Preliminary findings from a prospective, randomized trial of two tongue-base surgeries for sleep-disordered breathing.
This study compares the efficacy of 2 tongue-base surgical procedures in the treatment of patients with moderate to severe sleep-disordered breathing. We conducted a prospective, randomized crossover surgical trial at a university hospital. Seventeen patients with moderate to severe sleep-disordered breathing and Fujita type II upper airway collapse for whom conservative treatment failed were enrolled into an institutional review board-approved surgical protocol. They were randomly assigned to undergo palatopharyngoplasty combined with either tongue advancement (mandibular osteotomy) or tongue suspension. Parameters assessed included severity of sleep-disordered breathing (polysomnography), sleepiness (Epworth Sleepiness Scale), and anatomic changes (upper airway endoscopy), as well as demographic factors. Patients not achieving satisfactory improvement in their condition were offered nonsurgical management or additional surgical treatment that varied based on the postoperative assessment but included crossing over to the other tongue surgical procedure. Nine of the 17 patients were randomized to the tongue suspension group, and 8 to the tongue advancement group. In the 9 tongue suspension patients, Epworth Sleepiness Scale scores fell from 12.1 to 4.1 (P = 0.007). Airway collapse for all 9 patients measured on Müller maneuver improved, by a mean of 64% (P = 0.0006) at the palate and 83% (P = 0.0003) at the base of the tongue. In the 8 tongue advancement patients, Epworth Sleepiness Scale scores fell from a mean of 13.3 to 5.4 (P = 0.004). Airway collapse for 5 of 8 patients measured on Müller maneuver improved by a mean of 31% (P = 0.1) at the palate and 75% (P = 0.03) at the base of the tongue. Prospective, randomized trials of tongue-base surgery for sleep-disordered breathing are possible. Preliminary findings from the current protocol reveal a slight advantage of tongue suspension over tongue advancement.


Evaluation of erythropoiesis by serum transferrin receptor and ferritin in infants aged 0-6 months.
The aim of this study was to evaluate erythropoiesis in 198 healthy babies aged 0-6 months by determination of their blood count, serum transferrin receptor (STfR), and ferritin levels. Anemia and microcytosis were present in 9% and 13% of the sample, respectively. Microcytosis rate was as high as 45% in 6-month-old babies. In infants with normal blood counts, the values of sTfR/ferritin and sTfR-F index were increasing with the increase of sTfR and decrease of ferritin beginning from 2 months of age. In the 5- to 6-month-old group, sTfR concentrations, sTfR/ferritin ratio, and sTfR-F index were higher in infants with anemia and microcytosis. This research showed a high frequency of iron deficiency detected in otherwise healthy babies. Only problems with early weaning practices were found to be significantly more common in babies with iron deficiency.


Selectivity changes in site-directed mutants of the VDAC ion channel: structural implications.
The gene encoding the yeast mitochondrial outer membrane channel VDAC was subjected to site-directed mutagenesis to change amino acids at 29 positions to residues differing in charge from the wild-type sequence. The mutant genes were then expressed in yeast, and the physiological consequences of single and multiple amino acid changes were assessed after isolation and insertion of mutant channels into phospholipid bilayers. Selectivity changes were observed at 14 sites distributed throughout the length of the molecule. These sites are likely to define the position of the protein walls lining the aqueous pore and hence, the transmembrane segments. These results have been used to develop a model of the open state of the channel in which each polypeptide contributes 12 beta strands and one alpha helix to form the aqueous transmembrane pathway.


Experimental infection of anole lizards (Anolis carolinensis) with Mycobacterium ulcerans by the subcutaneous route.
To test whether herpetofauna could be a laboratory model for Mycobacterium ulcerans, 21 anole lizards were inoculated subcutaneously with viable M. ulcerans, 21 with autoclaved organisms, and 14 with an aqueous solution of 0.01% Tween 80. M. ulcerans was recovered in culture from the slowly progressive lesions which developed at the inoculation site in lizards receiving the viable bacteria. Progressive lesions did not occur in the two control groups. Three patterns of inflammatory response to viable M. ulcerans were observed: 14 lizards developed a diffuse, granulomatous reaction in which acid fast bacilli (AFB) were predominantly intracellular; 1 developed focal, encapsulated granulomas; 5 developed a diffuse, necrotizing granulomatous response in which most AFB were extracellular--similar to the characteristic lesion found in human infections.


Severe combined immunodeficiency (SCID) and rotavirus vaccination: reports to the Vaccine Adverse Events Reporting System (VAERS).
Rotavirus vaccines are the only live vaccines recommended for infants in the US. Postmarketing reports have described severe gastroenteritis with vaccine viral shedding in infants who received rotavirus vaccine and were later diagnosed with SCID. The US Food and Drug Administration recently approved labeling changes for RotaTeq and Rotarix contraindicating administration to individuals with a history of SCID. We queried VAERS to characterize reports of SCID after rotavirus vaccination. VAERS inclusion criteria included current US-licensed rotavirus vaccines, report dates from February 3, 2006 to January 15, 2010, and queries for the MedDRA preferred term "combined immunodeficiency" as well as any text containing the terms, "SCID" or "combined immunodeficiency." We identified nine reports of SCID and rotavirus vaccination in infants between 3 and 9 months of age. All but one case presented with diarrhea among other symptoms. All infants were hospitalized and had workups leading to the SCID diagnosis. Stool rotavirus testing was positive in all cases and the virus was identified as the vaccine strain in six cases. Prolonged viral shedding was documented in five cases. No deaths were reported. The aforementioned labeling changes were warranted given the risk posed by live rotavirus vaccine to individuals with SCID, as illustrated by these VAERS cases. Although congenital, SCID was not diagnosed in these infants until after rotavirus vaccination. Earlier identification of SCID (e.g., from expanded newborn screening or heightened clinical vigilance) could prevent inadvertent live rotavirus vaccine administration and also potentially result in earlier life-saving stem cell transplants.


Molecular identification of pathogenic fungi in formalin-fixed and paraffin-embedded tissues.
Introduction. Histopathological examination (HPE) of tissue helps in the diagnosis of invasive fungal infections (IFIs) but cannot identify the fungus to the genus/species levelGap Statement Available protocols for the molecular identification of fungi from formalin-fixed and paraffin-embedded (FFPE) tissues have limitations in terms of extraction and target selection, and standardisation.Aim. Development of sequence-based fungal identification protocol after extraction of DNA from formalin-fixed and paraffin-embedded (FFPE) tissues.Methodology. A total of 63 FFPE tissues from histopathology proven IFI cases were used to standardize the DNA extraction (commercial QIAamp kit-based extraction and conventional phenol-chloroform-isoamyl alcohol [PCI] method) and sequence-based fungal identification protocols. The PCR targeted different ribosomal DNA (rDNA) regions including complete internal transcribed spacer (ITS1-5.8S-ITS2), separate ITS1 and ITS2, 18S and D1/D2 of 28S regions. Semi-nested PCR targeting Mucorales-specific 18S rDNA region was performed in tissues having aseptate hyphae. The optimized ITS1-PCR protocol was evaluated in 119 FFPE tissues containing septate hyphae or yeast, and Mucorales-specific semi-nested PCR in 126 FFPE tissues containing aseptate hyphae.Results. The DNA yield by conventional PCI method was significantly higher (P<0.0001) than commercial kit, though the quality of DNA was similar by both protocols. The test accuracy was best while using ITS1 (61.9 %) as the target compared to 7.9, 29.9 and 22.2 % on targeting ITS1-5.8S-ITS2, ITS2, the D1/D2 region of 28S, respectively. The test accuracies of ITS1-PCR in tissues containing septate hyphae, aseptate hyphae and yeasts were 75.5, 18.7 and 100 %, respectively. The amplification (targeting ITS1 region) improved by increasing the thickness of tissue section (up to 50 µm) used for DNA extraction. ITS1-PCR protocol could amplify fungal DNA in 76 (63.8 %) tissues and Mucorales-specific semi-nested PCR in 86 (68.3 %) tissues.Conclusion. Conventional PCI-based DNA extraction from thick tissue (50 µm) may be used until optimal commercial fungal DNA extraction kit is developed. Subsequent ITS1-PCR for septate fungi and yeast, and semi-nested PCR targeting 18S rDNA for Mucorales are recommended to identify the fungus in FFPE tissues.


E2F1 induces LSINCT5 transcriptional activity and promotes gastric cancer progression by affecting the epithelial-mesenchymal transition.
Long noncoding RNAs (lncRNAs) have been shown to play important regulatory roles in human cancer. We previously verified that the lncRNA long stress-induced noncoding transcript 5 (LSINCT5) is overexpressed in gastric cancer (GC) cells and closely correlated with cell proliferation and patient prognosis. However, whether aberrant LSINCT5 expression has an important effect on GC progression is unclear, and the potential mechanisms remain unknown. In GC, E2F1 expression is also aberrant, but the biological functions of E2F1 are controversial, and the correlation between E2F1 and lncRNAs remains unknown. Expression of LSINCT5 was analyzed in metastatic GC tissues compared with nonmetastatic tissues using quantitative real-time PCR (qRT-PCR) assays. Gain and loss of function approaches were used to investigate the biological role of LSINCT5 in GC cell migration and invasion. A computational screen of LSINCT5 promoter was conducted to search for transcription factor-binding sites. LSINCT5 promoter activities were examined by ChIP and luciferase reporter assays. qRT-PCR and western blotting assays were performed to detect the expression of multiple EMT markers in cells in which LSINCT5 was overexpressed or knocked down. An integrated quantitative analysis revealed that LSINCT5 was significantly over-expressed in metastatic GC tissues. Forced LSINCT5 expression promoted cell migration and invasion, whereas loss of LSINCT5 function decreased cell migration and invasion. Mechanistic investigations showed that LSINCT5 is a direct transcriptional target of E2F1. Moreover, LSINCT5 overexpression was found to play an important role in the epithelial-to-mesenchymal transition by regulating the expression of E-cadherin, N-cadherin, vimentin, and matrix metalloproteinase-2. These data suggest that E2F1-mediated activation of LSINCT5, a regulator of cell migration and invasion, constitute the mechanistic link between the E2F1-mediated pathway and lncRNA that regulates cell migration and invasion. Thus, LSINCT5 may be a target for new GC therapies.


