Normative Reference Value for Tactile Localization Acuity among School-going Children: A Normative Research.
Tactile localization (TL) is one of the standard assessments to be performed under combined cortical sensory assessment. TL is the ability to locate the point of sensory contact and surprisingly, till date there is no normal reference available for estimating TL. Hence, there is a need to calculate the normative reference of TL among school-going children aged between 8 and 13 years. A total of 365 healthy school-going children aged between 8 and 13 years were included in this cross-sectional observational study. Children with any neurological condition and other conditions, which prevent them from taking part in the study were excluded. The sample was recruited by stratified random sampling method from the recognized schools in Ambala district, Haryana, India. After the anthropometric measurements, TL acuity was established by point-to-point tactile localization (PPTL) technique. In this technique, the children were asked to relocate the point of contact made by the investigator over identified 15 areas, and after that the distance between the point of contact made by the principal investigator and the relocation point made by the children is measured in centimeters (cm). The mean of three readings were used to estimate TL acuity. TL acuity ranges from 0.9 (0.5, 1.5) cm in little finger of palm to 1.5 (1.0, 2.5) cm in middle of posterior arm. TL acuity increases with increasing age. There exist no significant (P ≥ 0.05) difference in the normative reference value between male and female among the identified 15 areas. Normative reference values of TL acuity have been established among school-going children between 8 and 13 years.


Clinical outcomes of acute stroke patients with atrial fibrillation.
Evaluation of: Kazumi K, Yasuyuki I, Kensaku S, Takeshi I, Shinji Y, Junya A. IV-tPA therapy in acute stroke patients with atrial fibrillation. J. Neurol. Sci. 276(1-2), 6-8 (2009). Stroke is the leading cause of disability and the second most common cause of death worldwide. The care and treatment of stroke patients have evolved over the last two decades, with increasing use of thrombolysis (e.g., intravenous tissue plasminogen activator in acute stroke patients), which has improved survival and recovery following stroke. The article under evaluation offers a greater insight into the relationship of clinical outcome of stroke and atrial fibrillation after tissue plasminogen activator infusion.


Handwriting Impairments in People With Parkinson's Disease and Freezing of Gait.
Recent studies show that patients with Parkinson's disease (PD) and freezing of gait (FOG) experience motor problems outside their gait freezing episodes. Because handwriting is also a sequential movement, it may be affected in PD patients with FOG relative to those without. The current study aimed to assess the quality of writing in PD patients with and without FOG in comparison to healthy controls (CTs) during various writing tasks. Handwriting was assessed by the writing of cursive loops on a touch-sensitive writing tablet and by means of the Systematic Screening of Handwriting Difficulties (SOS) test in 30 PD patients with and without freezing and 15 healthy age-matched CTs. The tablet tests were performed at 2 different sizes, either continuously or alternatingly, as indicated by visual target lines. Patients with freezing showed decreased writing amplitudes and increased variability compared with CTs and patients without freezing on the writing tablet tests. Writing problems were present during both tests but were more pronounced during writing at alternating compared with writing at continuous size. Patients with freezing also had a higher total score on the SOS test than patients without freezing and CTs, reflecting more extensive handwriting problems, particularly with writing fluency. Writing is more severely affected in PD patients with FOG than in those without FOG. These results indicate that deficient movement sequencing and adaptation is a generic problem in patients with FOG.


Severe laryngeal edema caused by Pseudoterranova species: A case report.
Severe laryngeal edema can cause upper airway obstruction, which is fatal. Pseudoterranova, an uncommon nematode of the family Anisakidae, predominantly invades the stomach after ingestion of the nematodes in raw or undercooked marine fish. There have been a few reports of development of severe laryngeal edema caused by the nematode invading the base of the tongue. A 69-year-old Japanese woman complained of stuffy and scratchy throat for 8 hours and reported eating sashimi, fresh slices of raw jacopever, 4 days before the first visit. Endoscopy revealed a white-yellowish wriggling worm at the left side of the base of the tongue and severe edema of the larynx. The worm was extracted using endoscopic forceps. The patient was hospitalized and treated with intravenous injection of an antibiotic and steroid. The symptoms and laryngeal edema disappeared the next day. The worm was identified as a 4th-stage larva of Pseudoterranova spp based on morphologic features. The serum Anisakis-specific IgE antibody level was high, at 38.6 UA/mL. Clinicians should be aware of the possibility of severe laryngeal edema due to invasion by anisakid nematodes in the pharyngolaryngeal area in cases involving previous ingestion of raw or uncooked marine fish.


The biostatistician in medical research: allocating time and effort.
Biostatisticians in research juggle many responsibilities: short-term consulting; long-term collaboration; teaching/training, and statistical research. In an institutionally-supported service group, the biostatistician frequently faces allocation of limited resources (time and effort) over multiple projects, none of which individually supports the biostatistician. In addition to the level of support provided by a specific project, there are several major issues with resource allocation: the quality of the science and data in the project; the possibility that long-term support develops from the work; personal and institutional considerations that involve the specific investigator or project. In this paper, we discuss these considerations along with some examples. We present guidelines for making decisions about allocation of time and effort and the possible implications of setting such priorities.


[The diagnosis and treatment of hepatic artery complications in 107 cases of orthotopic liver transplantation].
To investigate the diagnosis and managements of hepatic artery complications in orthotopic liver transplantation. The clinical data of 107 consecutive orthotopic liver transplantation patients was reviewed retrospectively to assess the risk factors and the diagnosis and treatment of the vascular complications. The incidence of the artery related complications in orthotopic liver transplantation was associated with the quality of the donor organ artery and the reconstruction way of donor-recipient artery intimately. The main hepatic artery related complications were hepatic artery thrombosis and stenosis. The incidence of the vascular complications was 6.54%, and the mortality rate was 85.7%. The main influence factors of vascular complications were the quality of the donor organ artery and the reconstruction way of donor-recipient artery. The key steps of organ salvaging and the patients' life saving were early diagnosis and treatment of those complications.


Spousal caregiving in late midlife versus older ages: implications of work and family obligations.
This study examined life-stage differences in the provision of care to spouses with functional impairment. We examined 1,218 married adults aged 52 and older from the 2000 wave of the Health and Retirement Study who received impairment-related help with at least one activity of daily living. We examined the differential likelihood that spouses served as primary caregiver and the hours of care provided by spousal primary caregivers by life stage. We found that late middle-aged care recipients were more likely than their older counterparts to receive the majority of their care from their spouse but received fewer hours of spousal care, mostly when spouses worked full time. Competing demands of caring for children or parents did not affect the amount of care provided by a spouse. Late middle-aged adults with functional limitations are more likely than older groups to be married and cared for primarily by spouses; however, they may be particularly vulnerable to unmet need for care. As the baby boom generation ages, retirement ages increase, and federal safety nets weaken, people with health problems at older ages may soon find themselves in the same caregiving predicament as those in late middle age.


Androgen receptor CAG repeat lengths in ductal carcinoma in situ of breast, longest in apocrine variety.
CAG repeat number in the androgen receptor (AR) has been associated with decreased prostate cancer risk, and AR expression has been found in female breast cancer, often associated with apocrine differentiation. Because trinucleotide expansion can alter gene expression and protein function, we hypothesized that it might occur in breast neoplasms. We used a repeat expansion detection technique to determine CAG repeat lengths in DNA from breast biopsies. Three lesion types were microdissected: fibroadenoma (48 cases), ductal carcinoma in situ (DCIS, 24 cases), and invasive mammary carcinoma (18 cases). The maximum number of CAG repeats in either allele of each patient in these three groups was compared. Microsatellite repeat lengths in DCIS were longer than in fibroadenomas or invasive carcinomas (P= 0.017 comparing DCIS vs invasive carcinomas). Two cases of apocrine DCIS had very long repeat lengths, both exhibiting microsatellite lengths at the longest range of normal (32 and 33). Inherited differences in AR CAG length might influence the transition from DCIS to invasive breast cancer, perhaps by modulating function of AR in breast tissue. AR microsatellite polymorphisms could influence cellular differentiation in DCIS lesions, promoting formation of the apocrine subtype in the presence of longer CAG repeats.


The effects of intrapartum magnesium sulfate therapy on fetal serum interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha at delivery: a randomized, placebo-controlled trial.
Elevated levels of inflammatory cytokines in the fetus have been linked to neurologic morbidities in preterm neonates. Magnesium sulfate is currently being studied in clinical trials as a potential fetal neuroprotective agent. The purpose of this study was to determine whether intrapartum magnesium sulfate therapy has an effect on the umbilical venous concentrations of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha at delivery. Women with singleton gestations >32 weeks with no clinical indications for magnesium sulfate therapy (preeclampsia or tocolysis) and either clinical chorioamnionitis or prolonged rupture of membranes were recruited for the study. Consenting patients were randomly assigned, in a double-blinded fashion, to receive either magnesium sulfate (6-g load then 2 g/hr) or matched volumes of lactated Ringer's solution until delivery. Fetal blood specimens were obtained by aspiration of the umbilical vein after cord clamping but before placental separation. Umbilical cytokine levels were measured with a sensitive and specific immunoassay. Twenty-two patients were randomly assigned to groups and received either magnesium sulfate (n = 11) or placebo (n = 11). There were no differences in the demographic or clinical characteristics between groups. The umbilical venous ionized magnesium concentration was significantly higher in the magnesium sulfate group (2.32 +/- 0.27 mg/dL vs 1.23 +/- 0.15 mg/dL; P <.001). There were no statistically significant differences between groups with respect to umbilical levels of interleukin-1beta (1.5 pg/mL [1.5-58] vs 1.5 pg/mL [1.5-10]; P =.5); interleukin-6 (8.5 pg/mL [1-1000] vs 11.2 pg/mL [1-113]; P =.9); or tumor necrosis factor-alpha (16 pg/mL [7.6-20.3] vs 16.6 pg/mL [8.3-22.2]; P =.5). In this pilot study the intrapartum administration of magnesium sulfate does not appear to affect the concentration of inflammatory cytokines in fetal blood at delivery.


Vitamin B6 and cognitive development: recent research findings from human and animal studies.
Numerous studies have suggested that pregnant and lactating women may have dietary intakes of vitamin B6 that are well below the recommended dietary allowance, which may affect the vitamin B6 status of their offspring. This nutrient is an essential cofactor in the developing central nervous system and may influence brain development and cognitive function. Recent work in animal models suggests that vitamin B6 deficiency during gestation and lactation alters the function of N-methyl-D-aspartate receptors, a subtype of receptors of the glutamatergic neurotransmitter system thought to play an important role in learning and memory.


