and miR-191-5p), with an area under the receiver operating characteristic curve (AUC) for identifying ULMS of 0.97 (95% confidence interval [CI], 0.91-1.00). In contrast, serum lactate dehydrogenase had an AUC of only 0.64 (95% CI, 0.34-0.94). Seven serum miRNAs with high diagnostic performance for preoperative US screening were detected, and a promising diagnostic model for ULMS was generated.


Human cardiospheres as a source of multipotent stem and progenitor cells.
Cardiospheres (CSs) are self-assembling multicellular clusters from the cellular outgrowth from cardiac explants cultured in nonadhesive substrates. They contain a core of primitive, proliferating cells, and an outer layer of mesenchymal/stromal cells and differentiating cells that express cardiomyocyte proteins and connexin 43. Because CSs contain both primitive cells and committed progenitors for the three major cell types present in the heart, that is, cardiomyocytes, endothelial cells, and smooth muscle cells, and because they are derived from percutaneous endomyocardial biopsies, they represent an attractive cell source for cardiac regeneration. In preclinical studies, CS-derived cells (CDCs) delivered to infarcted hearts resulted in improved cardiac function. CDCs have been tested safely in an initial phase-1 clinical trial in patients after myocardial infarction. Whether or not CDCs are superior to purified populations, for example, c-kit(+) cardiac stem cells, or to gene therapy approaches for cardiac regeneration remains to be evaluated.


Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice.
Thymic atrophy is a prominent feature of malnutrition. Forty-eight hours' starvation of normal mice reduced the total thymocyte count to 13% of that observed in freely fed controls, predominantly because of a diminution in the cortical CD4(+)CD8(+) thymocyte subpopulation. Prevention of the fasting-induced fall in the level of the adipocyte-derived hormone leptin by administering exogenous recombinant leptin protected mice from these starvation-induced thymic changes. The ob/ob mouse, which is unable to produce functional leptin because of a mutation in the obese gene, has impaired cellular immunity together with a marked reduction in the size and cellularity of the thymus. We found that ob/ob mice had a high level of thymocyte apoptosis resulting in a ratio of CD4(+)CD8(+) (cortical) to CD4(-)CD8(-) (precursor) thymocytes that was 4-fold lower than that observed in wild-type mice. Peripheral administration of recombinant leptin to ob/ob mice reduced thymocyte apoptosis and substantially increased both thymic cellularity and the CD4(+)CD8(+)/CD4(-)CD8(-) ratio. In contrast, a comparable weight loss in pair-fed PBS-treated ob/ob mice had no impact on thymocyte number. In vitro, leptin protected thymocytes from dexamethasone-induced apoptosis. These data indicate that reduced circulating leptin concentrations are pivotal in the pathogenesis of starvation-induced lymphoid atrophy.


Characteristics and opinions of MD-PhD students and graduates from different European countries: a study from the European MD-PhD Association.
MD-PhD programmes throughout the world provide a platform for medical trainees to commit to a physician-scientist career, qualifying with both a medical degree (MD or equivalent) and Doctor of Philosophy (PhD). However, there are limited studies assessing the characteristics of MD-PhD programmes in Europe and the outcomes of MD-PhD students and graduates. This study aims at a first country-wise exploration of characteristics, opinions, and academic outcomes of MD-PhD students and graduates in Europe. Two questionnaires were developed to assess the demographics, MD-PhD programme characteristics, opinions, future career paths and academic outcomes of European MD-PhD students and graduates. An online survey of 278 MD-PhD students and 121 MD-PhD graduates from nine and six European countries, respectively, was completed between April 2016 and December 2017. The country-wise categorical responses were then compared through chi-square analysis followed by multiple logistic regression. Responses from 266 MD-PhD students and 117 MD-PhD graduates were considered valid. Significant country-wise differences (p <0.05) were observed for age group, resident status, clinical time allocation, duration of studies, sources of funding, publications, average impact factor of the journals in which the research was published, satisfaction with the duration of MD-PhD studies and future career choices of MD-PhD students. Responses related to self-perception about clinical and research competence and challenges faced during MD-PhD training did not show a significant country-wise difference. The MD-PhD workforce in Europe is highly diverse in their demographics, programme characteristics and career paths but does not differ in opinions related to the challenges faced. The results of this study may be helpful for implementation and improvement of MD-PhD programmes.


Systemic lupus erythematosus and dermatitis herpetiformis: concurrence with Marfan's syndrome.
There is increasing evidence that, as in systemic lupus erythematosus (SLE), deposition of immune complexes plays a role in the pathogenesis of dermatitis herpetiformis (DH). Dermatitis herpetiformis and SLE were diagnosed in a 15-year-old girl with Marfan's syndrome who died of cardiac tamponade secondary to cystic medial necrosis of the ascending aorta. The concurrence of these diseases suggests that predisposition to immune-mediated disorders may be associated with the expression of multiple clinical entities.