Long-Term Safety Experience with Telotristat Ethyl Across Five Clinical Studies in Patients with Carcinoid Syndrome.
Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience considerable morbidity and mortality; carcinoid syndrome may be associated with shorter survival. Carcinoid syndrome is linked to tumoral secretion of serotonin and other bioactive substances. The subsequent debilitating diarrhea and urgency to defecate pose significant health risks. In previous studies, telotristat ethyl, a tryptophan hydroxylase inhibitor, was effective and well tolerated in treating carcinoid syndrome diarrhea. We present pooled safety data from five clinical trials with telotristat ethyl in patients with carcinoid syndrome. Adverse events reported during telotristat ethyl treatment were pooled from two phase II and three phase III clinical trials in 239 patients with carcinoid syndrome. Long-term safety of telotristat ethyl and causes of hospitalization and death were reviewed; overall survival was estimated. Mean (median; range) duration of exposure and follow-up was 1.3 years (1.1 years; 1 week to 5.7 years), with 309 total patient-years of exposure. Leading causes of hospitalization were gastrointestinal disorders or were related to the underlying tumor and related treatment. Survival estimates at 1, 2, and 3 years were 93%, 88%, and 77%. Nearly all deaths were due to progression or complication of the underlying disease; none were attributable to telotristat ethyl. There was one death in year 4. Based on long-term safety data, telotristat ethyl is well tolerated and has a favorable long-term safety profile in patients with carcinoid syndrome. Carcinoid syndrome can cause persistent diarrhea, even in patients treated with somatostatin analogs. Across five clinical trials in patients with carcinoid syndrome, telotristat ethyl has been well tolerated and efficacious, providing clinicians with a new approach to help control carcinoid syndrome diarrhea, in addition to somatostatin analog therapy. By reducing the stool frequency in patients with carcinoid syndrome whose diarrhea is refractory to anticholinergics, such as loperamide and atropine/diphenoxylate, and somatostatin analog dose escalation, improvement in quality of life becomes an achievable goal.


Fossil basicranium clarifies the origin of the avian central nervous system and inner ear.
Among terrestrial vertebrates, only crown birds (Neornithes) rival mammals in terms of relative brain size and behavioural complexity. Relatedly, the anatomy of the avian central nervous system and associated sensory structures, such as the vestibular system of the inner ear, are highly modified with respect to those of other extant reptile lineages. However, a dearth of three-dimensional Mesozoic fossils has limited our knowledge of the origins of the distinctive endocranial structures of crown birds. Traits such as an expanded, flexed brain, a ventral connection between the brain and spinal column, and a modified vestibular system have been regarded as exclusive to Neornithes. Here, we demonstrate all of these 'advanced' traits in an undistorted braincase from an Upper Cretaceous enantiornithine bonebed in southeastern Brazil. Our discovery suggests that these crown bird-like endocranial traits may have originated prior to the split between Enantiornithes and the more crownward portion of avian phylogeny over 140 Ma, while coexisting with a remarkably plesiomorphic cranial base and posterior palate region. Altogether, our results support the interpretation that the distinctive endocranial morphologies of crown birds and their Mesozoic relatives are affected by complex trade-offs between spatial constraints during development.


Stoichiometry of the topa quinone biogenesis reaction in copper amine oxidases.
The stoichiometry of the topa quinone biogenesis reaction in phenylethylamine oxidase from Arthrobacter globiformis (AGAO) has been determined. We have shown that the 6e- oxidation of tyrosine to topa quinone (TPQ) consumes 2 mol of O2 and produces 1 mol of H2O2/mol of TPQ formed. The rate of H2O2 production is first-order (kobs = 1.0 +/- 0.2 min-1), a rate only slightly lower than the rate of TPQ formation directly determined previously (kobs = 1.5 +/- 0.2 min-1). This gives the following net reaction stoichiometry for TPQ biogenesis: E-Tyr + 2O2 --> E-TPQ + H2O2. This stoichiometry is in agreement with recently proposed mechanisms for TPQ biogenesis, and rules out several possible alternatives.


The clinical features and surgical outcomes of pediatric patients with primary spinal cord tumor.
Primary spinal cord tumors (PSCTs) in pediatric patients are rare, with a reported overall incidence rate of 1-2.6 per one million children. We reviewed our experience of surgically treated 27 pediatric patients with PSCT and discussed the clinical features, radiological findings, surgical outcomes, and prognostic factors. Between March 1999 and March 2010, a total of 27 pediatric patients with PSCT were surgically treated in a single institution. We retrospectively analyzed their data. There were 13 females and 14 males, and their ages ranged from 6 months to 19 years (mean age, 12.1 years). The most common presenting symptom was motor weakness, and the histologic type of the tumors were mainly schwannoma, astrocytoma, and ependymoma. The tumor was completely resected in 17 patients, subtotally resected in 7 patients, and partial resection or biopsy was performed in 3 patients. Adjuvant chemotherapy was performed in 9 patients, and radiotherapy in 12 patients, respectively. The average follow-up period was 33.5 months (1.17-129). Five patients experienced the progression of disease, and three of them expired. The mean time for disease progression was 19.0 months (4.5-48.7). PSCT in pediatric patients can be surgically removed with an acceptable low surgical morbidity. Progression-free survival was found to be related to the grade of tumor and the extent of tumor resection. Early diagnosis and treatment anticipate good functional neurologic outcome.


An overview of the types of physicians treating acute cardiac conditions in Canada.
As the issue of physician supply and distribution increases in intensity in Canada, the scope of practice of different types of physicians becomes increasingly important. To determine the type of physician treating hospitalized patients with acute cardiac conditions in the provinces and health regions in Canada. Data from the Canadian Institute for Health Information Discharge Abstract Database for all available provinces and the Maintenance et Exploitation des Données pour l'Etude de la Clientèle Hospitalière for Quebec were used to determine the most responsible physician treating patients hospitalized for congestive heart failure and acute myocardial infarction from fiscal years 1997/1998 to 1999/2000. For patients whose most responsible physician was a general practitioner/family doctor, the proportion receiving a consult from a specialist (cardiologist or general internist) was calculated. The type of physician most responsible for treating the acute cardiac conditions with respect to age, sex and urban versus rural hospital was also examined. For approximately 50% of patients in Canada, and in 84% (99 of 118) of the health regions across Canada for which data were available, a general practitioner/family physician was the most responsible physician for patients admitted with congestive heart failure. On a national average, a specialist was the most responsible physician for treating acute myocardial infarction for 65% of patients and in 50% (57 of 115) of the health regions for which data were available. Younger patients, men and people living in urban areas were more likely to be cared for by specialists for both congestive heart failure (age, P<0.0001; sex, P<0.0001; area of admission, P<0.0001) and acute myocardial infarction (age, P<0.0001; sex, P<0.0001; area of admission, P<0.0001). The results of this study show that general practitioners/family physicians take a leading role in the treatment of hospitalized congestive heart failure patients, whereas cardiologists or internists are more often responsible for treating acute myocardial infarction in Canada. This distribution has important implications for cardiac educational strategies and may aid in the determination of health human resource policies.


Phase I/II study of escalating doses of vinorelbine in combination with oxaliplatin in patients with advanced non-small-cell lung cancer.
Oxaliplatin is a platinum compound active in non-small-cell lung cancer (NSCLC) patients, and vinorelbine (VNB) is an active reference agent. This phase I/II study was performed to determine the dose-limiting toxicity (DLT), the maximum-tolerated dose (MTD), and the recommended dose (RD) of a VNB/oxaliplatin combination given to previously untreated patients with advanced NSCLC. Oxaliplatin was given at the fixed dose of 130 mg/m2 (2-hour intravenous [IV] infusion) on day 1. VNB was administered on days 1 and 8 (10-minute IV infusion), with doses starting at 22 mg/m2/d and escalated by 2 mg/m2 increments until MTD. Treatment was repeated every 3 weeks. No special hydration measures or prophylactic granulocyte colony-stimulating factors were used. Twenty-seven patients (20 men, 7 women) received 110 cycles total at six different VNB dose levels. Neutropenia was the DLT. Although no patient experienced DLT at the highest dose level (32 mg/m2/d), multiple treatment delays (54% of cycles) and dose reductions (34% of cycles) were required at this dose level. Others toxicities were mainly limited to grade 1 peripheral neuropathy and grade 1/2 nausea/vomiting. The relative dose-intensity of administered VNB from dose levels 3 to 6 (26 to 32 mg/m2) remained stable, whereas grade 3/4 neutropenia increased. All patients were assessable for activity; there were 10 objective responses, including one complete response (37% response rate). The present combination can be safely administered in an outpatient setting. The RD is VNB 26 mg/m2 days 1 and 8 with oxaliplatin 130 mg/m2 day 1 every 3 weeks.


Purification and characterization of a novel extracellular neutral metalloprotease from Cerrena albocinnamomea.
We selected a fungus secreting a neutral protease from soil and identified it as the basidiomycete fungus Cerrena albocinnamomea according to its ITS-5.8S rDNA and 28S rDNA-D1/D2 sequences. A major extracellular protease isolated from C. albocinnamomea was purified approximately 44-fold through two purification steps. SDS-PAGE analyses of the purified protease revealed a single band, and its molecular mass of 39,756 Da was determined using MALDI-TOF-MS. The enzyme was optimally active at approximately pH 7.0 and 45°C. The Km and Vmax values for the hydrolysis of azocasein were 2.46 mg/mL and 989 units/min/mg protein, respectively. The enzyme was stable at pH 3.6-8.6 for 16 h and at temperatures ≤35°C for 1 h. Enzymatic activity was completely inhibited by Cu2+ and Zn2+ and markedly by EDTA and phosphoramidon. The N-terminal amino acid sequence ASYRVLPIT is highly similar to those of the members of the metalloprotease family M36, such as keratinase and elastinase. However, the protease did not detectably hydrolyze keratin or elastin. In contrast, the protease hydrolyzed fibrinogen, although there were no significant sequence similarities to the N-terminal amino acid sequences of other fibrinolytic enzymes. These results suggest that the purified protease represents a new neutral metalloprotease with fibrinogenolytic activity.