Tethered bilayer lipid membranes based on monolayers of thiolipids mixed with a complementary dilution molecule. 1. Incorporation of channel peptides.
Tethered bilayer lipid membranes (tBLMs) are described based on the self-assembly of a monolayer on template stripped gold of an archea analogue thiolipid, 2,3-di-o-phytanyl-sn-glycerol-1-tetraethylene glycol-d,l-alpha-lipoic acid ester lipid (DPTL), and a newly designed dilution molecule, tetraethylene glycol-d,l-alpha-lipoic acid ester (TEGL). The tBLM is completed by fusion of liposomes made from a mixture of diphytanoylphosphatidyl choline (DPhyPC), cholesterol, and 1,2-diphytanoyl-sn-glycero-3-phosphate (DPhyPG) in a molar ratio of 6:3:1. Melittin and gramicidin are incorporated into these tBLMs as shown by surface plasmon resonance (SPR) and electrochemical impedance spectroscopy (EIS) studies. Ionic conductivity at 0 V vs Ag|AgCl, 3 M KCl, measured by EIS measurements are comparable to the results obtained by other research groups. Admittance plots as a function of potential are discussed on a qualitative basis in terms of the kinetics of ion transport through the channels.


Insulin-like growth factor-II in endocrine pancreatic tumours. Immunohistochemical, biochemical and in situ hybridization findings.
In earlier studies a high-molecular-weight (HMW) insulin-like growth factor-II (IGF-II) peptide was identified in adult human pancreas and localized to the insulin-producing B-cells. This peptide has now been investigated in neoplastic insulin cells. Forty endocrine pancreatic tumours and 17 pancreatic adenocarcinomas of ductal type were included in the study. All cases were investigated with immunohistochemical techniques using antibodies to IGF-II, insulin, pro-insulin, glucagon, somatostatin, pancreatic polypeptide, gastrin and vasoactive intestinal peptide (VIP). Frozen tissue from nine tumours and two normal pancreatic glands was extracted, gel separated, and quantified using radioimmunoassay. The tumours were also investigated by in situ hybridization. IGF-II-immunoreactive cells were found in nearly all the 18 insulin-producing tumours (16/18), in a minority of the other endocrine tumours, but not in pancreatic adenocarcinomas. All extracts from the endocrine tumours showed varying amounts of IGF-II and had different molecular-weight forms. The immunohistochemical and radioimmunoassay findings are both based on immunological binding and were further confirmed by Northern blot and in situ hybridization. These results show that IGF-II is expressed in insulin-producing tumours as well as in pancreatic tumours producing other peptides, in contrast to normal pancreatic islets where IGF-II is found exclusively in insulin-producing cells.


Domain averaged Fermi hole analysis for open-shell systems.
The Article reports the extension of the new original methodology for the analysis and visualization of the bonding interactions, known as the analysis of domain averaged Fermi holes (DAFH), to open-shell systems. The proposed generalization is based on straightforward reformulation of the original approach within the framework of unrestricted Hartree-Fock (UHF) and/or Kohn-Sham (UKS) levels of the theory. The application of the new methodology is demonstrated on the detailed analysis of the picture of the bonding in several simple systems involving the doublet state of radical cation NH(3)((+)) and the triplet ground state of the O(2) molecule.


Biotransformation Enables Innovations Toward Green Synthesis of Steroidal Pharmaceuticals.
Steroids have been widely used in birth-control, prevention, and treatment of various diseases, representing the largest sector after antibiotics in the global pharmaceutical market. The steroidal active pharmaceutical ingredients (APIs) have been produced via partial synthetic processes first mainly from sapogenins, which was converted into 16-dehydropregnenolone by the famous "Marker Degradation". Traditional mutation and screening, and process engineering have resulted in the industrial production of 4-androstene-3,17-dione (AD), androst-1,4-diene-3,17-dione (ADD), 9α-hydroxy-androsta-4-ene-3,17-dione (9α-OH-AD), and so on, which serve as the key intermediates for the synthesis of steroidal APIs. Recently, genetic and metabolic engineering have generated highly efficient microbial strains for the production of these precursors, leading to the replacement of sapogenins with phytosterols as the starting materials. Further advances in synthetic biology hold promise in the design and construction of microbial cell factories for the industrial production of steroidal intermediates and/or APIs from simple carbon sources such as glucose. Integration of biotransformation into the synthesis of steroidal APIs can greatly reduce the number of reaction steps, achieve lower waste discharge and higher production efficiency, thus enabling a greener steroidal pharmaceutical industry.


Quality of life and symptom burden in cancer patients admitted to an acute palliative care unit.
This paper describes the quality of life and symptom burden of 211 cancer patients admitted to an acute palliative care unit (PCU) in a comprehensive cancer centre. Participants completed the McGill Quality of Life Questionnaire (MQOL), Edmonton Symptom Assessment Scale (ESAS), Short Orientation-Memory-Concentration Test, and Palliative Performance Scale within 24 hours of admission to the PCU. The mean MQOL total was 6.1 +/- 1.4, and the mean single-item scale score was 4.9 +/- 2.4. The mean total ESAS score was 36.3 +/- 15.8, with a median of six reported symptoms. Women and younger patients reported a lower quality of life (QoL) and a higher symptom burden. Regression and correlational analyses highlighted the importance of the existential and psychological domains to overall QoL. These findings emphasize the need for interdisciplinary, collaborative approaches to managing the complex physical, psychosocial, and existential needs of cancer patients admitted to acute PCUs.


Moderating influence of proteins on nonplanar tetrapyrrole deformations: coenzyme F430 in methyl-coenzyme-M reductase.
Normal-coordinate structural decomposition, cluster analysis, and molecular mechanics calculations were undertaken to examine the effect of methyl-coenzyme-M reductase (MCR) on the nonplanar deformations of coenzyme F430. Although free 12,13-diepi-F430 has a lower energy conformation than free F430, the protein restraints exerted by MCR are responsible for F430 having a lower energy conformation than the 12,13-diepimer in MCR. According to the NSD analysis, the crystal structure of free diepimerized F430M is highly distorted. In MCR the protein prevents 12,13-diepi-F430 from undergoing nonplanar deformations; therefore, MCR favors F430 over the 12,13-diepimeric form. The strain imposed on 12,13-diepi-F430 in the protein is so large that although 88% of free F430 is found in the diepimeric form, none of the diepimeric form is found in MCR. This is of significance since the two forms have different chemistries. MCR also moderates the nonplanar deformations of coenzyme F430, which are known to affect redox potentials and axial ligand affinities in tetrapyrroles, suggesting that the protein environment (MCR) is responsible for tuning the chemistry of the active site nickel ion. F430 is bound to MCR by hydrogen bonds between the protein and the F430 carboxylate groups. Conformational searches have shown that F430 has very little rotational and translational freedom within MCR.


Efferent protection from acoustic injury is mediated via alpha9 nicotinic acetylcholine receptors on outer hair cells.
Exposure to intense sound can damage the mechanosensors of the inner ear and their afferent innervation. These neurosensory elements are innervated by a sound-activated feedback pathway, the olivocochlear efferent system. One major component of this system is cholinergic, and known cholinergic effects are mediated by the alpha9/alpha10 nicotinic acetylcholine receptor (nAChR) complex. Here, we show that overexpression of alpha9 nAChR in the outer hair cells of bacterial artificial chromosome transgenic mice significantly reduces acoustic injury from exposures causing either temporary or permanent damage, without changing pre-exposure cochlear sensitivity to low- or moderate-level sound. These data demonstrate that efferent protection is mediated via the alpha9 nAChR in the outer hair cells and provide direct evidence for a protective role, in vivo, of a member of the nAChR family.


Significance of two different ranking methods for studying fish fauna: a case study on the fish fauna from upper and middle portions from Mekong River.
Studies on fish fauna should not only focus on fish composition and the comparison of fish composition among the study region and adjacent regions, but should also explore the origin and uniqueness of different taxa as well as the substitution of genera and species. In this study, the value of floristic presence method was modified and renamed the value of fish fauna presence (VFFP) method. The specific steps of the VFFP method and the traditional fish fauna analysis (TFFA) method were refined and standardized. Then, the VFFP and TFFA methods were applied to study the fish fauna of the upper and middle portions of the Mekong River basin. The results indicate that the TFFA method reflects the families (subfamilies) and genera that constitute the main body of fish in the studied river basin. The results of the VFFP method show which families (subfamilies) and genera are representative for the basin. Therefore, combining the TFFA and VFFP methods to analyze the composition of fish fauna can reflect the characteristics of fish fauna from different perspectives. The case study shows that the fish fauna of the Mekong River is a part of the fish fauna of Southeast Asia. Although it shows some similarities to the composition of South Asian fish fauna, it does not belong to the South Asian fish fauna as a whole, and is essentially different from the East Asian fish fauna. This study provides an objective, quantitative, and verifiable method for studying fish fauna.


Inhibitory effect of oral doxycycline on neovascularization in a rat corneal alkali burn model of angiogenesis.
To examine the efficacy of oral doxycycline treatment (as compared to oral and topical dexamethasone) for inhibiting corneal neovascularization (CNV). Following corneal alkali burn, rats were treated daily with oral doxycycline, oral dexamethasone, or topical dexamethasone for 14 days. Control rats were injured but were not treated. At days 3, 7, and 14 post injury, length and area of CNV were evaluated, as well as corneal epithelial healing and ulceration. Tissues were obtained from a subset of rats from each group for histopathological analysis. At days 7 and 14 post-injury, CNV length in the doxycycline group was significantly less than in the untreated control (p < 0.008). The area of CNV was significantly smaller in doxycycline as compared to control rats on days 3, 7, and 14 post-injury. Inhibition of CNV (indicated by area and length) was significantly greater in both dexamethasone groups compared to the doxycycline group (p < 0.008 for all comparisons). However, epithelial healing was significantly more rapid in the doxycycline group compared to both dexamethasone groups (p < 0.008). Epithelial ulceration was apparent in both oral and topically treated dexamethasone rats, but not in doxycycline-treated rats. Oral doxycycline inhibits CNV without the harmful side effects associated with dexamethasone use. Further investigation is warranted to assess the mechanisms through which doxycycline acts to cause CNV inhibition, and the applicability of doxycycline use for treating CNV in the clinical setting.


Effect of MPEP on rat's behavioral activity in experimental episodes of hypoxia.
The influence of the selective antagonism of metabotropic glutamate receptor subtype 5 (mGluR5) by MPEP (2-methyl-6-(phenylethynyl)-pyridine) on some behaviors was tested in control groups of rats and in rats exposed to short-term hypoxia once or to repeated episodes of hypoxia. We used the following methods: the open field test, the passive avoidance test and the object recognition test. Experimental hypoxia was produced by placing rats in a glass chamber flushed with a mixture of 2% O2 in N2. MPEP applied intravenously (IV) at the dose of 1 mg kg-1 significantly enhanced locomotor and exploratory activity, impaired acquisition, but improved consolidation and retrieval in the passive avoidance situation and did not alter rats' activity in the object recognition test. The single short-term hypoxia significantly inhibited motility of rats and profoundly impaired acquisition, consolidation and retrieval processes, but the positive effect of MPEP on retrieval was preserved. Hypoxia also did not influence the activity of rats in the object recognition object. The repeated episodes of short-term hypoxia were induced for five consecutive days and it also inhibited motility of rats, but did not change consolidation and retrieval processes. The episodes of hypoxia significantly diminished the beneficial effect of MPEP on consolidation and retrieval, and also the enhancement of locomotor and exploratory activity. MPEP, used in rats subjected to the single or the repeated episodes of short-term hypoxia, did not change recognition memory. MPEP used before the single episode of hypoxia only, had beneficial effect on retrieval.