[Combination of ipsilateral supracondylar humeral- and forearm fractures in children].
In an 11-year period, from 01. 08. 1987 to 31. 08. 1998, a total of 72 children (mean age 7.6 years, range 2-12 years) with dislocated supracondylar humeral fractures were treated surgically in the Department for Traumatology, University Hospital, Essen. The combination of supracondylar humeral fracture and ipsilateral forearm fracture occurred in 8 children (11.1 %). 4 revealed a complete forearm fracture in the distal third, 4 children a fracture of the distal physis (Salter-Harris type II). The supracondylar humeral fractures were reduced openly via a single lateral approach and stabilized by crossed K-wire fixation. The distal forearm fractures were treated by closed reduction and percutaneous pinning. Fractures of the distal physis were treated by closed reduction and application of an above elbow cast. Excellent results were achieved in all children with ipsilateral supracondylar and forearm fractures.


Characterization of genetic diversity in the nematode Pristionchus pacificus from population-scale resequencing data.
The hermaphroditic nematode Pristionchus pacificus is an established model system for comparative studies with Caenorhabditis elegans in developmental biology, ecology, and population genetics. In this study, we present whole-genome sequencing data of 104 P. pacificus strains and the draft assembly of the obligate outcrossing sister species P. exspectatus. We characterize genetic diversity within P. pacificus and investigate the population genetic processes shaping this diversity. P. pacificus is 10 times more diverse than C. elegans and exhibits substantial population structure that allows us to probe its evolution on multiple timescales. Consistent with reduced effective recombination in this self-fertilizing species, we find haplotype blocks that span several megabases. Using the P. exspectatus genome as an outgroup, we polarized variation in P. pacificus and found a site frequency spectrum (SFS) that decays more rapidly than expected in neutral models. The SFS at putatively neutral sites is U shaped, which is a characteristic feature of pervasive linked selection. Based on the additional findings (i) that the majority of nonsynonymous variation is eliminated over timescales on the order of the separation between clades, (ii) that diversity is reduced in gene-rich regions, and (iii) that highly differentiated clades show very similar patterns of diversity, we conclude that purifying selection on many mutations with weak effects is a major force shaping genetic diversity in P. pacificus.


Role of Saline Infusion Sonohysterography in Infertility Evaluation.
Etiology of infertility is multifactorial, and fallopian tube abnormality being one of the most important causes accounts for up to 40% of female subfertility if not less and is further increasing. Saline infusion sonohysterography (SIS) procedure is gaining popularity and is being widely practiced and accepted as a screening tool in assessing tubal patency in infertile patients attending infertility clinic and has become popular as a routine test for the evaluation of the uterine cavity in the investigation of infertility and abnormal uterine bleeding. To compare the results of SIS with that of hysterosalpingography in infertility evaluation and to observe the role of SIS to find out endometrial pathology and tubal patency in infertility patients. A retrospective, observational study was done on the basis of record maintained in the ultrasound register and case record sheets of all infertile women who underwent infertility treatment and fulfilled the inclusion criteria from June 2015 to August 2016. SIS had sensitivity of 91%, specificity of 76% positive predictive value (PPV) of 95%, negative predictive value (NPV) of 66%, and accuracy of 89% of SIS in evaluating tubal patency. Further, SIS showed sensitivity of 83.3%, specificity of 60%, PPV of 75%, NPV of 75%, and accuracy of 72% in detecting pelvic pathology. In a low-resource country like India where patients are also less educated, SIS can prove to be a useful tool in initial workup of infertility patients with better compliance, low cost, and better results in a single visit.


The era of direct-acting antivirals has begun: the beginning of the end for HCV?
The year 2011 marks the dawn of the new era of direct-acting antivirals for hepatitis C. For the first time since 1998, the U.S. Food and Drug Administration approved two new antiviral drugs for the treatment of chronic hepatitis C virus genotype 1. Dual therapy with pegylated interferon and ribavirin is no longer the standard of care for genotype 1. The new treatment paradigm includes one direct-acting antiviral, a protease inhibitor, in combination with pegylated interferon and ribavirin. This combination nearly doubles the chances of response to treatment, but at the cost of increased toxicity. Many agents with different mechanisms of action and improved safety profiles are in clinical development. The holy grail of HCV treatment is an all oral, interferon-free treatment. The ideal regimen will be potent, well tolerated, with minimal drug-drug interactions and once daily. This article covers new concepts of treatment of hepatitis C with DAAs and gives an overview of the recent highlights in direct-acting antiviral development.


Developing a formulary for enteral nutrition products.
A formulary for enteral nutrition products was developed at a university hospital. Advice was solicited from clinical dietetics and the medical staff. Reported important product variables were osmolality, caloric density, protein content and source, fat content and source, freedom from lactose, and, for oral supplements, available flavors. Data were also obtained from manufacturers regarding the composition of their products. Products were categorized as follows: liquid supplemental feedings, high calorie supplemental feedings, isotonic tube feedings, high caloric/high nitrogen tube feedings, high nitrogen tube feedings, and blenderized tube feedings. Bids were solicited in April 1981 (and annually thereafter) from manufacturers of the classified enteral nutrition products, and a contract was signed with the manufacturer in each category submitting the lowest bid. In contrast with previous experience, there was no loss from outdated products during the first year of the formulary. Categorizing enteral nutrition products into therapeutic categories appears to be a workable method to limit the number of products used in a hospital, thereby potentially decreasing inventory, waste, and hospital costs. The descriptive category titles also may encourage rational use of these products without promoting allegiance to a particular company or product.