Anethum graveloens flower extracts inhibited a lipopolysaccharide-induced inflammatory response by blocking iNOS expression and NF-κB activity in macrophages.
Inflammation is a system used by a host to defend against the presence of bacteria, viruses, or yeasts. Toll-like receptors (TLRs) in the plasma membranes of macrophages are activated when they recognize the molecular structure of a virus or bacterium. Lipopolysaccharide (LPS), an outer cell-wall component of Gram-negative bacteria, initiates an inflammatory process via TLR4. We investigated the effect of the extract of Anethum graveloens flowers (AGFs) on LPS-mediated inflammation in RAW 264.7 cells. The extract markedly suppressed nitric oxide generation in a concentration-dependent manner in LPS-stimulated RAW 264.7 cells. It inhibited inducible nitric oxide synthase (iNOS) and the mRNA expression of cytokines such as interleukin-1 beta and interleukin-6 in LPS-stimulated RAW 264.7 cells. It also inhibited iNOS protein levels in LPS-stimulated RAW 264.7 cells. In addition, AGF decreased the LPS-induced phosphorylation of mitogen-activated protein kinases in LPS-stimulated RAW 264.7 cells. AGF inhibited the phosphorylation of Akt, an upstream molecule of the nuclear factor kappa B (NF-κB) pathway, and thus inhibited NF-κB activity in LPS-stimulated RAW 264.7 cells. These results suggest that AGF exerts an anti-inflammatory effect in LPS-stimulated RAW 264.7 cells by inhibiting iNOS expression and blocking the NF-κB pathway.


Production of platelet thromboxane A2 inactivates purified human platelet thromboxane synthase.
Human platelet thromboxane synthase was partially purified by DEAE-cellulose, Affi-Gel Blue, and Sephacryl S-300 chromatography to a specific activity of 259 nmol of thromboxane B2/min per mg. Thromboxane synthase retained 75-90% of its enzymic activity when bound to phenyl-Sepharose. The immobilized enzyme was inactivated at pH 3.0 and inhibited by 1-benzylimidazole and U-63,557A. The ability of the enzyme to produce thromboxane A2 from prostaglandin H2 was dramatically reduced by multiple additions of prostaglandin H2. Our data suggest that the production of thromboxane A2 by the enzyme is self-limiting and that the enzyme is inactivated during the reaction.


Olanzapine in the treatment of low body weight and obsessive thinking in women with anorexia nervosa: a randomized, double-blind, placebo-controlled trial.
Anorexia nervosa is associated with high mortality, morbidity, and treatment costs. Olanzapine, an atypical antipsychotic, is known to result in weight gain in other patient populations. The objective of this trial was to assess the efficacy of olanzapine in promoting weight gain and in reducing obsessive symptoms among adult women with anorexia nervosa. The study was a double-blind, placebo-controlled, 10-week flexible dose trial in which patients with anorexia nervosa (N=34) were randomly assigned to either olanzapine plus day hospital treatment or placebo plus day hospital treatment. Compared with placebo, olanzapine resulted in a greater rate of increase in weight, earlier achievement of target body mass index, and a greater rate of decrease in obsessive symptoms. No differences in adverse effects were observed between the two treatment conditions. These preliminary results suggest that olanzapine may be safely used in achieving more rapid weight gain and improvement in obsessive symptoms among women with anorexia nervosa. Replication, in the form of a large multicenter trial, is recommended.


Monochromatic aberrations as a function of age, from childhood to advanced age.
To describe monochromatic optical aberrations of the eye as a function of age. One hundred fourteen subjects with a spherical equivalent within +/-3.50 D from emmetropia, corrected visual acuity of 20/40 or better, and normal findings in an ophthalmic examination were enrolled. The mean age was 43.2 +/- 24.5 years (range, 5.7-82.3). Monochromatic optical aberrations were measured with a Hartmann-Shack wavefront sensor after pharmacological dilation and cycloplegia. For a 5-mm pupil and for third- to seventh-, third-, fourth-, and fifth- to seventh-order aberrations, as well as for coma and spherical aberrations, the root mean square (RMS) error as a function of age was modeled by a second-order polynomial regression. It decreased progressively through childhood, adolescence, and early adulthood; reached a minimum level during the fourth decade of life, then increased progressively with age, to age 82. For a 5-mm pupil, the mean modulation transfer function (MTF) was reduced in both the child-teenage (5-20 years; n = 29) and the elderly (61-82 years; n = 37) groups versus the middle-aged adult group (41-60 years; n = 24; P < 0.05). In young adults (21-40 years; n = 23) and elderly subjects, the MTF curves were very close and almost superimposed at spatial frequencies higher than 38 cyc/deg. Aberrations of the whole eye were objectively measured from early childhood to an advanced age, and the relationship between monochromatic aberrations and age has been shown to fit a quadratic model. The results suggest that the definition of emmetropization should be broadened to include the reduction of higher order aberrations.


Red light activates the sigmaB-mediated general stress response of Bacillus subtilis via the energy branch of the upstream signaling cascade.
The sigma(B)-dependent general stress response in the common soil bacterium Bacillus subtilis can be elicited by a range of stress factors, such as starvation or an ethanol, salt, or heat shock, via a complex upstream signaling cascade. Additionally, sigma(B) can be activated by blue light via the phototropin homologue YtvA, a component of the environmental branch of the signaling cascade. Here we use a reporter-gene fusion to show that sigma(B) can also be activated by red light via the energy branch of its upstream signaling cascade. Deletion mutagenesis and homologous overproduction experiments indicate that the RsbP protein (composed of an N-terminal Per-ARNT-Sim [PAS] domain and a C-terminal PP2C-type phosphatase domain) is involved in the red light response. This second light input pathway functions complementarily to YtvA; it shows broader spectral sensitivity but requires higher light intensities. These results are confirmed by transcriptome analyses, which show that both light effects result in upregulation of the sigma(B) regulon, with minimal activation of other responses.


Splenic Infarction in Plasmodium vivax Infection in South Korea.
Splenic infarction caused by malaria can be fatal, but its incidence and clinical presentation are not well-known. Thus, we investigated the prevalence and characteristics of splenic complications in patients with vivax malaria from 2005 to 2017 in a university hospital. Among 273 patients who were diagnosed with Plasmodium vivax infection by blood smear, 92 underwent abdominal computed tomography or ultrasonography. Twelve patients had splenic infarction. All patients with splenic infarction recovered after treatment with antimalarial drugs, without surgery and intervention. Although anemia and prolonged fever may be risk factors for splenic infarction, the incidence of these events was insufficient for a detailed analysis.


[DNA content of the mitochondria of the developing rat brain].
Studies have been made on the content of DNA in the mitochondria from the brain of 1, 5, 10, 15, 21, 60, and 400 days old rats. Isolated DNA preparations contained 7% of RNA and 3% of proteins. It was shown that the amount of DNA in 21- and 60-day rats is 4 times higher that than in newborn ones. DNA content of the mitochondria increases during the first 3 weeks of postnatal life of rats.


Shoe microclimate: An objective characterisation and subjective evaluation.
Shoe microclimate (temperature and humidity) has been suggested to contribute to perceptions of foot thermal comfort. However, limited data is available for perceptual responses in relation to shoe microclimate development both over time and within different areas of the shoe. This study evaluates perceptions of foot thermal comfort for two running shoes different in terms of air permeability in relation to temporal and spatial characteristics of shoe microclimate. The temporal characteristics of shoe microclimate development were similar for both shoes assessed. However, higher temperatures and humidity were observed for the less permeable shoe. Changes to shoe microclimate over time and differences between shoes were perceivable by the users. This study provides the most detailed assessment of shoe microclimate in relation to foot thermal comfort to date, providing relevant information for footwear design and evaluation.


Association between folate levels and CpG Island hypermethylation in normal colorectal mucosa.
Gene-specific promoter methylation of several genes occurs in aging normal tissues and may predispose to tumorigenesis. In the present study, we investigate the association of blood folate levels and dietary and lifestyle factors with CpG island (CGI) methylation in normal colorectal mucosa. Subjects were enrolled in a multicenter chemoprevention trial of aspirin or folic acid for the prevention of large bowel adenomas. We collected 1,000 biopsy specimens from 389 patients, 501 samples from the right colon and 499 from the rectum at the follow-up colonoscopy. We measured DNA methylation of estrogen receptor alpha (ERα) and secreted frizzled related protein-1 (SFRP1), using bisulfite pyrosequencing. We used generalized estimating equations regression analysis to examine the association between methylation and selected variables. For both ERα and SFRP1, percentage methylation was significantly higher in the rectum than in the right colon (P = 0.001). For each 10 years of age, we observed a 1.7% increase in methylation level for ERα and a 2.9% increase for SFRP1 (P < 0.0001). African Americans had a significantly lower level of ERα and SFRP1 methylation than Caucasians and Hispanics. Higher RBC folate levels were associated with higher levels of both ERα (P = 0.03) and SFRP1 methylation (P = 0.01). Our results suggest that CGI methylation in normal colorectal mucosa is related to advancing age, race, rectal location, and RBC folate levels. These data have important implications regarding the safety of supplementary folate administration in healthy adults, given the hypothesis that methylation in normal mucosa may predispose to colorectal neoplasia.


Current recommendations and importance of antifungal stewardship for the management of invasive candidiasis.
Invasive candidiasis can have a major effect on patient prognosis and medical economics. Quickly eliminating the focus of the infection and administering appropriate antifungal therapy are important. Clinical guidelines for invasive candidiasis have been issued in the USA, Europe and recently in Japan. The purpose of this review is to summarize the current recommendations on how to diagnose and treat invasive candidiasis based on the evidence gathered to date and by referencing guidelines from various countries. Echinocandin antifungals play a central role in the prevention and treatment of invasive candidiasis although a recent increase in echinocandin-resistant Candida glabrata is seen as problematic. In the future, promoting the appropriate use of antifungal agents by antifungal stewardship teams will be necessary to suppress adverse effects, appearance of resistant strains and unnecessary medical expenses, as well as improve positive clinical outcomes and prognoses.


Safety and efficacy of thrombectomy in patients undergoing primary percutaneous coronary intervention for acute ST elevation MI: a meta-analysis of randomized controlled trials.
Clinical trials comparing thrombectomy devices with conventional percutaneous coronary interventions (PCI) in patients with acute ST elevation myocardial infarction (STEMI) have produced conflicting results. The objective of our study was to systematically evaluate currently available data comparing thrombectomy followed by PCI with conventional PCI alone in patients with acute STEMI. Seventeen randomized trials (n = 3,909 patients) of thrombectomy versus PCI were included in this meta-analysis. We calculated the summary odds ratios for mortality, stroke, post procedural myocardial blush grade (MBG), thrombolysis in myocardial infarction (TIMI) grade flow, and post procedural ST segment resolution (STR) using random-effects and fixed-effects models. There was no difference in risk of 30-day mortality (44/1914 vs. 50/1907, OR 0.84, 95% CI 0.54-1.29, P = 0.42) among patients randomized to thrombectomy, compared with conventional PCI. Thrombectomy was associated with a significantly greater likelihood of TIMI 3 flow (1616/1826 vs. 1533/1806, OR 1.41, P = 0.007), MBG 3 (730/1526 vs. 486/1513, OR 2.42, P < 0.001), STR (923/1500 vs. 715/1494, OR 2.30, P < 0.001), and with a higher risk of stroke (14/1403 vs. 3/1413, OR 2.88, 95% CI 1.06-7.85, P = 0.04). Outcomes differed significantly between different device classes with a trend towards lower mortality with manual aspiration thrombectomy (MAT) (21/949 vs.36/953, OR 0.59, 95% CI 0.35-1.01, P = 0.05), whereas mechanical devices showed a trend towards higher mortality (20/416 vs.10/418, OR 2.07, 95% CI 0.95-4.48, P = 0.07). Thrombectomy devices appear to improve markers of myocardial perfusion in patients undergoing primary PCI, with no difference in overall 30-day mortality but an increased likelihood of stroke. The clinical benefits of thrombectomy appear to be influenced by the device type with a trend towards survival benefit with MAT and worsening outcome with mechanical devices.