The first 3 minutes: Optimising a short realistic paediatric team resuscitation training session.
Inadequate resuscitation leads to death or brain injury. Recent recommendations for resuscitation team training to complement knowledge and skills training highlighted the need for development of an effective team resuscitation training session. This study aimed to evaluate and revise an interprofessional team training session which addressed roles and performance during provision of paediatric resuscitation, through incorporation of real-time, real team simulated training episodes. This study was conducted applying the principles of action research. Two cycles of data collection, evaluation and refinement of a 30-40 minute resuscitation training session for doctors and nurses occurred. Doctors and nurses made up 4 groups of training session participants. Their responses to the training were evaluated through thematic analysis of rich qualitative data gathered in focus groups held immediately after each training session. Major themes included the importance of realism, teamwork, and reflective learning. Findings informed important training session changes. These included; committed in-situ training; team diversity; realistic resources; role flexibility, definition and leadership; increased debriefing time and the addition of a team goal. In conclusion, incorporation of interprofessional resuscitation training which addresses team roles and responsibilities into standard medical and nursing training will enhance preparedness for participation in paediatric resuscitation.


Ischemic rats as a model in the study of the neurobiological role of human beta-amyloid peptide. Time-dependent disappearing diffuse amyloid plaques in brain.
Brains from patients with Alzheimer's disease contain diffuse and senile amyloid plaques. Using an experimental model, we have addressed the issue whether diffuse plaques of amyloid persist, develop with time, or both, in rats injected with human beta-amyloid-(1-42)-peptide for 3 and 12 mon after brain ischemia. Rats receiving beta-amyloid peptide for 3 months after brain ischemia demonstrated widespread diffuse amyloid plaques in hippocampus and cerebral cortex. Neuronal, glial, ependymal, endothelial and pericyte cell bodies were observed filled with beta-amyloid peptide. No staining was observed in control brains. In the group alive 1 year no deposition of human beta-amyloid peptide was observed, too. Direct evidence that diffuse amyloid plaques can disappear in the brain is thus provided for the first time.


Effect of the lysosomotropic drug suramin on islet lysosomal enzyme activities and the insulin-secretory response induced by various secretagogues.
The trypanocidal drug suramin is known to concentrate in lysosomes and to depress the activity of different lysosomal enzymes. We have previously shown that suramin can inhibit the activity of the islet lysosomal enzyme acid amyloglucosidase, a glycogenolytic glucose-producing hydrolase, which seems to be involved in certain insulin-secretory processes. In the present investigation we studied the pH dependency and dose-response effects of suramin on islet lysosomal enzyme activities as well as the effect of suramin treatment on the insulin-secretory response to various secretagogues in mice. It was found that two injections of suramin (0.18 mmol/kg) to normal NMRI mice at -24 and -2 h induced a moderate depression of the activities of islet acid amyloglucosidase (-22%) and acid phosphatase (-13%), whereas no effect was recorded for the activities of acid alpha-glucosidase, N-acetyl-beta-D-glucosaminidase and the non-lysosomal enzyme neutral alpha-glucosidase. Direct addition of different concentrations of suramin to islet homogenates showed that the drug was a potent inhibitor of acid amyloglucosidase and acid alpha-glucosidase at pH 4.0. At pH 5.0, suramin induced a large increase in acid alpha-glucosidase activity, whereas acid amyloglucosidase and acid phosphatase were inhibited. Suramin-injected mice showed a reduced insulin-secretory response to the sulphonylurea drug glibenclamide (-45%), whereas the insulin response to the cholinergic agonist carbachol or the phosphodiesterase inhibitor IBMX (1-isobutyl-3-methylxanthine) was unaffected. It is concluded that suramin inhibits islet acid amyloglucosidase activity in vivo and in vitro, whereas its effect on acid alpha-glucosidase is complex and pH dependent.(ABSTRACT TRUNCATED AT 250 WORDS)


Pnictogen-hydride activation by (silox)3Ta (silox = (t)Bu3SiO); attempts to circumvent the constraints of orbital symmetry in N2 activation.
Activation of N(2) by (silox)(3)Ta (1, silox = (t)Bu(3)SiO) to afford (silox)(3)Ta═N-N═Ta(silox)(3) (1(2)-N(2)) does not occur despite ΔG°(cald) = -55.6 kcal/mol because of constraints of orbital symmetry, prompting efforts at an independent synthesis that included a study of REH(2) activation (E = N, P, As). Oxidative addition of REH(2) to 1 afforded (silox)(3)HTaEHR (2-NHR, R = H, Me, (n)Bu, C(6)H(4)-p-X (X = H, Me, NMe(2)); 2-PHR, R = H, Ph; 2-AsHR, R = H, Ph), which underwent 1,2-H(2)-elimination to form (silox)(3)Ta═NR (1═NR; R = H, Me, (n)Bu, C(6)H(4)-p-X (X = H (X-ray), Me, NMe(2), CF(3))), (silox)(3)Ta═PR (1═PR; R = H, Ph), and (silox)(3)Ta═AsR (1═AsR; R = H, Ph). Kinetics revealed NH bond-breaking as critical, and As > N > P rates for (silox)(3)HTaEHPh (2-EHPh) were attributed to (1) ΔG°(calc)(N) < ΔG°(calc)(P) ∼ ΔG°(calc)(As); (2) similar fractional reaction coordinates (RCs), but with RC shorter for N < P∼As; and (3) stronger TaE bonds for N > P∼As. Calculations of the pnictidenes aided interpretation of UV-vis spectra. Addition of H(2)NNH(2) or H(2)N-N((c)NC(2)H(3)Me) to 1 afforded 1═NH, obviating these routes to 1(2)-N(2), and formation of (silox)(3)MeTaNHNH2 (4-NHNH(2)) and (silox)(3)MeTaNH(-(c)NCHMeCH(2)) (4-NH(azir)) occurred upon exposure to (silox)(3)Ta═CH(2) (1═CH(2)). Thermolyses of 4-NHNH(2) and 4-NH(azir) yielded [(silox)(2)TaMe](μ-N(α)HN(β))(μ-N(γ)HN(δ)H)[Ta(silox)(2)] (5) and [(silox)(3)MeTa](μ-η(2)-N,N:η(1)-C-NHNHCH(2)CH(2)CH(2))[Ta(κ-O,C-OSi(t)Bu(2)CMe(2)CH(2))(silox)(2)] (7, X-ray), respectively. (silox)(3)Ta═CPPh(3) (1═CPPh(3), X-ray) was a byproduct from Ph(3)PCH(2) treatment of 1 to give 1═CH(2). Addition of Na(silox) to [(THF)(2)Cl(3)Ta](2)(μ-N(2)) led to [(silox)(2)ClTa](μ-N(2)) (8-Cl), and via subsequent methylation, [(silox)(2)MeTa](2)(μ-N(2)) (8-Me); both dimers were thermally stable. Orbital symmetry requirements for N(2) capture by 1 and pertinent calculations are given.


Tracheal extubation under intravenous xylocaine.
The quality of extubation and circulatory changes during extubation of the trachea with or without prior xylocaine (1 mg/kg iv) were observed in 30 patients having CAD or 2 or more cardiac risk factors. 73.33 per cent of the patients receiving xylocaine had smooth extubation (grade I) in contrast to only 46.66 per cent in the control group. Also, in patients in the xylocaine group, the circulatory changes were statistically insignificant as compared to highly significant rise in rate pressure product in the control group.


Enucleated parotid tumours.
Five pleomorphic, one monomorphic adenoma and one acinic cell lower pole parotid tumours were thought to be lymph nodes and enucleated. Wide excision of the operative site within 2 months revealed microscopic recurrence in three cases. Three carcinomas were enucleated and two had recurred rapidly. It is suggested that such cases of inadvertent enucleation should undergo wide resection of the operative site with nerve dissection.


Deterministic models of inhalational anthrax in New Zealand white rabbits.
Computational models describing bacterial kinetics were developed for inhalational anthrax in New Zealand white (NZW) rabbits following inhalation of Ames strain B. anthracis. The data used to parameterize the models included bacterial numbers in the airways, lung tissue, draining lymph nodes, and blood. Initial bacterial numbers were deposited spore dose. The first model was a single exponential ordinary differential equation (ODE) with 3 rate parameters that described mucociliated (physical) clearance, immune clearance (bacterial killing), and bacterial growth. At 36 hours postexposure, the ODE model predicted 1.7×10⁷ bacteria in the rabbit, which agreed well with data from actual experiments (4.0×10⁷ bacteria at 36 hours). Next, building on the single ODE model, a physiological-based biokinetic (PBBK) compartmentalized model was developed in which 1 physiological compartment was the lumen of the airways and the other was the rabbit body (lung tissue, lymph nodes, blood). The 2 compartments were connected with a parameter describing transport of bacteria from the airways into the body. The PBBK model predicted 4.9×10⁷ bacteria in the body at 36 hours, and by 45 hours the model showed all clearance mechanisms were saturated, suggesting the rabbit would quickly succumb to the infection. As with the ODE model, the PBBK model results agreed well with laboratory observations. These data are discussed along with the need for and potential application of the models in risk assessment, drug development, and as a general aid to the experimentalist studying inhalational anthrax.


[Scientific publications from the Spanish anesthesiology departments in 1989-1998. Authorship of the articles].
To quantify the scientific publication of Spanish anesthesiologists and analyse article authorship. Bibliometric study. On MEDLINE we identified articles from Spanish anesthesiology departments published between 1989 and 1998. An entry for each article was created to record name, number and order of authors, journal source and length of article. The data base also noted where the article was published (Spain or abroad). Several bibliographic indices were calculated (authors per article, pages per article, articles per year, and more). The number of articles published by Spanish anesthesiologists was compared to the number published around the world. We analyzed 604 articles from 12 Spanish journals and 176 from 40 foreign journals. The numbers of authors per article in Spanish publications during the first and last three-year periods were 4.86 and 5.28, respectively (p < 0.05). The numbers of authors per article published abroad for the same periods were 5.73 and 5.01, respectively. The number of pages published in international journals in the last three-year period was four-fold greater than in the first. The bibliographic indices that reflect publication by Spanish anesthesiologists internationally is evolving positively. Data from Spanish journals allow us to deduce the existence of a certain degree of unjustified addition of authors. A quantitative-qualitative method for rating curriculum vitae is proposed in order to reduce that tendency.