Palliative embolization of renal tumors.
Palliative embolization of renal tumors is the method of choice in the treatment of advanced inoperable renal cell carcinoma in patients with hematuria and pain. Patients with small tumors in the remaining solitary kidney who refuse surgery are suitable for this type of therapy as well as patients with centrally located inoperable tumors. The prerequisite for successful capillary embolization is the closure of the main arterial trunk with metal spirals. In the period from 2000 to 2010 we conducted 42 palliative embolizations. The average age of the patients was 75 years, including 26 men and 16 women. In 8 of the patients the intervention was repeated and in one with severe AV shunts embolization was performed 4 times. Embolization was performed with alcohol, Ivalon 150-250 µm and with metal coils. No serious complications were observed during and after the intervention. Fourteen patient were still alive then and among the deceased patients the average survival time was 13.5 ± 10.8 months with the range of 1 to 56 months. The minimal survival time was 1 month with a maximum survival time of 56 months. Our results are consistent with data in the literature. Survival in patients without metastases was longer than in those with metastases, as confirmed by the 14 of the patients from the study. An additional therapeutic safety in the treatment of small cancers is provided with a combination therapy of embolization and radiofrequency thermoablation.


Middle meningeal artery embolization as standalone treatment versus combined with surgical evacuation for chronic subdural hematomas: systematic review and meta-analysis.
Middle meningeal artery embolization (MMAE) is a novel treatment for chronic subdural hematomas (cSDHs) with high variability of use across practitioners and institutions. This study sought to investigate whether standalone MMAE may be an effective alternative to combined MMAE and surgery for select patients with cSDH. The authors searched the Medline and Embase databases for studies reporting outcomes specific to standalone MMAE and combined MMAE and surgery. The Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool was used to assess risk of bias in each included study. Patient characteristics were compared between cohorts, and rates of surgical recurrence of standalone MMAE and combined MMAE and surgery were pooled using random-effects models. Four hundred two unique patients (156 with standalone MMAE and 246 with combined MMAE and surgery) were identified across 8 studies. Overall, the subdural thickness for the standalone MMAE group was modestly but statistically significantly smaller (16.8 vs 18.8 mm, estimated p value 0.002), and the mean follow-up time was significantly longer for the standalone MMAE group (5.4 vs 2.3 months, estimated p value < 0.001); there were no significant differences between age, sex, and anticoagulant use. The surgical recurrence rates were not significantly different between the two groups (estimated p value 0.63). Using random-effects models, the surgical recurrence rates were estimated at 6.8% (95% CI 3.5%-11.2%) and 4.6% (95% CI 2.3%-7.7%) for standalone MMAE and combined MMAE and surgery, respectively. Standalone MMAE for cSDH may yield a low rate of surgical recurrence, which may be comparable to that of combined MMAE and surgery. However, studies in this systematic review and meta-analysis were primarily single-arm studies prone to treatment bias. Future studies are needed to further investigate whether standalone MMAE may be an effective alternative to combined MMAE and surgical treatment for cSDH in select patients.


A computational study of the reactivities of four-membered heavy carbene systems.
The potential energy surfaces for the chemical reactions of four-membered N-heterocyclic group 14 heavy carbene species have been studied using density functional theory (B3LYP/LANL2DZ). Five four-membered group 14 heavy carbene species, (i-Pr)(2) NP(NR)(2) E:, in which E = C, Si, Ge, Sn, and Pb, were chosen as the model reactants in this work. Also, four kinds of chemical reactions, C-H bond insertion, water addition, alkene cycloaddition, and dimerization, have been used to study the chemical reactivities of these group 14 four-membered N-heterocyclic carbene species. Basically, our present theoretical work predicts that the larger the ∠NEN bond angle of the four-membered group 14 heavy carbene species, the smaller the singlet-triplet splitting, the lower the activation barrier, and, in turn, the more rapid, its chemical reactions to various chemical species. Moreover, our theoretical investigations suggest that the relative carbenic reactivity decreases in the order: C > Si > Ge > Sn > Pb. That is, the heavier the group 14 atom (E), the more stable is its four-membered carbene toward chemical reactions. As a result, our results predict that the four-membered group 14 heavy carbene species (E = Si, Ge, Sn, and Pb) should be more kinetically stable than the observed carbene species and, thus, can be also readily synthesized and isolated at room temperature. Furthermore, the singlet-triplet energy splitting of the four-membered group 14 carbene species, as described in the configuration mixing model attributed to the work of Pross and Shaik, can be used as a diagnostic tool to predict their reactivities. The results obtained allow a number of predictions to be made.