Reverse transformation of Modic type 2 changes to Modic type 1 changes during sustained chronic low-back pain severity. Report of two cases and review of the literature.
Modic Type 2 (MT2) neuroimaging changes are considered stable or invariant over time and relatively quiescent, whereas Modic Type 1 (MT1) changes are considered unstable and more symptomatic. The authors report two cases in which MT2 changes were symptomatic and evidently unstable, and in which chronic low-back pain severity remained unaltered despite a MT2-MT1 reverse transformation. Two women (41 and 48 years old) both presented with chronic low-back pain. Magnetic resonance (MR) images demonstrated degenerating discs at L5-S1 associated with well-established MT2 changes in adjacent vertebrae. Repeated MR imaging in these two patients after 11 months and 7 years, respectively, revealed reverse transformation of the MT2 changes into more florid MT1 changes, despite unaltered chronic low-back pain severity. Following anterior discectomy and disc arthroplasty, immediate abolition of chronic low-back pain was achieved in both patients and sustained at 3-year follow up. Modic Type 2 changes are therefore neither as stable nor as quiescent as originally believed. Each type can change, with equal symptom-generating capacity. More representative imaging-pathological correlates are required to determine the precise nature of MT changes.


Irrational Beliefs, Dietary Habits and 10-Year Incidence of Type 2 Diabetes; the ATTICA Epidemiological Study (2002-2012).
OBJECTIVE: The aim of this study was to evaluate the dietary habits and irrational beliefs of apparently healthy individuals in relation to their 10-year diabetes incidence. METHODS: The ATTICA study (2002-2012) is a prospective populationbased cohort study, in which 853 participants (453 men (aged 45 ± 13 years) and 400 women (aged 44 ± 18 years)) without a history of cardiovascular disease (CVD) underwent psychological evaluations. Among other things, participants completed the Irrational Beliefs Inventory (IBI, range 0-88), a brief, self-reported measure consistent with the Ellis model of psychological disturbance. Demographic characteristics, detailed medical history, and dietary and other lifestyle habits were evaluated as well. Diagnosis of diabetes at follow-up examination was based on the criteria of the American Diabetes Association. RESULTS: Mean IBI score was 53 ± 10 in men and 51± 11 in women (p = 0.68). IBI was positively associated with the 10-year type 2 diabetes incidence (hazard ratio: 1.14; 95% CI: 1.04-1.25) in both men and women, and even more distinctly associated with participants with the following characteristics: lower education status, married, overweight, smokers, anxiety and depressive symptomatology, and unhealthy dietary habits. Especially, participants with increased irrational beliefs and low adherence to the Mediterranean diet were 37% more likely to develop type 2 diabetes than those with the reverse status (hazard ratio: 3.70; 95% CI: 2.32-5.88). CONCLUSIONS: These data support the need for lifestyle changes towards healthier nutrition which can be achieved by educating people so that they are equipped to recognize false and unhelpful thoughts and thus to prevent negative psychological and clinical outcomes such as mental health disorders and type 2 diabetes.


An MRI study of superior temporal gyrus volume in women with schizotypal personality disorder.
An abnormal superior temporal gyrus has figured prominently in schizophrenia research, and left superior temporal gyrus volume has been shown to be smaller in male subjects with schizotypal personality disorder. This is the first structural magnetic resonance imaging study to examine a group of female subjects with schizotypal personality disorder. The superior temporal gyrus was drawn on coronal images acquired from female subjects recruited from the community (schizotypal personality disorder group: N=21, comparison group: N=29). There were no gray matter volume differences in the left or right superior temporal gyrus between the subjects with schizotypal personality disorder and the comparison subjects. Within the schizotypal personality disorder group, however, there was an interaction between hemisphere and family history of mental illness. Moreover, subjects with schizotypal personality disorder did demonstrate formal thought disorder and a negative correlation between left superior temporal gyrus volume and odd speech. This study of female subjects with schizotypal personality disorder showed no superior temporal gyrus volume differences, but preliminary findings indicate that among female subjects with schizotypal personality disorder, there is a left-right difference in those who have a family history of mental illness relative to those who do not. These data also suggest an association between abnormal speech and left superior temporal gyrus volume, a finding similar to that found in schizophrenia. Results from this study thus clearly reinforce the importance of studying female subjects separately.


Role of adenosine 5'-triphosphate hydrolysis in the assembly of the bacteriophage T4 DNA replication holoenzyme complex.
Steady-state and pre-steady-state rates of ATP hydrolysis by the 44/62 accessory protein were determined to elucidate the role of ATP hydrolysis in bacteriophage T4 holoenzyme complex formation. Steady-state ATPase measurements of the 44/62 protein under various combinations of 45 protein, DNA substrate, and T4 exo- polymerase indicate that although the 44/62 protein synergistically hydrolyzes ATP in the presence of 45 protein and DNA substrate, the ATPase activity of 44/62 is diminished substantially upon the formation of the holoenzyme complex. The decrease in activity is primarily in kcat while the K(m) for ATP is changed unsubstantially by the various combinations. Data suggest that the decrease in the rate of ATP hydrolysis upon the addition of T4 exo- polymerase in the presence of 45 protein and DNA substrate is due to formation of a stable holoenzyme complex consisting of only the 45 protein and T4 exo- polymerase in a 1:1 ratio. The 44/62 protein acts catalytically to load 45 protein onto the DNA substrate and does not remain a component of the holoenzyme complex. Pre-steady-state kinetic analysis of the ATP hydrolysis reaction catalyzed by the 44/62 protein loading the 45 protein onto the DNA substrate in the absence or presence of polymerase is biphasic, in which a burst in ATP hydrolysis precedes the steady-state rate of ATP hydrolysis. An identical burst in ATP consumption is obtained under either condition, indicating that ATP hydrolysis is not required to load polymerase into the holoenzyme complex. The data suggest one turnover of ATP at each of the four ATPase active sites of the 44/62 protein per 45 protein loaded. ATP hydrolysis by the 44/62 protein under conditions of holoenzyme complex formation is the rate-limiting step in holoenzyme complex formation. The process of holoenzyme formation appears to be identical for leading and lagging strand synthesis.


[Epidemiologic surveillance of hospital infection. Preliminary analysis of a 5-year series].
The epidemiological surveillance provides opportunities to know the magnitude and determinants of nosocomial infection and permits, at the same time, the planning, implementation and evaluation of prevention and treatment activities in order to approach the rates of infection in the hospital, as near as possible, to the irreducible minimum. We show data collected by surveillance system Guadalajara General Hospital from 1982 to 1987. In order to analyze general trends, seasonality, accidental variations and endemic levels, we have used statistical methods as linear regression, chi 2, equality proportions and built of an endemic channel with confidence intervals of 95%. We have observed a decreasing trend, locating endemic levels around to 4% of monthly accumulated incidence. There is a possible seasonal influence concurring with holidays periods and someone accidental variation over that we expected, it was related with a deteriorated situation about medical care.


Construction and validation of the Rhodobacter sphaeroides 2.4.1 DNA microarray: transcriptome flexibility at diverse growth modes.
A high-density oligonucleotide DNA microarray, a genechip, representing the 4.6-Mb genome of the facultative phototrophic proteobacterium, Rhodobacter sphaeroides 2.4.1, was custom-designed and manufactured by Affymetrix, Santa Clara, Calif. The genechip contains probe sets for 4,292 open reading frames (ORFs), 47 rRNA and tRNA genes, and 394 intergenic regions. The probe set sequences were derived from the genome annotation generated by Oak Ridge National Laboratory after extensive revision, which was based primarily upon codon usage characteristic of this GC-rich bacterium. As a result of the revision, numerous missing ORFs were uncovered, nonexistent ORFs were deleted, and misidentified start codons were corrected. To evaluate R. sphaeroides transcriptome flexibility, expression profiles for three diverse growth modes--aerobic respiration, anaerobic respiration in the dark, and anaerobic photosynthesis--were generated. Expression levels of one-fifth to one-third of the R. sphaeroides ORFs were significantly different in cells under any two growth modes. Pathways involved in energy generation and redox balance maintenance under three growth modes were reconstructed. Expression patterns of genes involved in these pathways mirrored known functional changes, suggesting that massive changes in gene expression are the major means used by R. sphaeroides in adaptation to diverse conditions. Differential expression was observed for genes encoding putative new participants in these pathways (additional photosystem genes, duplicate NADH dehydrogenase, ATP synthases), whose functionality has yet to be investigated. The DNA microarray data correlated well with data derived from quantitative reverse transcription-PCR, as well as with data from the literature, thus validating the R. sphaeroides genechip as a powerful and reliable tool for studying unprecedented metabolic versatility of this bacterium.


Alcoholism amongst geriatric patients attending general practice clinic of a Teaching Hospital in Benin City, Nigeria.
Alcoholism or alcohol use disorder (AUD) is common among the elderly, though under-recognised and underreported. This under-reporting is especially so in Africa, including Nigeria where there is near absence of study on the subject matter. This study aims to determine the prevalence of alcoholism amongst geriatric patients at the general practice clinic (GPC) of a teaching hospital and to assess some associated socio-demographic factors. The study was cross-sectional and descriptive, conducted at the GPC of the University of Benin Teaching Hospital, Benin City, Nigeria. Four hundred and twenty-two geriatric outpatients completed the geriatric version of the Short Michigan Alcoholism Screening Test and a socio-demographic data collection sheet. Cross-tabulation of categorical variables was performed by means of IBM SPSS statistics for windows version 19.0, with the level of significance set at P <0.05. The prevalence of AUD was 10.2%; the prevalence amongst males and females was 18.1% and 5.3%, respectively. AUD was present in 14.4%, 6.84% and 4.55% of those who had marital conflict, chronic pain and difficulty with walking, respectively. Sex, age group, financial difficulty, chronic pain and difficulty with walking were significantly associated with AUD. The prevalence of AUD amongst geriatric patients is relatively high. The deleterious effects of alcoholism may be worse in the elderly due to changes that occur with aging and their likelihood to be on medications that may interact adversely with alcohol.