The Adenovirus E1A gene blocks the differentiation of a thyroid epithelial cell line, however the neoplastic phenotype is achieved only after cooperation with other oncogenes.
The PC Cl 3 cell line is a well characterized epithelial thyroid cell line of Fischer rat origin. This cell line has the peculiarity of retaining in vitro the typical markers of thyroid differentiation (i.e. thyroglobulin synthesis and secretion, iodide uptake and dependence on TSH for growth). The PC Cl 3 cells have been transfected with the E1A gene of Adenovirus 5. The E1A transfected cells, PC E1A, partially lost the dependency on TSH for growth and completely lost the ability to trap iodide and synthesize thyroglobulin; however they did not acquire the typical markers of the neoplastic phenotype. A highly malignant phenotype was achieved after infection of the PC E1A cells with retroviruses carrying the v-raf, v-abl and polyoma virus middle T oncogenes. In contrast, the PC E1A cells transfected with the E1B gene of Adenovirus were not tumorigenic at all, and those infected with retroviruses carrying oncogenes of the ras family displayed a very weak tumorigenic phenotype.


Modulation of gamma delta T cells in mouse buccal epithelium following antigen priming.
T cells using the gamma delta T cell receptor (TCR) are abundant in mucosal and epidermal tissues in mice. Most studies of mucosal gamma delta T cells, however, have examined cells from the intestinal mucosa, whereas little is known about the presence or function of gamma delta T cells in the oral cavity. To better understand the involvement of oral gamma delta T cells in immunity, we have characterized TCR variable gamma-gene usage in the buccal epithelium from normal mice, and from mice challenged locally with a non-replicating antigen (bovine serum albumin [BSA]) or by influenza-virus infection as a replicating antigen. Our findings demonstrate a restricted use of V gamma genes by buccal gamma delta T cells, consisting primarily of V gamma 1.2, V gamma 3, and V gamma 5, with minimal use of V gamma 2 and V gamma 4 genes. Of particular interest, 3-4 days post-antigen challenge with BSA, there was a precipitous drop in the level of expression of V gamma 1.2, V gamma 3, and V gamma 5 genes, and to a lesser extent for the V gamma 2 gene, whereas V gamma 4 gene expression increased between days 1 and 2 post-priming. In influenza-infected mice, a similar pattern was observed for the V gamma 2 and V gamma 5 genes, but not other V gamma genes. The immune-modulating effects of oral antigen exposure on buccal gamma delta T cells suggest that these cells are functionally involved in the local immune response to both replicating and non-replicating antigens in oral mucosal surfaces.


[Surgical Treatment and Perioperative Management for Lung and Mediastinal Surgical Patient with Cerebrovascular Diseases].
The Japanese Joint Committee of Lung Cancer Registry reported that 1,091 patients( 5.8%) had cerebrovascular diseases as comorbidities in "A report from the Japanese Joint Committee of Lung Cancer Registry;a study of 18,973 surgical cases in 2010;secondary publication". They reported that 24 patients caused cerebral hemorrhage or cerebral infarction within 30 days after surgery. Since the elderly patient surgery is increasing, the incidence their perioperative stroke is increasing too, often leading to severe conditions. It is necessary to evaluate the risk factors and history of cerebrovascular disease prior to surgery. As most perioperative strokes occur within 3 days after surgery, and the recurrence rate is higher in patients with a history of cerebrovascular diseases, systematic perioperative management should be treated to prevent recurrence in the perioperative period. If patient taking antithrombotic drugs undergo surgery, it is necessary to be informed of the risks such as intraoperative stroke associated with pausing and resuming antithrombotic drugs. Patient with cerebrovascular disease must be diagnosed accurately and promptly, as cerebrovascular disease involves the conditions of ischemia and hemorrhage.


Perceptually-oriented hypnosis: removing a socially learned pathology and developing adequacy: the case of invisible girl.
This is the first case review to explicate perceptual hypnotic principles such as differentiation, characteristics of an adequate personality, and the need for adequacy, as utilized in clinical hypnosis in a complex case that altered the distorted perceptions and personal meanings of an eleven-year-old girl who believed that she had Bipolar Disorder and her body and mind were damaged. This qualitative case study examines aspects of hypnosis during therapy from a perceptual point of view to illustrate frustrations in difficult cases and identify some of the causes and origins of alleged clinical pathology in adverse environments. Some moments of effective self-healing through supporting internally controlled changes in perception during hypnotic experiencing are highlighted rather than externally focusing on observed thoughts and behavior. Factors relevant to social psychological research, such as family dynamics, poverty, and interactions with social service agencies and institutions, creating learned pathology, are pointed out for future research.


Dysregulation of granulocyte, erythrocyte, and NK cell lineages in Fli-1 gene-targeted mice.
Targeted disruption of the Friend leukemia integration 1 (Fli-1) proto-oncogene results in severe dysmegakaryopoiesis and embryonic lethality. We used morula-stage aggregation as a strategy to further clarify the hematopoietic defects of the Fli-1 gene-targeted mice. Analyses of lineage expression of Fli-1(+/-) and Fli-1(-/-) cells in the peripheral blood and bone marrow of chimeric mice consistently demonstrated reduced numbers of neutrophilic granulocytes and monocytes and increased numbers of natural killer (NK) cells. Transplantation studies using sorted Fli-1 mutant cells produced similar findings. Clonal culture studies of bone marrow cells revealed increased numbers of granulocytic and early erythroid progenitors in the Fli-1(+/-) cells. The sorted Fli-1(-/-) bone marrow cells revealed specific down-regulation of CCAAT/enhancer binding protein-alpha (C/EBPalpha) and C/EBPepsilon, and the receptors for granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF), consistent with their critical roles in granulopoiesis. Collectively, these observations suggest previously unknown physiologic roles for Fli-1 in granulocytic, erythroid, and NK cell proliferation and differentiation. Production of chimeras by morula-stage embryo aggregation is an effective way to unravel cell-autonomous hematopoietic defects in gene-targeted mice.


Mica Can Alleviate TNBS-Induced Colitis in Mice by Reducing Angiotensin II and IL-17A and Increasing Angiotensin-Converting Enzyme 2, Angiotensin 1-7, and IL-10.
To explore the treatment effect of mica on 2,4,6-trinitrobenzenesulfonic acid solution- (TNBS-) induced colitis in mice. Thirty male BALB/C mice were randomly divided into the control group, the TNBS group, and the mica group. Control mice were treated with saline solution. Experimental colitis was induced by TNBS (250 mg/kg/d) in the TNBS group and the mica group. After modeling, the mica group was treated with mica (180 mg/kg/d) for 3 days, while the TNBS group continued the treatment with TNBS. All solutions were injected intrarectally. During treatment, body weight and mice activity were monitored daily. After treatment, the colon tissues of mice were collected; angiotensin II (Ang II), angiotensin-converting enzyme 2 (ACE2), angiotensin 1-7 (Ang (1-7)), IL-17A, and IL-10 expression was analyzed by ELISA and immunohistochemistry. Food intake, activity, and body weight gradually decreased in the TNBS group compared to the control group and the mica group (all P < 0.05). Also, black stool adhesion in the anus and thin and bloody stool were observed in the TNBS group, but not in the other two groups. Moreover, the expression of Ang II, ACE2, Ang (1-7), IL-17A, and IL-10 in the TNBS group increased compared to that in the control group. Compared to the TNBS group, ACE2, Ang (1-7), and IL-10 in the mica group increased, while Ang II and IL-17A decreased (all P < 0.05). Mica can alleviate TNBS-induced colitis in mice by regulating the inflammation process; it reduces Ang II and IL-17A and increases ACE2, IL-10, and Ang (1-7).


Ethanol modulates corticotropin releasing hormone release from the rat hypothalamus: does acetaldehyde play a role?
Ethanol (EtOH) activates hypothalamic-pituitary-adrenal (HPA) axis, resulting in adrenocorticotropin hormone, glucocorticoid release, and in modifications of the response of the axis to other stressors. The initial site of EtOH action within the HPA system seems to be the hypothalamus. Thus, to determine the mechanisms responsible for these effects, we investigated: (i) whether EtOH was able to release corticotrophic releasing hormone (CRH) from incubated hypothalamic explants; (ii) whether acetaldehyde (ACD), its first metabolite formed in the brain by catalase activity, might play a role in EtOH activity. To this aim, rat hypothalamic explants were incubated with: (i) medium containing EtOH at 32.6 x 10(3) microM; (ii) different concentration of ACD (1, 3, 10, and 30 microM); (iii) EtOH plus 3amino-1,2,4-triazole (3AT, 32 x 10(3) microM) an inhibitor of cerebral catalase; (iv) ACD plus D-penicillamine (DP, 50.3 x 10(3) microM) an ACD-trapping agent. CRH levels were evaluated by a radioimmunoassay. Incubation with EtOH induced a 7-fold increase in CRH secretion, with respect to basal levels; ACD was able to stimulate CRH release in a dose-dependent manner; the inhibition of cerebral catalase by 3AT blocked EtOH-induced CRH outflow; the inactivation of ACD by DP reverted the ACD-stimulating effect on CRH secretion. These data show that both EtOH and acetaldehyde are able to increase hypothalamic CRH release from the rat hypothalamus and that acetaldehyde itself appears to be the mediator of EtOH activity.


The effect of hyperbaric oxygen on nasal mucociliary transport.
Nasal mucociliary transport was measured in a group of 30 adult patients (eight women and 22 men; age range 21-78 years, mean 47.9 years) treated with hyperbaric oxygen (HBO) therapy and in a control group of 32 adult subjects (two women and 30 men; age range 20-50 years, mean 32.0 years) compressed in a hyperbaric chamber without oxygen therapy. The treated patients breathed 100% oxygen at 250 kPa pressure for 60 min. Subjects from the control group were compressed in the hyperbaric chamber at 250 kPa for 70 min. Nasal mucociliary transport was measured with the saccharin clearance test. After exposure to HBO, the nasal mucociliary transport time was significantly decreased by 26% (P < 0.01) and returned to the original value after 24 h (increased by 8.3%, P = 0.25). In the control group, compressed in air, there were no statistically significant changes. This study shows that simultaneous compression and pure oxygen cause an increase in nasal mucociliary transport. The mechanism of activation of mucociliary clearance is probably the increased oxygenation of blood plasma and enhancement of metabolism in ciliated epithelium.