Comparison of flunixin meglumine and meloxicam influence on postoperative and oxidative stress in ovariohysterectomized bitches.
The aim of this study was to compare the effect of flunixin meglumine (FM) and meloxicam (M) on postoperative and oxidative stress in ovariohysterectomized bitches. Twenty four bitches were divided into three groups (n = 8 in each) and treated during premedication as follows: FM (2.2 mg/kg, iv, Fluvil, Vilsan, Turkey), M (0.2 mg/kg, sc, Maxicam, Sanovel, Turkey) or 0.9% saline (1 ml, iv, IE, Turkey)--control (C) group. The concentrations of serum cortisol, nitric oxide (NO), malondialdehyde (MDA), antioxidant potential (AOP) and glutation (GSH) were measured in blood samples collected during incision (0 h), closure of incision line (0.5 h) and 1, 2.5, 12 and 24 hours after incision. It was observed that cortisol level was higher at 0.5, 1 and 2.5 h in group C (p < 0.05), 0.5 h in group FM (p < 0.001), and 1 and 2.5 h in group M (p < 0.01), as compared to that determine at 0 h. Group C showed higher cortisol level during 0.5 h (p < 0.05) than that found in the other groups. Group FM displayed lower levels during 1 h (p < 0.01) and 2.5 h (p < 0.05) as compared to those observed in other groups. Concentrations of MDA, AOP and GSH between all the groups did not show any significant differences. MDA level was higher at 0.5 and 1 h in group M (p < 0.05) than that found in group C and it was the lowest at 2.5 h in group C (p < 0.05). AOP was higher at 2.5 h in group FM and M (p < 0.05) than that observed in group C, and at 12 and 24 h in group M than that found in group C and FM. GSH did not show any significant differences between the groups. NO level in group FM after 12 h was higher (p < 0.05) than that at 0.5, 1 and 24 h. Moreover, NO level was lower at 0.5 (p < 0.01), 1 (p < 0.05) and 24 h (p < 0.05) in group FM than that observed in group C and M. In conclusion, flunixin meglumine decreases cortisol and NO levels more efficiently than meloxicam. Therefore, it is suggested that postoperative stress following ovariohysterectomy may be prevented by flunixin meglumine in bitches.


Detection of Entamoeba histolytica DNA from liver abscess aspirate using polymerase chain reaction (PCR): a diagnostic tool for amoebic liver abscess.
Amoebic liver abscess is common in Bangladesh. It is usually diagnosed by suggestive clinical features, ultrasound findings and positive serology. However, none of these are definitive and the picture overlaps with pyogenic liver abscess. It is critical to differentiate amoebic liver abscess from pyogenic liver abscess as the treatment are different. This study was designed to evaluate the feasibility of using polymerase chain reaction (PCR) for detection of Entamoeba histolytica (E.histolytica) DNA in liver abscess pus for confirmatory diagnosis of amoebic liver abscess. This study was carried out in the department of Hepatology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. Thirty patients of amoebic liver abscess were included in this study. PCR was done to detect E.histolytica DNA in liver abscess aspirate of all patients by real time PCR method, using oligonucleotide primer containing small-subunit rRNA gene of E.histolytica. Real time PCR detected E.histolytica in liver abscess aspirate in 29 cases out of 30 cases and the sensitivity was 97% (p<0.001). This study also showed that antigen detection by ELISA in liver abscess aspirate was positive in 12 cases only and sensitivity was 40%. The study indicates that detection of E.histolytica by PCR is more sensitive than amoebic antigen detection and PCR assay can be successfully used to confirm the diagnosis of amoebic liver abscess.


Clinical features and molecular epidemiology of diarrheagenic Escherichia coli pathotypes identified by fecal gastrointestinal multiplex nucleic acid amplification in patients with cancer and diarrhea.
Diarrheagenic Escherichia coli (DEC) pathotypes with differing epidemiology and clinical features, are known causes of disease with worldwide occurrence. At a major cancer center in the U.S., we studied patients with cancer and diarrhea for whom a GI Biofire FilmArray multiplex GI panel (BFM) was performed. An enteropathogen was identified in 382 of 2017 (19%) samples distributed across 311 patients. Of these, 60/311(19%) were positive for DEC. Patients receiving hematopoietic stem cell transplants (HSCT) 29/60 (48%) or with a hematologic malignancy 17/60 (28%) accounted for the majority of DEC cases. Enteropathogenic E. coli (EPEC, n=35 [58%]), enteroaggregative E. coli (EAEC, n=10 [17%]) and Shiga toxin producing E. coli (STEC, n=3 [5%]) were the most common DEC identified and peaked in the summer months. Stool cultures confirmed infections in 6/10 (60%) EAEC (five typical AggR+), and EPEC was recovered in 8/35 (22%) samples (all atypical eaeA+, bfp-). DEC was identified in 22 cases (37%) that developed diarrhea >48hours after admission suggesting health care acquisition. Chronic infections were found in 2 EPEC and 1 EAEC cases that were tested at 1month or beyond with shedding that ranged from 58 to >125days. Two patients that underwent hematopoietic stem cell transplantation carried EAEC strains resistant to multiple antibiotics including fluoroquinolones and expressed extended spectrum beta lactamases. While in some instances BFM results were not verified in culture and could represent false positives, DEC pathotypes, especially EPEC and EAEC, caused chronic infections with antimicrobial-resistant strains in a subset of immunosuppressed cancer patients.


External photon radiation treatment for prostate cancer: Uncomplicated and cancer-free control probability assessment of 36 plans.
To perform a systematic and thorough assessment, using the Uncomplicated and Cancer-Free Control Probability (UCFCP) function, of a broad range of photon prostate cancer RT treatments, on the same scenario (a unique pelvic CT set). UCFCP considers, together with the probabilities of local tumour control (TCP) and deterministic (late) sequelae (NTCP), the second primary cancer risk (SPCR) due to photon and neutron peripheral doses. Thirty-six radiotherapy plans were produced for the same CT. 6, 10, 15 and 18 MV 3DCRT, IMRT and VMAT (77.4 Gy in 43 fractions) and 6 and 10 MV SBRT (36.25 Gy in 5 fractions with flattened and FFF beams) for Elekta, Siemens and Varian Linacs plans were included. DVH and peripheral organ dosimetry were used to compute TCP, NTCP, and SPCR (the competition and LNT models) for further plan ranking. Biological models (and parameters) used predicted an outcome which is in agreement with epidemiological findings. SBRT plans showed the lowest SPCR and a below average NTCPrectal. High energy plans did not rank worse than the low energy ones. Intensity modulated plans were ranked above the 3D conformal techniques. According to UCFCP, the best plans were the10 MV SBRTs. SPCR rates were low and did not show a substantial impact on plan ranking. High energy intensity-modulated plans did not increase in excess the average of SPCR. Even more, they ranked among the best, provided that MU were efficiently managed.


Bidirectional Human-Swine Transmission of Seasonal Influenza A(H1N1)pdm09 Virus in Pig Herd, France, 2018.
In 2018, a veterinarian became sick shortly after swabbing sows exhibiting respiratory syndrome on a farm in France. Epidemiologic data and genetic analyses revealed consecutive human-to-swine and swine-to-human influenza A(H1N1)pdm09 virus transmission, which occurred despite some biosecurity measures. Providing pig industry workers the annual influenza vaccine might reduce transmission risk.


TNFR1 promotes tumor necrosis factor-mediated mouse colon epithelial cell survival through RAF activation of NF-kappaB.
Tumor necrosis factor (TNF) is a therapeutic target in the treatment of inflammatory bowel disease; however, the exact role of TNF signaling in the colon epithelium remains unclear. We demonstrate that TNF activation of TNF receptor (R)1 stimulates both pro- and anti-apoptotic signaling pathways in the colon epithelium; however, TNFR1 protects against colon epithelial cell apoptosis following TNF exposure. To investigate anti-apoptotic signaling pathways downstream of TNFR1, we generated an intestinal epithelium-specific Raf knock-out mouse and identified Raf kinase as a key regulator of colon epithelial cell survival in response to TNF. Surprisingly, Raf promotes NF-kappaB p65 phosphorylation, independent of MEK signaling, to support cell survival. Taken together, these data demonstrate a novel pathway in which Raf promotes colon epithelial cell survival through NF-kappaB downstream of TNFR1 activation. Thus, further understanding of colon epithelial cell-specific TNFR signaling may result in the identification of new targets for inflammatory bowel disease treatment and define novel mediators of colitis-associated cancer.


Spectroscopic studies of interaction between biologically synthesized silver nanoparticles and bovine serum albumin.
Binding interaction of biologically synthesized silver nanoparticles with bovine serum albumin (BSA) has been investigated by UV-Vis and fluorescence spectroscopic techniques. UV-Vis analysis implies the formation of the ground state complex between BSA and silver nanoparticles. The analysis of fluorescence spectrum and fluorescence intensity indicates that silver nanoparticles (SNP) have a strong ability to quench the intrinsic fluorescence of BSA by dynamic quenching mechanisms. The number of binding sites 'n' and binding constants 'K' were determined at different temperatures based on fluorescence quenching. The thermodynamic parameters namely deltaH, deltaG, and deltaS were calculated at different temperatures (20, 30, and 40 degrees C) and the results indicate that both hydrophobic and electrostatic interactions were predominantly present in the SNP-BSA complex. Negative deltaG values imply that the binding process is spontaneous.


Accessory cell function in tumor-bearing mice and effects of Corynebacterium parvum.
Primary in vivo production of antibody to sheep red blood cells (SRBC) was consistently suppressed in EL 4 tumor-bearing C57BL/6 mice, but the secondary response was not suppressed. This suppressed primary in vivo production of antibody was partially restored by systemic administration of Corynebacterium parvum. For investigation of the mechanism of the immunosuppression in tumor-bearing mice and the effects of C. parvum, the accessory cell function of adherent cells from tumor-bearing mice and C. parvum-treated tumor-bearing mice in in vitro cultures was studied. Peritoneal and splenic cells from tumor-bearing mice were less efficient in promoting in vitro production of antibody to SRBC by macrophage-depleted normal nonadherent cells than the adherent cells from normal mice. C. parvum treatment restored the accessory cell function of splenic adherent cells from tumor-bearing mice but not that of peritoneal cells. Furthermore, adherent cells from tumor-bearing mice did not show suppressive activity against the in vitro plaque-forming cell response.


Potent analgesic effects of GDNF in neuropathic pain states.
Neuropathic pain arises as a debilitating consequence of nerve injury. The etiology of such pain is poorly understood, and existing treatment is largely ineffective. We demonstrate here that glial cell line-derived neurotrophic factor (GDNF) both prevented and reversed sensory abnormalities that developed in neuropathic pain models, without affecting pain-related behavior in normal animals. GDNF reduces ectopic discharges within sensory neurons after nerve injury. This may arise as a consequence of the reversal by GDNF of the injury-induced plasticity of several sodium channel subunits. Together these findings provide a rational basis for the use of GDNF as a therapeutic treatment for neuropathic pain states.


Blunt pancreatic injury in children: Lessons from 11-year experience in a pediatric center.
To study the diagnosis, management strategies, and outcomes of pediatric patients with blunt pancreatic injury. The clinical data of patients with blunt pancreatic injury at Children's Hospital, Zhejiang University School of Medicine from January 2011 to September 2022 were collected and analyzed retrospectively. A total of 51 patients were enrolled. According to the American Association for the Surgery of Trauma (AAST) classification of pancreatic injury, 41 patients were categorized in the low-grade and nine in the high-grade groups. On admission, serum amylase and lipase levels in the high-grade group were significantly higher than in the low-grade group (P = 0.025 and P = 0.021, respectively). The peak levels of serum amylase and lipase in the high-grade group were considerably higher than in the low-grade group (P = 0.017 and P = 0.038, respectively). Two patients received surgical treatment, but none experienced pancreatectomy. The remaining 49 patients were successfully treated with conservative methods. The incidence of pancreatic pseudocysts in patients was 47.1% (24/51), and half required external drainage. Conservative management is safe for most children with blunt pancreatic injury, surgical intervention should be adopted in patients with hemodynamic instability or multiple organ failure.


Selective tumor localization and improved therapeutic index of anthracyclines encapsulated in long-circulating liposomes.
We have investigated the tissue distribution, toxicity, and antitumor activity of anthracyclines encapsulated in hydrogenated phosphatidylinositol (HPI)-containing liposomes which show a characteristic long circulation time in plasma (J. Natl. Cancer Inst., 81: 1484-1488, 1989). Phosphatidylglycerol (PG)-containing liposomes were used for comparison. Doxorubicin (DOX) or epirubicin (EPI) was encapsulated in the aqueous interior of small (65-100 nm mean diameter) HPI or PG liposomes. The DOX and EPI levels in i.m. tumor implants of the J6456 lymphoma were significantly raised by delivery in HPI liposomes but not by delivery in PG liposomes. No such increase was observed in normal muscle tissue. When DOX encapsulated in HPI liposomes was injected i.v. into BALB/c mice bearing an ascitic form of the J6456 lymphoma, more than 10% of the injected dose was recovered in the ascitic fluid in liposome-associated form. No significant accumulation of liposomal drug was observed in peritoneal washes from tumor-free mice. DOX encapsulation in either PG- or HPI-containing liposomes reduced the lethal toxicity of the drug in mice. However, only the HPI-DOX formulation was significantly more active than free DOX in the treatment of the ascitic J6456 tumor at all dose levels tested. Therapeutic results with EPI encapsulated in HPI liposomes also showed an efficacy superior to that of free EPI. These studies provide evidence that anthracyclines delivered in long-circulating liposomes extravasate with relative selectivity in tumor areas, improving the overall therapeutic index.


Morphological and ecological trait diversity reveal sensitivity of herbivorous fish assemblages to coral reef benthic conditions.
Herbivorous fishes play a critical role in the maintenance of coral reefs through grazing and cropping of various benthic algae types. Herbivorous fish assemblages are sensitive to changes in the reef environment and are often targeted by local fisheries. This can lead to a decline in ecosystem functions if key groups are reduced. The present study investigates the morphological and ecological trait diversity of herbivorous reef fish assemblages in habitats differing in relative benthic coverage: i) coral-dominated, ii) algae-dominated, and iii) an intermediate habitat. Trait diversity for conspicuous herbivorous fishes was measured using three trait diversity indices: trait richness, trait divergence, and trait evenness. These indices were derived from in situ community surveys and feeding observations, morphological assessment of feeding mechanics from locally collected specimens, and ecological information obtained from published data. Trait diversity, reflected in higher trait evenness and lower trait richness, was lower within algae-dominated habitats than coral-dominated habitats, suggesting that algae-dominated habitats may be compromised by the lack of essential functions provided by key species. These groups reduce algal biomass and may help facilitate the survival and growth of corals, which in turn can increase coral cover. Algae-habitats were dominated with species known to consume macroalgae (rabbitfish and surgeonfish), appearing to provide essential feeding and habitat resources. These species include browsers and croppers that are fundamental in reducing algal biomass and may help facilitate the survival and growth of corals, which in turn can promote reef health. However, this habitat lacked parrotfishes known to remove turf algae and sediments, an essential function for clearing benthic space for coral settlement and other key benthic invertebrates. This study identified several species with overlapping functional roles in the coral-dominated and intermediate habitats. Still, species that were not redundant showed high trait complementarity, suggesting that their removal may result in the loss of unique functions. Importantly, we show that algae-dominated habitats supported high numbers of juvenile fishes especially in species targeted by local artisanal fishers. We also showed that the loss of trait diversity is greater than the loss of species diversity through the comparison of taxonomic and trait β-diversity, further emphasizing the importance of trait diversity analysis in understanding ecosystem health and maintenance.


Response Element Composition Governs Correlations between Binding Site Affinity and Transcription in Glucocorticoid Receptor Feed-forward Loops.
Combinatorial gene regulation through feed-forward loops (FFLs) can bestow specificity and temporal control to client gene expression; however, characteristics of binding sites that mediate these effects are not established. We previously showed that the glucocorticoid receptor (GR) and KLF15 form coherent FFLs that cooperatively induce targets such as the amino acid-metabolizing enzymes AASS and PRODH and incoherent FFLs exemplified by repression of MT2A by KLF15. Here, we demonstrate that GR and KLF15 physically interact and identify low affinity GR binding sites within glucocorticoid response elements (GREs) for PRODH and AASS that contribute to combinatorial regulation with KLF15. We used deep sequencing and electrophoretic mobility shift assays to derive in vitro GR binding affinities across sequence space. We applied these data to show that AASS GRE activity correlated (r(2) = 0.73) with predicted GR binding affinities across a 50-fold affinity range in transfection assays; however, the slope of the linear relationship more than doubled when KLF15 was expressed. Whereas activity of the MT2A GRE was even more strongly (r(2) = 0.89) correlated with GR binding site affinity, the slope of the linear relationship was sharply reduced by KLF15, consistent with incoherent FFL logic. Thus, GRE architecture and co-regulator expression together determine the functional parameters that relate GR binding site affinity to hormone-induced transcriptional responses. Utilization of specific affinity response functions and GR binding sites by FFLs may contribute to the diversity of gene expression patterns within GR-regulated transcriptomes.


Tissue tropism and pathology of natural influenza virus infection in black-headed gulls (Chroicocephalus ridibundus).
Black-headed gulls (Chroicocephalus ridibundus) are a suitable host species to study the epidemiology of low-pathogenic avian influenza virus (LPAIV) infection in wild waterbirds because they are a common colony-breeding species in which LPAIV infection is detected frequently, limited mainly to the H13 and H16 subtypes. However, the sites of virus replication and associated lesions are poorly understood. We therefore performed virological and pathological analyses on tissues of black-headed gulls naturally infected with LPAIV. We found that 24 of 111 black-headed gulls collected from breeding colonies were infected with LPAIV (10 birds with H16N3, one bird with H13N8, 13 birds undetermined), based on virus and viral genome detection in pharyngeal and cloacal swabs. Of these 24 gulls, 15 expressed virus antigen in their tissues. Virus antigen expression was limited to epithelial cells of intestine and cloacal bursa. No histological lesions were detected in association with virus antigen expression. Our findings show that LPAIV replication in the intestinal tract of black-headed gulls is mainly a superficial infection in absence of detectable lesions, as determined recently for natural LPAIV infection in free-living mallards (Anas platyrhynchos). These findings imply that LPAIV in black-headed gulls has adapted to minimal pathogenicity to its host and that potentially the primary transmission route is faecal-oral.


Principles of structure building in music, language and animal song.
Human language, music and a variety of animal vocalizations constitute ways of sonic communication that exhibit remarkable structural complexity. While the complexities of language and possible parallels in animal communication have been discussed intensively, reflections on the complexity of music and animal song, and their comparisons, are underrepresented. In some ways, music and animal songs are more comparable to each other than to language as propositional semantics cannot be used as indicator of communicative success or wellformedness, and notions of grammaticality are less easily defined. This review brings together accounts of the principles of structure building in music and animal song. It relates them to corresponding models in formal language theory, the extended Chomsky hierarchy (CH), and their probabilistic counterparts. We further discuss common misunderstandings and shortcomings concerning the CH and suggest ways to move beyond. We discuss language, music and animal song in the context of their function and motivation and further integrate problems and issues that are less commonly addressed in the context of language, including continuous event spaces, features of sound and timbre, representation of temporality and interactions of multiple parallel feature streams. We discuss these aspects in the light of recent theoretical, cognitive, neuroscientific and modelling research in the domains of music, language and animal song.


Serum and urine galactomannan testing for screening in patients with hematological malignancies.
Testing for serum galactomannan (GM) has been established as an important method for diagnosing invasive aspergillosis (IA); however, limited data exist regarding the application of urine GM testing. The objective of this study was to evaluate the performance of GM screening of urine specimens and to compare results with serum GM. The study was performed between July 2012 and March 2013 in adult patients with underlying hematological malignancies who were hospitalized at the Medical University of Graz, Austria. Serum and urine screening samples were collected and tested twice weekly (always on the same day). In total, 242 serum samples and a similar number of urine samples were collected from 75 patients. A total of 21/242 (8.7%) serum samples from 13 patients were GM positive. Sensitivity, specificity, positive predictive value, and negative predictive value using a 0.1 optical density index cutoff for urine samples (compared with same-day serum results) were as follows: 47.6%, 86%, 24.4%, and 94.5%, respectively. In 8/10 patients with probable IA, at least one positive GM result was found with this cutoff. After calculating clinical performance of the urine GM test, we found that sensitivity increased to 71.4% and specificity to 88.2%. Spearman-Rho correlation analysis revealed a significant positive correlation between serum and urine samples (P < 0.001; ρ = 0.252). In conclusion, GM detection in urine might be a promising method for IA screening. However, further studies are needed.