Controlling hypertension. A research success story.
In the past 2 decades, deaths from stroke have decreased by 59% and deaths from heart attack by 53%. An important component of this dramatic change has been the increased use of antihypertensive drugs. This remarkable success resulted from broad-based and diverse research programs supported by the federal government, pharmaceutical companies, voluntary health agencies, and private foundations. It included basic research, drug development programs, epidemiologic studies, health surveys of US citizens, clinical research, and large-scale drug trials. Four of the categories of antihypertensive drugs in wide use--diuretics, beta-blockers, calcium antagonists, and angiotensin-converting enzyme inhibitors--emerged from widely different areas of investigation. In the beginning, the major breakthroughs that led to the development of these drugs were impossible to forecast, and their ultimate applications were impossible to predict. Although decreases in hypertension-related mortality are impressive, enthusiasm must be tempered because the mechanisms of hypertension are still incompletely understood and prevention is not yet possible. Continued research is needed to extend these advances.


Plasmapheresis in the therapy of hyperthyroidism associated with leukopenia.
Surgery, the treatment of choice for hyperthyroidism due to nodular goiter, requires an euthyroid state, which is generally achieved with thionamides. Leukopenia is the most serious toxic effect of thionamides, and it causes controindication. We report a 50-year old woman with severe hyperthyroidism and leukopenia, in whom an euthyroid state before thyroidectomy was obtained with the use of therapeutic plasmapheresis. This procedure was carried out immediately before surgery using an intermittent flow separator; three sessions removed a total of 6,300 cc of plasma. Plasmapheresis caused a rapid reduction of both total and free thyroid hormone levels. Thyroidectomy was performed without any complications. Plasmapheresis can be considered a valid and safe method to prepare hyperthyroid patients for thyroidectomy when other therapies are ineffective or counterindicated.


A flare-up of tuberculosis due to war in Congo Brazzaville.
Congo Brazzaville, a country with a population of 3 million, experienced a period of war from 1997 to 1999. Before this time the annual increase in numbers of tuberculosis cases was on average 20%; in 2000 it was 84%. This situation had a considerable impact on the activities of the National Tuberculosis Programme. Before the war the diagnostic and treatment centres had notified nearly 100% of new cases of tuberculosis; in 2000 this had dropped to 76.19%, whereas the number of tuberculosis patients had almost doubled, from 5125 in 1999 to 9436 in 2000. New cases of smear-positive pulmonary tuberculosis represent 45% of cases, in comparison with an average of 55% before the war, and extrapulmonary tuberculosis 30% versus 21% before the war. The relapse rate has not changed significantly, by approximately 2%, while the default rate has risen significantly, from 20% to about 26%. The rates of new smear-positive tuberculosis cases who are cured or have completed treatment remain unchanged (70%), while the mortality rate dropped after the war from 6% to 1.23%. The war led to an increase in rates of tuberculosis, particularly in the two main cities, Brazzaville and Pointe-Noire, to which refugees had fled from the rural areas. This resulted in an excessive workload for the health workers. Sustained financial support is needed to reduce tuberculosis transmission in the Congo population.


[Risk factors for surgical wound infection development in head and neck cancer surgery].
Over a period of 24 months, patients undergoing surgical procedures for head and neck cancer at the Cancer Hospital in Rio de Janeiro, Brazil were followed-up prospectively for identification of surgical wound risk factors. A total of 273 patients fulfilling the National Nosocomial Infection Surveillance (NNIS) surgical criteria completed the analysis. The overall wound infection rate was 25.3%. Of the 11 potential risk factors for postoperative wound infections analysed by stepwise multiple logistic regression, the five variables that were independent of each other and highly predictive were patient undergoing an operation classified as either contaminated or infected, a surgery lasting longer than 5 hours, an American Society of Anesthesiologist (ASA) preoperative assessment score of 4 and 5, age over 50 years and prior radiotherapy. The preoperative stay, antibiotic prophylaxis, surgical drains, preoperative nutritional status, sex and the presence of prior infection did not have an independent significant contribution to the risk of infection. This study reports specific risk factors for head and neck cancer surgeries and contributes substantially to the effectiveness of infection control strategies to prevent their occurrence in this high-risk group of patients.


Morphology and affinities of new hominin cranial remains from Member 4 of the Sterkfontein Formation, Gauteng Province, South Africa.
Descriptions are provided of 27 hominin cranial specimens recovered from Member 4 of the Sterkfontein Formation between 1968 and 1994. Provisional statements of taxonomic affinity are given. The principal conclusion of this overview is that the bulk of the cranial remains from Member 4 are attributable to Australopithecus africanus or are consistent with the anatomy of that species, while some others are indeterminate. No specimen can be assigned confidently to a known species other than A. africanus. However, two specimens document the possibility that a second, possibly new species is represented among the Member 4 hominins, although such a species is difficult to characterize on cranial evidence alone.


The optimization of turnaround time for blood samples in an emergency clinical laboratory.
The University Medical Centre Ljublijana is a 3200-bed general hospital. A laboratory information system, developed to improve the reliability and usefulness of test results, was installed in the emergency laboratory in November 1994. At that time, all test requests received by the laboratory were treated as equally urgent, but in December 1994, a reorganisation took place, which involved the introduction of a priority system. We conducted a study in the period from November 1994 to September 1995. The turnaround time for blood analyses was evaluated by the method of case study. The influence of information technology and organisational changes on individual components of the turnaround time was assessed. This study has shown a positive effect of the recently introduced information technology and organisational changes on the turnaround time. The median turnaround time improved for all phases of the laboratory process. The greatest improvement occurred in validity check time.


Tumor associated mesenchymal stem cells protects ovarian cancer cells from hyperthermia through CXCL12.
Hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promise in treatment of ovarian carcinosis. Despite its efficiency for the treatment of peritoneal carcinosis from digestive tract neoplasia, it has failed to demonstrate significant benefit in ovarian cancers. It is therefore essential to understand the mechanism underlying resistance to HIPEC in ovarian cancers. Mesenchymal stem cells (MSC) play an important role in the development of ovarian cancer metastasis and resistance to treatments. A recent study suggests that MSCs may be cytotoxic for cancer cells upon heat shock. In contrast, we describe the protective role of MSC against hyperthermia. Using cytokine arrays we determined that the tumor associated MSC (TAMC) secrete pro-tumoral cytokines. We studied the effect of hyperthermia in co-culture setting of TAMC or BM-MCS associated with ovarian cancer cell lines (SKOV3 and CaOV3) with polyvariate flow cytometry. We demonstrate that hyperthermia does not challenge survival of TAMC or bone marrow derived MSC (BM-MSC). Both TAMC and BM-MSC displayed strong protective effect inducing thermotolerance in ovarian cancer cells (OCC). Transwell experiments demonstrated the role of secreted factors. We showed that CXCL12 was inducing thermotolerance and that inhibition of CXCL12/CXCR4 interaction restored cytotoxicity of hyperthermia in co-culture experiments. Contrary to the previous published study we demonstrated that TAMC and BM-MSC co-cultured with OCC induced thermotolerance in a CXCL12 dependant manner. Targeting the interaction between stromal and cancer cells through CXCL12 inhibition might restore hyperthermia sensitivity in ovarian cancers, and thus improve HIPEC efficiency.


Continuous Flow α-Arylation of N,N-Dialkylhydrazones under Visible-Light Photoredox Catalysis.
The first direct α-arylation of aldehyde-derived N,N-dialkylhydrazones with electron deficient aryl and heteroaryl cyanides under visible-light photoredox catalysis has been developed. Structurally complex α,α'-diaryl-N,N-cycloalkylhydrazones were obtained in moderate yields by repetition of the direct arylation protocol. A continuous-flow procedure for the preparation of α-aryl-N,N-dialkylhydrazones on a multigram scale has also been established.


How to perform a critical analysis of a randomised controlled trial.
Given the large amount of medical literature of varying methodological quality, care must be taken when translating the results of randomised controlled trials into clinical practice. To assist in this translation process, we provide a method that involves answering three main questions: 'Can I trust the results?' 'How do I understand the results?' and 'To whom do the results apply?' To answer the first question, we describe important items that help in judging the reliability of the findings. For the second question, we address the clinical and statistical significance of results by looking at the size and precision of the effect. Finally, we raise the issue of external validity and of reporting adverse effects to determine which patients may best benefit from the new intervention.


Leukocyte-deactivating factor from macrophages: partial purification and biochemical characterization. A novel cytokine.
A deactivating factor (MDF) is released from granuloma-like lesions of mice (giant and epithelioid macrophages) to the surrounding medium. Test cells incubated in the presence of MDF display dramatic inhibition of superoxide anion (O2-) release when stimulated. This failure to manifest O2 release is observed whether PMA, all-transretinal, or fMet-Leu-Phe is the stimulating agent. MDF acts on different cell types from different species; mouse macrophages as well as guinea pig, human, and mouse neutrophils. Such results suggest that it is a universal regulatory cytokine with high affinity for phagocytic lineages. The factor was subjected to various purification methods: ultrafiltration, gel chromatography, and reversed phase HPLC. A crude preparation that resulted from conditioning of medium by old macrophages (MCM) shows two peaks of activity when subjected to gel filtration. These correspond to molecular weights for the active principle of 3 and 11 kD. When the factor was obtained by extraction of the same cells after washing and sonication, only the former peak was seen. Fractions corresponding to a MW of 3 kD from several preparations were combined and subjected to HPLC. MDF activity then appeared in a single fraction. MDF is thus putatively a modulator of the cidal activity of phagocytic cells that utilize release of reactive oxygen species for cytocidal activity.


Early decrease of apurinic/apyrimidinic endonuclease expression after transient focal cerebral ischemia in mice.
The authors examined the protein expression of apurinic/apyrimidinic endonuclease (APE/Ref-1), a multifunctional protein in the DNA base excision repair pathway, before and after transient focal ischemia in mice. Immunohistochemistry showed the nuclear expression of APE/Ref-1 in the entire region of the control brains. Nuclear immunoreactivity was decreased as early as 5 minutes after 60 minutes of ischemia in the ischemic core, which was followed by a significant reduction of APE/Ref-1-positive cells in the entire middle cerebral artery territory. Western blot analysis of the sample from the nonischemic brain showed a characteristic 37-kDa band, which was reduced after ischemia. A significant amount of DNA fragmentation was observed at 24 hours, but not at 4 hours, after ischemia. The authors' data provide the first evidence that APE/Ref-1 rapidly decreases after transient focal ischemia, and that this reduction precedes the peak of DNA fragmentation in the brain regions that are destined to show necrosis and apoptosis. Although further examination is necessary to elucidate the direct relationship between the APE/Ref-1 decrease and ischemic necrosis and apoptosis, our results suggest the possibility that rapid decrease of APE/Ref-1 and the failure of the DNA repair mechanism may contribute to necrosis or apoptosis after transient focal ischemia.


Effort testing in children: can cognitive and symptom validity measures differentiate malingered performances?
Recent efforts have contributed to significant advances in the detection of malingered performances in adults during cognitive assessment. However, children's ability to purposefully underperform has received relatively little attention. The purpose of the present investigation was to examine children's performances on common intellectual measures, as well as two symptom validity measures: the Test of Memory Malingering and the Dot-Counting Test. This was accomplished through the administration of measures to children ages 6 to 12 years old in randomly assigned full-effort (control) and poor-effort (treatment) conditions. Prior to randomization, children's general intellectual functioning (i.e., IQ) was estimated via administration of the Kaufman Brief Intellectual Battery-Second Edition (KBIT-2). Multivariate analyses revealed that the conditions significantly differed on some but not all administered measures. Specifically, children's estimated IQ in the treatment condition significantly differed from the full-effort IQ initially obtained from the same children on the KBIT-2, as well as from the IQs obtained in the full-effort control condition. These findings suggest that children are fully capable of willfully underperforming during cognitive testing; however, consistent with prior investigations, some measures evidence greater sensitivity than others in evaluating effort.


Effects of different types of physical activity on the cognitive functions and attention in older people: A randomized controlled study.
This study aimed to evaluate the effects of different types of exercise on cognition. Eighty participants, 32 males and 48 females, aged 66.96 ± 11.73, volunteered for this study. The participants were randomly divided into the four following groups: Resistance Group (RG; n=20), involved in high intensity strength training; Cardiovascular Group (CVG; n=20), involved in high intensity cardiovascular training; Postural Group (PG; n=20) involved in low intensity training, based on postural and balance exercises; and Control Group (CG; n=20). Exercises were performed over the course of 12 weeks. All participants were tested for their cognitive functions pre- and post-intervention using the following neurocognitive tests: the Attentive Matrices Test, Raven's Progressive Matrices, Stroop Color and Word Interference Test, Trail Making Test and Drawing Copy Test. Statistical analysis showed that the CVG group improved significantly in the Attentive Matrices Test and Raven's Progressive Matrices (both p=<0.05), whereas the RG group improved in Drawing Copy Test time (p=<0.05). These results confirm that different types of exercise interventions have unique effects on cognition. Cardiovascular training is effective in improving performance attentive and analytic tasks, whereas resistance training is effective in improving praxis. Further investigation is necessary to evaluate the combination of the two exercise types in order to ascertain if their respective effects can be summated when performed together.


Pamidronate Down-regulates Tumor Necrosis Factor-alpha Induced Matrix Metalloproteinases Expression in Human Intervertebral Disc Cells.
N-containing bisphosphonates (BPs), such as pamidronate and risedronate, can inhibit osteoclastic function and reduce osteoclast number by inducing apoptotic cell death in osteoclasts. The aim of this study is to demonstrate the effect of pamidronate, second generation nitrogen-containing BPs and to elucidate matrix metallo-proteinases (MMPs) mRNA expression under serum starvation and/or tumor necrosis factor alpha (TNF-α) stimulation on metabolism of intervertebral disc (IVD) cells in vitro. Firstly, to test the effect of pamidronate on IVD cells in vitro, various concentrations (10(-12), 10(-10), 10(-8), and 10(-6) M) of pamidronate were administered to IVD cells. Then DNA and proteoglycan synthesis were measured and messenger RNA (mRNA) expressions of type I collagen, type II collagen, and aggrecan were analyzed. Secondly, to elucidate the expression of MMPs mRNA in human IVD cells under the lower serum status, IVD cells were cultivated in full serum or 1% serum. Thirdly, to elucidate the expression of MMPs mRNA in IVD cells under the stimulation of 1% serum and TNF-α (10 ng/mL) In this study, IVD cells were cultivated in three dimensional alginate bead. Under the lower serum culture, IVD cells in alginate beads showed upregulation of MMP 2, 3, 9, 13 mRNA. The cells in lower serum and TNF-α also demonstrated upregulation of MMP-2, 3, 9, and 13 mRNA. The cells with various doses of pamidronate and lower serum and TNF-α were reveled partial down-regulation of MMPs. Pamidronate, N-containing second generation BPs, was safe in metabolism of IVD in vitro maintaining chondrogenic phenotype and matrix synthesis, and down-regulated TNF-α induced MMPs expression.


Epidemiology of traumatic spinal cord injury in childhood and adolescence in Galicia, Spain: report of the last 26-years.
To analyze the characteristics of traumatic spinal cord injury in children of Galicia (Spain). Descriptive and retrospective study. Data extracted from the internal registry of the Spinal Cord Injury Unit and the patient's medical records, between March 1988 and December 2014. Inclusion criteria: patients aged ≤ 17 years with a traumatic spinal cord injury. Outcome measures: Total patients, percentages, incidence, ASIA scale results and improvement. A total of 68 patients were included. The incidence was 5.6 cases/1,000,000 inhabitants/year. The mean age was 14.4 years (median: 16). Only 25% were younger than 15. Male patients accounted for 73.5% of the total. The main cause were traffic accidents (60.3%; n = 41), being higher (77.8%) in children ≤ 10 years. Other etiologies included falls (19.1%), diving accidents (16.2%) and other causes (4.4%). Eleven patients (16.2%) had injuries classified as SCIWORA, 8 (72.7%) of them aged ≤ 10 years. The mean age of the SCIWORA group was 7.5 years versus 15.7 years in the non-SCIWORA group (P < 0.001). Half (50%) of these patients had a complete spinal cord injury and, of these, 64.6% were paraplegic. Traumatic spinal cord injuries are rare in children, and most cases occur between 15 and 17 years. Unlike in adults, SCIs in children mostly involve the thoracic spine. Most patients aged ≤ 10 years have SCIWORA. The most common etiology continues to be traffic accidents, although sports accidents prevail among adolescent patients.


Treponema pallidum and Helicobacter pylori recovered in a case of chronic active gastritis.
A 49-year-old man complaining of epigastric pain underwent endoscopy, during which thickened stomach folds below the fundus were observed. Microscopic examination of gastric tissue biopsy specimens revealed chronic active gastritis. Dieterle stain revealed overwhelming numbers of "corkscrew-like" spirochetes. These were proved to be consistent with Treponema pallidum. A comprehensive study of the tissue revealed the added presence of Helicobacter pylori. This appears to be the first case report describing the involvement of H. pylori and T. pallidum together in a case of chronic active gastritis.


[Clinical efficacy of pegylated interferon in patients co-infected with HIV and HCV who failed standard interferon therapy].
To investigate the efficacy and safety of pegylated interferon-alpha (PEG-INF-α) combined with ribavirin in patients co-infected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) who failed prior standard interferon therapy. A prospective study was performed to analyze HCV RNA load, liver function, and CD4+ count at weeks 0 (baseline), 12, 24, and 48 of treatment and at 24 weeks after drug discontinuation in 20 patients co-infected with HIV and HCV who failed standard interferon therapy and were then treated with PEG-INF-αand ribavirin. Among the 20 patients, 14 were infected with HCV genotype 1b, 3 with HCV genotype 2a, and 3 failed sequencing. At baseline, the mean CD4(+)count, mean CD8(+)count, and mean CD4(+)/CD8(+)ratio were 406.45 ± 210.83 cells/ml, 1 076.45 ± 716.18 cells /ml, and 0.43 ± 0.17, respectively; the mean HCV RNA load was 6.01 ± 1.13 log10IU/ml; 12 patients (60%) had abnormal liver function. A total of 14 patients (70%) achieved complete early virologic response, 15 (75%) achieved end-of-treatment virologic response, 7 (35%) achieved sustained virologic response (SVR), and 8 (40%) experienced recurrence. The incidence rate of drug-related adverse events during the treatment was 50% (10/20); no serious adverse events occurred, and no patient withdrew from the treatment due to adverse events. At week 48, both CD4(+)and CD8(+)counts of all patients declined significantly compared with the baseline values (P= 0.001 and 0.001), but the CD4(+)/CD8(+)ratio increased significantly (P= 0.032). The SVR group had a significantly lower mean baseline HCV RNA load than the non-SVR group (4.95 ± 1.18 log10IU/ml vs 6.59 ± 0.53 log10IU/ml,t= 3.49,P= 0.009). In the patients co-infected with HIV and HCV who failed standard interferon therapy, PEG-INF-αcombined with ribavirin has good efficacy and safety, and the patients with a low baseline HCV RNA load are more likely to achieve SVR.


Cerebral microvascular disease predicts renal failure in type 2 diabetes.
Abnormalities in small renal vessels may increase the risk of developing impaired renal function, but methods to assess these vessels are extremely limited. We hypothesized that the presence of small vessel disease in the brain, which manifests as silent cerebral infarction (SCI), may predict the progression of kidney disease in patients with type 2 diabetes. We recruited 608 patients with type 2 diabetes without apparent cerebrovascular or cardiovascular disease or overt nephropathy and followed them for a mean of 7.5 years. At baseline, 177 of 608 patients had SCI, diagnosed by cerebral magnetic resonance imaging. The risk for the primary outcome of ESRD or death was significantly higher for patients with SCI than for patients without SCI [hazard ratio, 2.44; 95% confidence interval (CI) 1.36 to 4.38]. The risk for the secondary renal end point of any dialysis or doubling of the serum creatinine concentration was also significantly higher for patients with SCI (hazard ratio, 4.79; 95% CI 2.72 to 8.46). The estimated GFR declined more in patients with SCI than in those without SCI; however, the presence of SCI did not increase the risk for progression of albuminuria. In conclusion, independent of microalbuminuria, cerebral microvascular disease predicted renal morbidity among patients with type 2 diabetes.


Mechanisms of interaction between human skin fibroblasts and elastin: differences between elastin fibres and derived peptides.
3H-Labelled kappa-elastin peptides (kE:75 kDa molecular weight) were shown to bind to confluent human skin fibroblast (HSF) cultures in a time-dependent and saturable manner. Scatchard analysis indicated the presence of high affinity binding sites with kD = 2.7 x 10(-10) M and 19,000 sites per cell. Binding of kE to its receptor on HSF accelerates and intensifies the adhesion of insoluble elastin fibres (iE) to confluent HSF. Optimal effect was attained for a kE concentration of 0.3 x 10(-9) M close to kD. This stimulatory effect of kE on the binding of iE to HSF could be inhibited by neomycin, retinal and pertussis toxin, substances which act at different levels of the transduction mechanism following the activation of the receptor and the subsequent triggering of cell biological events (chemotaxis, modification of calcium fluxes). The stimulation of iE adhesion to HSF induced by kE as well as kE binding to the cells could be inhibited by lactose and laminin but not by Arg-Gly-Asp-Ser(RGDS) peptides. This indicates that the elastin peptide receptor on HSF possesses lectin-like properties and shares homology with the laminin receptor as also shown for other cell types. None of the substances tested, that is inhibitors of the transduction mechanism, lactose, laminin and Arg-Gly-Asp-Ser(RGDS) peptides were shown to interfere significantly with the binding of iE (in the absence of added kE) to confluent HSF. The proteins adhering strongly to elastin fibres were isolated by a sequential extraction procedure and the final hydrochloride guanidinium-DTT extract was analysed by SDS-PAGE under reducing conditions, Western blots using specific antibodies against several connective tissue proteins and affinity for [3H]-kE following nitrocellulose electro-transfer of proteins. Fibronectin, vitronectin, tropoelastin(s), and a 120 kDa cysteine rich glycoprotein previously designated as elastonectin were identified. Among these proteins, [3H]-kE was found to bind exclusively to a 65 kDa protein that could be eluted selectively from elastin fibres with a neutral buffer containing 100 mM lactose. Therefore the elastin peptide receptor on human skin fibroblasts shares properties with the elastin receptor characterized from other cell types. Conformational differences between elastin peptides and elastin fibres could explain the differences in the mechanisms of interactions between elastin fibres and elastin peptides with HSF in culture. The stimulatory effect of elastin-derived peptides on the adhesion of elastin fibres to HSF could have implications in the oriented biosynthesis of elastin fibres.