Nearly One In Five Skilled Nursing Facilities Awarded Positive Incentives Under Value-Based Purchasing.
Medicare's Skilled Nursing Facility Value-Based Purchasing Program, which awards value-based incentive payments based on hospital readmissions, distributed its first two rounds of incentives during fiscal years 2019 and 2020. Incentive payments were based on achievement or improvement scores-whichever was better. Incentive payments were as low as -2.0 percent in both program years and as high as +1.6 percent in FY 2019 and +3.1 percent in FY 2020. In FY 2019, 26 percent of facilities earned positive incentives and 72 percent earned negative incentives, compared with 19 percent positive and 65 percent negative incentives in FY 2020. Larger, rural, and not-for-profit facilities were more likely to earn positive incentives, as were those with the highest registered nurse staffing levels. Although these findings indicate the potential to reward high-quality care at skilled nursing facilities, intended and unintended outcomes of this new value-based purchasing program should be monitored closely for possible program refinements, particularly in light of the disproportionate impacts of coronavirus disease 2019 (COVID-19) on nursing facilities.


[Changes of lung function in sarcoidosis].
This paper reports the changes of lung function in 26 cases of sarcoidosis and the correlation of lung function tests with chest X-ray films. The results showed that in the first stage of sarcoidosis, the chest films were normal: however, there were changes in lung volumes, ventilation and diffusion function. Therefore, the lung function tests and chest films should be done at the same time in order to supplement each other.


Elucidation of a Human Urine Metabolite as a Seryl-Leucine Glycopeptide and as a Biomarker of Effective Anti-Tuberculosis Therapy.
The evaluation of new tuberculosis (TB) therapies is limited by the paucity of biomarkers to monitor treatment response. Previous work detected an uncharacterized urine metabolite with a molecular mass of 874.3547 Da that showed promise as a biomarker for successful TB treatment. Using mass spectrometry combined with enzymatic digestions, the metabolite was structurally characterized as a seryl-leucine core 1 O-glycosylated peptide (SLC1G) of human origin. Examination of SLC1G in urine revealed a significant abundance increase in individuals with active TB versus their household contacts and healthy controls. Moreover, differential decreases in SLC1G levels were observed by week one in TB patients during successful treatment versus those that failed treatment. The SLC1G levels were also associated with clinical parameters used to measure bacterial burden (GeneXpert) and inflammation (positron emission tomography-computed tomography (PET-CT)). These results demonstrate the importance of metabolite identification and provide strong evidence for applying SLC1G as a biomarker of TB treatment response.


Circular RNA-related CeRNA network and prognostic signature for patients with oral squamous cell carcinoma.
Background: Circular RNA (circRNA) has an important influence on oral squamous cell carcinoma (OSCC) progression as competing endogenous RNAs (ceRNAs). However, the link between ceRNAs and the OSCC immune microenvironment is unknown. The research aimed to find circRNAs implicated in OSCC carcinogenesis and progression and build a circRNA-based ceRNA network to create a reliable OSCC risk prediction model. Methods: The expression profiles of circRNA in OSCC tumors and normal tissues were assessed through RNA sequencing. From the TCGA database, clinicopathological data and expression patterns of microRNAs (miRNAs) and mRNAs were obtained. A network of circRNA-miRNA-mRNA ceRNA was prepared according to these differentially expressed RNAs and was analyzed through functional enrichment. Subsequently, based on the mRNA in the ceRNA network, the influence of the model on prognosis was then evaluated using a risk prediction model. Finally, considering survival, tumor-infiltrating immune cells (TICs), clinicopathological features, immunosuppressive molecules, and chemotherapy efficacy were analyzed. Results: Eleven differentially expressed circRNAs were found in cancer tissues relative to healthy tissues. We established a network of circRNA-miRNA-mRNA ceRNA, and the ceRNA network includes 123 mRNAs, six miRNAs, and four circRNAs. By the assessment of Genomes pathway and Kyoto Encyclopedia of Genes, it is found that in the cellular senescence, PI3K-AKT and mTOR signaling pathway mRNAs were mainly enrichment. An immune-related signature was created utilizing seven immune-related genes in the ceRNA network after univariate and multivariate analysis. The receiver operating characteristic of the nomogram exhibited satisfactory accuracy and predictive potential. According to a Kaplan-Meier analysis, the high-risk group's survival rate was signally lower than the group with low-risk. In addition, risk models were linked to clinicopathological characteristics, TICs, immune checkpoints, and antitumor drug susceptibility. Conclusion: The profiles of circRNAs expression of OSCC tissues differ significantly from normal tissues. Our study established a circRNA-associated ceRNA network associated with OSCC and identified essential prognostic genes. Furthermore, our proposed immune-based signature aims to help research OSCC etiology, prognostic marker screening, and immune response evaluation.


Glomerular filtration rate: which method should we measure in daily clinical practice?
In this study, we compared estimated glomerular filtration rate (eGFR) calculated with the formulas of Cockcroft-Gault (C&G), Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Mayo Clinic Quadratic (Mayo Q) and, GFR (mGFR) that was scintigraphically measured with creatinine clearance (CrCl) and technetium-99m diethylene triamine penta-acetic acid (99mTc-DTPA). Objective of this study was to define the correlations between the formulas, provide a reliable method for measurement and estimation of GFR in daily clinical practice and demonstrate the potential errors. C&G, CKD-EPI, Mayo Q and MDRD eGFR of 84(37 males, 47 females) patients diagnosed with chronic kidney disease were calculated. Values of 99mTc-DTPA based on mGFR were compared with eGFR values of the formulas. Significant correlations were found with the values of 99mTc-DTPA mGFR, CrCl, MDRD, CKD-EPI, Mayo Q and C&G eGFR. The highest correlation was found between LBM(lean body mass) corrected C&G, MDRD-6, Mayo Q and CKD-EPI eGFR. The best estimate was made with MDRD-6 in the cases with 99mTc-DTPA mGFR<30 mL/min/1.73 m(2) and with MDRD-4 in the cases with 99mTc-DTPA mGFR≥30 mL/min/1.73 m(2), while the worst estimate was made with uncorrected C&G formula in both groups. All eGFR formulas can be used in daily clinical practice. However, using MDRD-6 in the cases with GFR<30 mL/min/1.73 m(2) and MDRD-4 in the cases with GFR≥30 mL/min/1.73m(2) as well as using LBM for C&G eGFR or correction according to LBM when AW (actual weight) is used, might provide a more accurate estimation.


SAS-4 is recruited to a dynamic structure in newly forming centrioles that is stabilized by the gamma-tubulin-mediated addition of centriolar microtubules.
Centrioles are surrounded by pericentriolar material (PCM), which is proposed to promote new centriole assembly by concentrating gamma-tubulin. Here, we quantitatively monitor new centriole assembly in living Caenorhabditis elegans embryos, focusing on the conserved components SAS-4 and SAS-6. We show that SAS-4 and SAS-6 are coordinately recruited to the site of new centriole assembly and reach their maximum levels during S phase. Centriolar SAS-6 is subsequently reduced by a mechanism intrinsic to the early assembly pathway that does not require progression into mitosis. Centriolar SAS-4 remains in dynamic equilibrium with the cytoplasmic pool until late prophase, when it is stably incorporated in a step that requires gamma-tubulin and microtubule assembly. These results indicate that gamma-tubulin in the PCM stabilizes the nascent daughter centriole by promoting microtubule addition to its outer wall. Such a mechanism may help restrict new centriole assembly to the vicinity of preexisting parent centrioles that recruit PCM.


Evaluation of systemic inflammation in response to remote ischemic preconditioning in patients undergoing transcatheter aortic valve replacement (TAVR).
Systemic inflammation can occur after transcatheter aortic valve replacement (TAVR) and correlates with adverse outcome. The impact of remote ischemic preconditioning (RIPC) on TAVR associated systemic inflammation is unknown and was focus of this study. We performed a prospective controlled trial at a single center and included 66 patients treated with remote ischemic preconditioning (RIPC) prior to TAVR, who were matched to a control group by propensity score. RIPC was applied to the upper extremity using a conventional tourniquet. Definition of systemic inflammation was based on leucocyte count, C-reactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6), assessed in the first 5 days following the TAVR procedure. Mortality was determined within 6 months after TAVR. RIPC group and matched control group showed comparable baseline characteristics. Systemic inflammation occurred in 66% of all patients after TAVR. Overall, survival after 6 months was significantly reduced in patients with systemic inflammation. RIPC, in comparison to control, did not significantly alter the plasma levels of leucocyte count, CRP, PCT or IL-6 within the first 5 days after TAVR. Furthermore, inflammation associated survival after 6 months was not improved by RIPC. Of all peri-interventional variables assessed, only the amount of the applied contrast agent was connected to the occurrence of systemic inflammation. Systemic inflammation frequently occurs after TAVR and leads to increased mortality after 6 months. RIPC neither reduces the incidence of systemic inflammation nor improves inflammation associated patient survival within 6 months.


Evaluation of Six Weekly Oral Fecal Microbiota Transplants in People with HIV.
Reduced microbiota diversity (dysbiosis) in people with HIV (PWH) likely contributes to inflammation, a driver of morbidity and mortality. We aimed to evaluate the safety and tolerability of 6 weekly oral fecal microbiota transplants (FMT) administered to reverse this dysbiosis. Six PWH on suppressive antiretroviral therapy (ART) received 6 weekly doses of lyophilized fecal microbiota product from healthy donors. Shotgun sequencing on stool before, after last FMT, and 20 weeks thereafter was performed. Inflammation and gut permeability biomarkers were measured. Median age at week 0 was 39 years, CD4+ T cell count 496 cells/mm3, HIV RNA levels <20 copies/mL. FMT was safe and well-tolerated. α diversity increased in 4 participants from weeks 0 to 6, including the 3 with the lowest α diversity at week 0. At week 26, α diversity more closely resembled week 0 than week 6 in these 4 participants. Metagenomic analysis showed no consistent changes across all participants. One participant had high gut permeability and inflammation biomarker levels and low α diversity that improved between weeks 0 and 6 with a shift in distribution. Weekly FMT was safe and well-tolerated. α diversity increased in participants with the lowest baseline α diversity during the treatment period. Future randomized, controlled trials of FMT should consider evaluating PWH with greater inflammation, gut damage, or dysbiosis as this population may be most likely to show a significant response.ClinicalTrials.gov Identifier: NCT03329560.


Diffusion Restriction in the Splenium: A Comparative Study of Cytotoxic Lesions of the Corpus Callosum (CLOCCs) versus Lesions of Vascular Etiology.
Cytotoxic lesions of the corpus callosum (CLOCCs) have broad differential diagnoses. Differentiating these lesions from lesions of vascular etiology is of high clinical significance. We compared the clinical and radiological characteristics and outcomes between vascular splenial lesions and CLOCCs in a retrospective cohort study. We examined the clinical and radiologic characteristics and outcomes in 155 patients with diffusion restriction in the splenium of the corpus callosum. Patients with lesions attributed to a vascular etiology (N = 124) were older (64.1 vs. 34.6 years old, p < 0.001) and had >1 vascular risk factor (91.1% vs. 45.2%, p < 0.001), higher LDL and A1c levels, and echocardiographic abnormalities (all p ≤ 0.05). CLOCCs (N = 31) more commonly had midline splenial involvement (p < 0.001) with only splenial diffusion restriction (p < 0.001), whereas vascular etiology lesions were more likely to have multifocal areas of diffusion restriction (p = 0.002). The rate of in-hospital mortality was significantly higher in patients with vascular etiology lesions (p = 0.04). Across vascular etiology lesions, cardio-embolism was the most frequent stroke mechanism (29.8%). Our study shows that corpus callosum diffusion restricted lesions of vascular etiology and CLOCCs are associated with different baseline, clinical, and radiological characteristics and outcomes. Accurately differentiating these lesions is important for appropriate treatment and secondary prevention.


Venous Thromboembolism: Genetics and Thrombophilias.
Venous thromboembolism (VTE) is a major cause of morbidity and mortality throughout the world. Up to one half of patients who present with VTE will have an underlying thrombophilic defect. This knowledge has led to a widespread practice of testing for such defects in patients who develop VTE. However, identifying a hereditary thrombophilia by itself does not necessarily change outcomes or dictate therapy. Furthermore, family history of VTE by itself can increase an asymptomatic person's VTE risk several-fold, independent of detecting a known inherited thrombophilia. In this article, we will describe the current validated hereditary thrombophilias including their history, prevalence, and association with VTE. With a focus on evaluating both risks and benefits of testing, we will also explore the controversies of why, who, and when to test as well as discuss contemporary societal guidelines. Lastly, we will share how these tests have been integrated into clinical practice and how to best utilize them in the future.


Numerical simulation of the free surface and water inflow of a slope, considering the nonlinear flow properties of gravel layers: a case study.
Groundwater is an important factor of slope stability, and 90% of slope failures are related to the influence of groundwater. In the past, free surface calculations and the prediction of water inflow were based on Darcy's law. However, Darcy's law for steady fluid flow is a special case of non-Darcy flow, and many types of non-Darcy flows occur in practical engineering applications. In this paper, based on the experimental results of laboratory water seepage tests, the seepage state of each soil layer in the open-pit slope of the Yanshan Iron Mine, China, were determined, and the seepage parameters were obtained. The seepage behaviour in the silt layer, fine sand layer, silty clay layer and gravelly clay layer followed the traditional Darcy law, while the gravel layers showed clear nonlinear characteristics. The permeability increases exponentially and the non-Darcy coefficient decreases exponentially with an increase in porosity, and the relation among the permeability, the porosity and the non-Darcy coefficient is investigated. A coupled mathematical model is established for two flow fields, on the basis of Darcy flow in the low-permeability layers and Forchheimer flow in the high-permeability layers. In addition, the effect of the seepage in the slope on the transition from Darcy flow to Forchheimer flow was considered. Then, a numerical simulation was conducted by using finite-element software (FELAC 2.2). The results indicate that the free surface calculated by the Darcy-Forchheimer model is in good agreement with the in situ measurements; however, there is an evident deviation of the simulation results from the measured data when the Darcy model is used. Through a parameter sensitivity analysis of the gravel layers, it can be found that the height of the overflow point and the water inflow calculated by the Darcy-Forchheimer model are consistently less than those of the Darcy model, and the discrepancy between these two models increases as the permeability increases. The necessity of adopting the Darcy-Forchheimer model was explained. The Darcy-Forchheimer model would be applicable in slope engineering applications with highly permeable rock.


Differential Resistance of Borrelia burgdorferi Clones to Human Serum-Mediated Killing Does Not Correspond to Their Predicted Invasiveness.
Reservoir host associations have been observed among and within Borrelia genospecies, and host complement-mediated killing is a major determinant in these interactions. In North America, only a subset of Borrelia burgdorferi lineages cause the majority of disseminated infections in humans. We hypothesize that differential resistance to human complement-mediated killing may be a major phenotypic determinant of whether a lineage can establish systemic infection. As a corollary, we hypothesize that borreliacidal action may differ among human subjects. To test these hypotheses, we isolated primary B. burgdorferi clones from field-collected ticks and determined whether the killing effects of human serum differed among those clones in vitro and/or whether these effects were consistent among human sera. Clones associated with human invasiveness did not show higher survival in human serum compared to noninvasive clones. These results indicate that differential complement-mediated killing of B. burgdorferi lineages is not a determinant of invasiveness in humans. Only one significant difference in the survivorship of individual clones incubated in different human sera was detected, suggesting that complement-mediated killing of B. burgdorferi is usually similar among humans. Mechanisms other than differential human complement-mediated killing of B. burgdorferi lineages likely explain why only certain lineages cause the majority of disseminated human infections.


Common changes in cerebral blood flow in patients with social phobia treated with citalopram or cognitive-behavioral therapy.
Neurofunctional changes underlying effective antianxiety treatments are incompletely characterized. This study explored the effects of citalopram and cognitive-behavioral therapy on regional cerebral blood flow (rCBF) in social phobia. By means of positron emission tomography with oxygen 15-labeled water, rCBF was assessed in 18 previously untreated patients with social phobia during an anxiogenic public speaking task. Patients were matched for sex, age, and phobia severity, based on social anxiety questionnaire data, and randomized to citalopram medication, cognitive-behavioral group therapy, or a waiting-list control group. Scans were repeated after 9 weeks of treatment or waiting time. Outcome was assessed by subjective and psychophysiological state anxiety measures and self-report questionnaires. Questions were readministered after 1 year. Symptoms improved significantly and roughly equally with citalopram and cognitive-behavioral therapy, whereas the waiting-list group remained unchanged. Four patients in each treated group and 1 waiting-list patient were classified as responders. Within both treated groups, and in responders regardless of treatment approach, improvement was accompanied by a decreased rCBF-response to public speaking bilaterally in the amygdala, hippocampus, and the periamygdaloid, rhinal, and parahippocampal cortices. Between-group comparisons confirmed that rCBF in these regions decreased significantly more in treated groups than control subjects, and in responders than nonresponders, particularly in the right hemisphere. The degree of amygdalar-limbic attenuation was associated with clinical improvement a year later. Common sites of action for citalopram and cognitive-behavioral treatment of social anxiety were observed in the amygdala, hippocampus, and neighboring cortical areas, ie, brain regions subserving bodily defense reactions to threat.


Glucagon in acute ureteral colic. A randomized trial.
The effect of glucagon administered as a bolus (1 mg) followed by a continuous infusion (2 mg/h) for 8 h and a placebo was compared in 37 adults with urographically demonstrated ureteral calculi less than 6 mm. The bolus injection was given 20 min after start of intravenous urography, and the infusion was initiated immediately afterwards. No effect on pain relief or passage of calculi was found. Nausea and/or vomiting were recorded significantly more frequently in patients who had glucagon than in patients who had the placebo. It is concluded that glucagon is of no value in acute ureteral colic.


Association between Social Frailty and Sleep Quality among Community-dwelling Older Adults: A Cross-sectional Study.
We examined the association between social frailty and subjective sleep quality among community-dwelling adults. This cross-sectional study recruited Japanese adults over the age of 60 years from health check-ups held in a public townhall in a suburban area between 2018 and 2019. Social frailty was evaluated using five criteria (living alone, not visiting friends sometimes, going out less frequently than the last year, not feeling helpful to friends or family, and not talking to someone every day) and categorized into three groups: non-frailty, pre-frailty, and frailty. Sleep quality was assessed according to the Pittsburgh Sleep Quality Index (PSQI) by giving participants a self-reported questionnaire. We performed multivariable linear regression analysis, denoting social frailty as an independent variable, and the global PSQI score as a dependent variable. Data from 300 older adults were analyzed, 51.0% of whom were female. The participants' mean age was 73.0 years (standard deviation = 5.8). Multivariable analysis revealed the notable association between social frailty and a high global PSQI score (compared with non-frailty, frailty: β = 0.94, 95% CI = 0.08 to 1.80, p = 0.033). Of the five determiners of social frailty, not talking with someone every day was especially associated with a high global PSQI score (β = 1.57, 95% CI = 0.49 to 2.66, p = 0.005). The present study suggests that social frailty is associated with poor sleep quality among community-dwelling older adults. Our findings indicate the importance of social frailty on sleep quality among older adults.


Experiences of fatherhood among men who were sexually abused in childhood.
Fatherhood is a complex psychological process, which is shaped at a profound level by reflections on past childhood memories and parenting experienced in childhood. Fathers who were sexually abused in childhood may experience particular challenges for their fathering identity and parenting role. This qualitative study explored the experiences of fatherhood for men who were sexually abused in childhood and how they perceived themselves in the fathering role. Eleven participants were recruited to the study from three therapy services for adult survivors of abuse in the Republic of Ireland. Data collection comprised face to face semi-structured interviews, which were audio recorded and subsequently transcribed verbatim. Data analysis drew on Interpretative Phenomenological Analysis and two superordinate themes with associated subthemes were identified. Participants' experience of childhood sexual abuse provided a lens through which they experienced fatherhood and themselves in a fathering role. Fatherhood influenced participants to confront unintegrated aspects of the trauma they experienced in childhood, which manifested in hypervigilance with regard to their children's safety and doubt that they were good enough fathers. However, fatherhood also offered an opportunity to heal. This occurred through striving to provide a better father-child relationship and through connection in restorative relationships, including the therapeutic relationship. Fatherhood was seen as a potential resource for positive change and can influence long held internal working models of the self and others.