An overview of Internal Medicine Point-of-Care Ultrasound rotations in Canada.
Point-of-care ultrasound (POCUS) is a growing part of internal medicine training programs. Dedicated POCUS rotations are emerging as a particularly effective tool in POCUS training, allowing for longitudinal learning and emphasizing both psychomotor skills and the nuances of clinical integration. In this descriptive paper, we set out to review the state of POCUS rotations in Canadian Internal Medicine training programs. We identify five programs currently offering a POCUS rotation. These rotations are offered over two to thirteen blocks each year, run over one to four weeks and support one to four learners. Across all programs, these rotations are set up as a consultative service that offers POCUS consultation to general internal medicine inpatients, with some extension of scope to the hospitalist service or surgical subspecialties. The funding model for the preceptors of these rotations is predominantly fee-for-service using consultation codes, in addition to concomitant clinical work to supplement income. All but one program has access to hospital-based archiving of POCUS exams. Preceptors dedicate ten to fifty hours to the rotation each week and ensure that all trainee exams are reviewed and documented in the patient's medical records in the form of a consultation note. Two of the five programs also support a POCUS fellowship. Only two out of five programs have established learner policies. All programs rely on In-Training Evaluation Reports to provide trainee feedback on their performance during the rotation. We describe the different elements of the POCUS rotations currently offered in Canadian Internal Medicine training programs. We share some lessons learned around the elements necessary for a sustainable rotation that meets high educational standards. We also identify areas for future growth, which include the expansion of learner policies, as well as the evolution of trainee assessment in the era of competency-based medical education. Our results will help educators that are endeavoring setting up POCUS rotations achieve success.


An Indian family of multiple endocrine neoplasia type 1 (MEN1): molecular diagnosis, treatment and follow up.
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal, dominant syndrome, characterized mainly by the combination of tumors involving the parathyroid, pancreatic and pituitary glands. Genetic sequencing leading to early treatment of family members has not yet been reported in Indian patients. We performed molecular analysis of the MEN1 gene to identify mutations in an Indian family with MEN1 syndrome. The proband was identified with multiple peptic ulcers because of multifocal recurrent gastrinomas, as well as parathyroid and pituitary adenomas. All the 10 exons of the MEN1 gene were amplified using the polymerase chain reaction (PCR). The MEN1 gene was then screened by direct DNA sequencing. The proband is asymptomatic 3 years after total pancreatectomy and removal of parathyroid adenomas. DNA sequencing revealed the presence of a heterozygous Y227X mutation in exon 4 of the MEN1 gene in the proband. Four of the seven mutant-carrying family members are at present asymptomatic. Following screening, one asymptomatic child has been identified with and treated for insulinoma and parathyroid adenoma. Detection of the MEN1 gene mutation enables selection of family members for screening and long-term follow up.


Chiral indium alkoxide complexes as initiators for the stereoselective ring-opening polymerization of rac-lactide.
The indium complex InL(2)N'' has been prepared from the reaction of 2 equiv of ((t)Bu)(2)P(O)CH(2)CH((t)Bu)OH (HL) with InN''(3) (N'' = N(SiMe(3))(2)). This complex reacts with a further equivalent of 2,6-di-tert-butylphenol or HL to afford the adducts InL(2)(OAr) and InL(3), respectively. Confirmation that the anion L(-) exhibits "ligand self-recognition" in the formation of predominantly homochiral complexes RR-InL(2)N'' and SS-InL(2)N'' is obtained from (1)H and (31)P NMR spectroscopic data. However, the self-recognition is less effective at the indium cation, and mixtures of InL(3) complexes with different configurations are observed. Single-crystal X-ray diffraction data confirm the five-coordinate, distorted bipyramidal In center in InL(2)N'' and InL(2)(OAr) as anticipated. Selected crystals of InL(3) show two of the possible configurations: one is the fac-RRR-InL(3) complex, analogous to the lanthanide complexes LnL(3) reported previously (Ln = Y, Eu, Er, Yb); another is the alternative, homochiral mer form RRR'-InL(3). All three complexes are efficient single-component initiators for the ring-opening polymerization of rac-lactide over a wide range of temperatures and monomer-to-initiator ratios, exhibiting reasonable control over the synthesis of isotactic polylactide. Despite its poorly defined structure, InL(3) is the fastest initiator among the three complexes for the polymerization of rac-lactide, and shows the best tacticity control. The polylactide samples have high molecular weights M(n,exp) (between 44 000 and 270 000 g/mol at completion) and narrow polydispersities (as low as 1.25 at completion).


UrgoClean: a new dressing for desloughing exuding wounds.
Wound debridement plays a key role in wound bed preparation and the healing of chronic wounds. A variety of techniques can be used to achieve debridement and autolytic debridement is frequently the clinician's first choice. This is aided by dressings including hydrogels and hydrocolloids, which provide the moist environment required for white blood cells to function. This product focus uses 12 case studies to examine the effectiveness of UrgoClean in wound debridement.


["Euthanasia"--victims and test subjects. The fate of diseased, disabled children in Berlin during World War II].
This article shows, through a study of the Berlin-Brandenburg region, that children and juveniles who were subjected to the killings of diseased and disabled, or mentally retarded, persons during the Third Reich did not only fall victim to the operations of the "Reichsausschuss" ("Reich Commission for Registration of Severe Disorders in Childhood"). Many were also included in the gas chamber killings of the "T4"-action and in various decentralized killing actions. Furthermore, the co-operation of various medical disciplines in the misuse of children for scientific research is demonstrated by looking into the research on a tuberculosis vaccine. It can be shown that the purpose of the killings was not the painless ending of individual suffering, but that they constituted a means of freeing the public from so-called "ballast existences", whose lives were only prolonged if they could be of scientific use.


Surveillance strategies after definitive therapy of invasive bladder cancer.
Following definitive therapy for muscle invasive bladder cancer, patients remain at risk for local and distant recurrence. Additionally, recurrences can result from formation of new tumours elsewhere in the urinary tract. We review patterns of recurrence and the prognosis associated with recurrence. Optimal surveillance strategies are discussed.


New chromosomal regions with high-level amplifications in squamous cell carcinomas of the larynx and pharynx, identified by comparative genomic hybridization.
Squamous cell carcinomas of the head and neck generally exhibit complex karyotypes. To gain better knowledge of the changes in the subgroup of laryngeal and pharyngeal squamous cell carcinoma, chromosomal gains and losses were investigated in 42 predominantly late-stage tumours, using comparative genomic hybridization. On average, 11.2 gains and 6.8 losses were found. Gains were detected in high frequencies at 1q, 3q, 5p, 7q, 8q, 11q13, 17q, and 18p, and losses at 3p, 4p, 5q, 11qter, and 18q. Neither the number nor the type of abnormalities, nor the occurrence of specific chromosome changes, was found to be related to DNA ploidy, tumour stage, or degree of differentiation. Apart from low-level gains, many high-level amplifications were identified, in particular 3q24-qter (15 cases). Other regions recurrently involved were 11q13 (7 cases), 18p (5 cases), 18q11.2 (4 cases), and 8q23-24 and 11q14-22 (3 cases). Many of these amplified regions have not been reported before. Over half of all loci harbour genes coding for growth factors and growth factor receptors, suggesting an important role for such genes in squamous cell tumourigenesis and in the progression of late-stage tumours.


Evolutionary re-organisation of a large operon in adzuki bean chloroplast DNA caused by inverted repeat movement.
We have sequenced two sections of chloroplast DNA from adzuki bean (Vigna angularis), containing the junctions between the inverted repeat (IR) and large single copy (LSC) regions of the genome. The gene order at both junctions is different from that described for other members of the legume family, such as Lotus japonicus and soybean. These differences have been attributed to an apparent 78-kb inversion that spans nearly the entire LSC region and which is present in adzuki and its close relative, the common bean. This 78-kb rearrangement broke the large S10 operon of ribosomal proteins into two smaller operons, one at each end of the LSC, without affecting the gene content of the genome. It disrupted the physical and transcriptional relationship between the six-gene rpl23-rpl14 cluster and the four-gene rps8-rpoA cluster that is conserved in most land plants. Analysis of the endpoints of the rearrangement indicates that it probably occurred by means of a two-step process of expansion and contraction of the IR and not by a 78-kb inversion.


Asymmetric synthesis and cytotoxic activity of isomeric phytosphingosine derivatives.
New phytosphingosine analogues have been conceived, synthesised and their cytotoxicity in B16 murine melanoma cells tested. These compounds embed an isomeric substitution pattern resulting from a formal permutation of the C-2 and C-4 substituents along the aliphatic skeleton of the original sphingoid base. Five different stereoisomers have been accessed through regio- and stereocontrolled opening of the oxirane of long chain epoxyamine precursors. The corresponding N-hexyl and N-octanoyl derivatives have also been prepared. In cell viability experiments all the primary amines were found to be more active than the natural phytosphingosine with IC(50) in the low μM range for the most potent compounds.


Genetic epidemiology using whole genome sequencing and haplotype networks revealed the linkage of SARS-CoV-2 infection in nosocomial outbreak.
A characteristic feature of SARS-CoV-2 is its ability to transmit from pre- or asymptomatic patients, complicating the tracing of infection pathways and causing outbreaks. Despite several reports that whole genome sequencing (WGS) and haplotype networks are useful for epidemiologic analysis, little is known about their use in nosocomial infections. We aimed to demonstrate the advantages of genetic epidemiology in identifying the link in nosocomial infection by comparing single nucleotide variations (SNVs) of isolates from patients associated with an outbreak in Showa University Hospital. We used specimens from 32 patients in whom COVID-19 had been diagnosed using clinical reverse transcription-polymerase chain reaction tests. RNA of SARS-CoV-2 from specimens was reverse-transcribed and analysed using WGS. SNVs were extracted and used for lineage determination, phylogenetic tree analysis, and median-joining analysis. The lineage of SARS-CoV-2 that was associated with outbreak in Showa University Hospital was B.1.1.214, which was consistent with that found in the Kanto metropolitan area during the same period. Consistent with canonical epidemiological observations, haplotype network analysis was successful for the classification of patients. Additionally, phylogenetic tree analysis revealed three independent introductions of the virus into the hospital during the outbreak. Further, median-joining analysis indicated that four patients were directly infected by any of the others in the same cluster. Genetic epidemiology with WGS and haplotype networks is useful for tracing transmission and optimizing prevention strategies in nosocomial outbreaks.


Effect of lidocaine on the minimum alveolar concentration of isoflurane in dogs.
To determine the influence of a low-dose constant rate infusion (LCRI; 50 microg kg(-1) minute(-1)) and high-dose CRI (HCRI; 200 microg kg(-1) minute(-1)) lidocaine infusion on the minimum alveolar concentration (MAC) of isoflurane (I) in dogs. Prospective experimental study. Ten mongrel dogs (four females, six males), weighing 20-26.3 kg. Dogs were anesthetized with I in oxygen and their lungs mechanically ventilated. Baseline MAC was determined using mechanical or electrical stimuli. Lidocaine (2 mg kg(-1) IV) was administered over 3 minutes, followed by the LCRI and MAC determination commenced 30 minutes later. Once MAC was determined following LCRI, the lidocaine infusion was stopped for 30 minutes. A second bolus of lidocaine (2 mg kg(-1), IV) was administered, followed by the HCRI and MAC re-determined. Concentrations of lidocaine and its metabolites were measured at end-tidal I concentrations immediately above and below MAC. Heart rates and blood pressures were measured. Minimum alveolar concentration of I was 1.34 +/- 0.11 (%; mean +/- SD) for both types of stimulus. The LCRI significantly reduced MAC to 1.09 +/- 0.13 (18.7% reduction) and HCRI to 0.76 +/- 0.10 (43.3% reduction). Plasma concentrations (ng mL(-1), median; value below and above MAC, respectively) for LCRI were: lidocaine, 1465 and 1537; glycinexylidide (GX), 111 and 181; monoethylglycinexylidide (MEGX), 180 and 471 and for HCRI were: lidocaine, 4350 and 4691; GX, 784 and 862; MEGX, 714 and 710. Blood pressure was significantly increased at 30 minutes after high dose infusion. Lidocaine infusions reduced the MAC of I in a dose-dependent manner and did not induce clinically significant changes on heart rate or blood pressure.


A role for polyproline motifs in the spinal muscular atrophy protein SMN. Profilins bind to and colocalize with smn in nuclear gems.
Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by the loss of alpha-motoneurons in the spinal cord followed by atrophy of skeletal muscles. SMA-determining candidate genes, SMN1 and SMN2, have been identified on human chromosome 5q. The corresponding SMN protein is expressed ubiquitously. It is coded by seven exons and contains conspicuous proline-rich motifs in its COOH-terminal third (exons 4, 5, and 6). Such motifs are known to bind to profilins (PFNs), small proteins engaged in the control of actin dynamics. We tested whether profilins interact with SMN via its polyproline stretches. Using the yeast two-hybrid system we show that profilins bind to SMN and that this binding depends on its proline-rich motifs. These results were confirmed by coimmunoprecipitation and by in vitro binding studies. Two PFN isoforms, I and II, are known, of which II is characteristic for central nervous system tissue. We show by in situ hybridization that both PFNs are highly expressed in mouse spinal cord and that PFN II is expressed predominantly in neurons. In motoneurons, the primary target of neurodegeneration in SMA, profilins are highly concentrated and colocalize with SMN in the cytoplasm of the cell body and in nuclear gems. Likewise, SMN and PFN I colocalize in gems of HeLa cells. Although SMN interacts with both profilin isoforms, binding of PFN II was stronger than of PFN I in all assays employed. Because the SMN genes are expressed ubiquitously, our findings suggest that the interaction of PFN II with SMN may be involved in neuron-specific effects of SMN mutations.


[Tumstatin185-191 increases the sensitivity to cisplatin in a cisplatin-resistant human lung adenocarcinoma cell line].
To investigate the effects and related mechanisms of Tumstatin 185-191 as a single agent or in combination with cisplatin on proliferation and apoptosis in a cisplatin-resistant human lung adenocarcinoma cell line A549-DDP cells. A549-DDP cells were treated with Tumstatin185-191 and cisplatin at varying concentrations. Cell viability was assessed by a modified 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. 50% inhibiting concentration (IC(50)) values of the chemotherapeutic drugs were analyzed by MTT assay. Cell apoptosis was measured by flow cytometry. The activation of Akt and ERK was evaluated by Western blotting. Tumstatin185-191 inhibited the proliferation of A549-DDP cells and its IC(50) value was 80.25 micromol/L. After cotreatment with 20 micromol/L Tum185-191, the IC(50) value of cisplatin in A549-DDP cells reduced from 77.16 micromol/L to 57.97 micromol/L, the reverse index was 1.33, while with 40 micromol/L Tumstatin185-191 the IC(50) was reduced from 77.16 to 26.40 micromol/L and the reverse index was 2.92. The early apoptosis rate was 19.5% +/- 1.1% in the cotreatment group, while 13.3% +/- 1.5% in cisplatin group and 10.2% +/- 2.0% in Tum185-191 group (F = 4.09, P < 0.05). The levels of phospho-Akt (p-Akt) and phospho-ERK (p-ERK) in the A549-DDP cells were remarkably lower after treatment with Tumstatin 185-191. The Tumstatin 185-191 treatment alone or in combination with cisplatin had a similar effect on the protein levels of p-Akt and p-ERK in A549-DDP cells. Our data suggest that Tumstatin185-191 may promote apoptosis, downregulate proliferation and partly reverse the drug resistance of A549-DDP cells to cisplatin. The effects induced by Tum185-191 may be mediated through inactivation of the Akt and ERK pathways.


Predictive Value of Endometrial Length Measurement by Transvaginal Ultrasound and IVF/ICSI Outcomes.
The purpose of this study to determine the relationship between endometrial length and positive pregnancy test in patients who underwent assisted reproductive technology (ART). This cross-sectional study included patients who were referred for in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) therapy from 2013 to 2016. All nulliparous women who met the inclusion criteria were between 20-38 years of age and presented for ultrasound measurements prior to fresh embryo transfer (ET). Endometrial length was measured by transvaginal ultrasound (TVS) with a Medison Accuvix device on the day of human chorionic gonadotropin (hCG) administration. The relationship between endometrial length and treatment success was assessed. The independent sample t test, receiver operating characteristic (ROC) curve and the area under the curve (AUC) index and chi-square test were used for data analysis. P<0.05 were statistically significant. There was a significant relationship between endometrial length (41.5%) and treatment success (P<0.05). The endometrial length of 41.5(mm) with a sensitivity of 66.7%, specificity of 50.6%, positive predictive value of 46.8%, negative predictive value of 69.4%, and efficiency of 56.62% can be used as a proper cut-off point with an AUC of 0.63. The value of 41.5(mm) for endometrial length can be used as a proper cut-off point for prediction of a higher ART success rate. We recommend TVS as the first step for assessment of uterine and endometrium receptivity in the ART cycle.


Structure and relative potency of several karlotoxins from Karlodinium veneficum.
The karlotoxins are a family of amphidinol-like compounds that play roles in avoiding predation and in prey capture for the toxic dinoflagellate Karlodinium veneficum. The first member of the toxin group to be reported was KmTx 1 (1), and here we report an additional five new members of this family (3-7) from the same strain. Of these additional compounds, KmTx 3 (3) differs from KmTx 1 (1) in having one less methylene group in the saturated portion of its lipophilic arm. In addition, 64-E-chloro-KmTx 3 (4) and 10-O-sulfo-KmTx 3 (5) were identified. Likewise, 65-E-chloro-KmTx 1 (6) and 10-O-sulfo-KmTx 1 (7) were also isolated. Comparison of the hemolytic activities of the newly isolated compounds to that of KmTx 1 shows that potency correlates positively with the length of the lipophilic arm and is disrupted by sulfonation of the polyol arm.


A hospitalist postgraduate training program for physician assistants.
Many hospitalist groups are hiring physician assistants (PAs) to augment their physician services. Finding PAs with hospitalist experience is difficult. Employers often have to recruit PAs from other specialties or hire new graduates who have limited hospital experience. Furthermore, entry-level PA training focuses on primary care, with more clinical rotations centered in the outpatient setting. In light of these challenges, our institution created a 12-month postgraduate training program in Hospital Medicine for 1 PA per year. It is the first reported postgraduate PA hospitalist fellowship to offer a certificate of completion. The program's curriculum is based on the Society of Hospital Medicine (SHM) "Core Competencies," and is comprised of 12 one-month rotations in different aspects of hospital medicine supplemented by formal didactic instruction. In addition, the PA fellow completes "teaching modules" on various topics not directly covered in their rotations. Furthermore, this postgraduate physician assistant training program represents a model that can be utilized at almost any institution, academic or community-based. As the need for hospitalists increases, so will the need for trained physician assistants in hospital medicine.


Amygdala regulation of fear and emotionality in fragile X syndrome.
Fear is a universal response to a threat to one's body or social status. Disruption in the detection and response of the brain's fear system is commonly observed in a variety of neurodevelopmental disorders, including fragile X syndrome (FXS), a brain disorder characterized by variable cognitive impairment and behavioral disturbances such as social avoidance and anxiety. The amygdala is highly involved in mediating fear processing, and increasing evidence supports the idea that inhibitory circuits play a key role in regulating the flow of information associated with fear conditioning in the amygdala. Here, we review the known and potential importance of amygdala fear circuits in FXS, and how developmental studies are critical to understand the formation and function of neuronal circuits that modulate amygdala-based behaviors.


Antihepatoma activity of the acid and neutral components from Ganoderma lucidum.
Ganoderma lucidum extracts or isolated components have been shown previously to acquire many potential biochemical and pharmacological activities, including cancer preventive or antitumor effects. The supercritical fluid extracts of Ganoderma lucidum (total component, TC) and its acid component (AC) and neutral component (NC), were evaluated in vitro and in vivo for their antihepatoma activities. The NC showed a conspicuous inhibitory effect on tumor growth of Heps-bearing mice, whereas AC was less effective. The TC, NC and AC all inhibited the proliferation of BEL-7402 cells through apoptosis pathway and cell cycle arrest. Additionally, the NC and TC induced cell cycle arrest at the G2/M phase, but the AC resulted in a marked increase in the percentage of cells at G1 phase by flow cytometry. It is suggested that NC is an indispensable effective component in terms of antihepatoma activity and its constituents need to be investigated in detail. It was found that the NC, which was detected by GC-MS, contained fatty acids and steroids; hence, it is proposed that some compounds such as long-chain fatty acids and steroids in the NC might also contribute to the antihepatoma activity, although the anticancer activities of G. lucidum traditionally have been considered to be associated with triterpenoids.