Characterization of Single-Nucleotide Polymorphisms in the Tumor Necrosis Factor α Promoter Region and in Lymphotoxin α in Squamous Intraepithelial Lesions, Precursors of Cervical Cancer.
Development of cervical cancer is a long process of abnormal cancerous cell growth in the cervix and is primarily the result of infection with specific high-risk types of human papillomavirus (HPV). The cytokines tumor necrosis factor α (TNFα) and lymphotoxin α (LTA) have an important role in all stages of cervical cancer and have the ability to induce the regression or promote the development of human tumors. Biologically important single-nucleotide polymorphisms (SNPs) occur within the TNFα and LTA genes. Therefore, the purpose of this study was to investigate the SNPs in the TNFα promoter region (-163, -238, -244, -308, -376, -857, -863, and -1031) and in the first intron of LTA (+252) in women with precursor lesions of cervical cancer. Overall, we studied 396 women from Mexico City. A total of 191 patients with HPV infection and precursor cervical lesions were subdivided in two groups: those with low-grade squamous intraepithelial lesions (n = 132) and those with high-grade squamous intraepithelial lesions (n = 59). Women (n = 205) negative for HPV and without cervical lesions were also included in the study. DNA was extracted from peripheral white blood cells and from cervical samples, and detection of biallelic polymorphisms of TNFα and LTA was performed using the polymerase chain reaction-sequence-specific oligonucleotide probe and restriction fragment length polymorphism techniques, respectively. We demonstrated that risk is associated with the genotype G/A (odds ratio = 2.48) and that protection is associated with the genotype G/G of SNP TNFα -376 (odds ratio = 0.37).


Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations.
Capillary malformation-arteriovenous malformation (CM-AVM) is a newly recognized autosomal dominant disorder, caused by mutations in the RASA1 gene in six families. Here we report 42 novel RASA1 mutations and the associated phenotype in 44 families. The penetrance and de novo occurrence were high. All affected individuals presented multifocal capillary malformations (CMs), which represent the hallmark of the disorder. Importantly, one-third had fast-flow vascular lesions. Among them, we observed severe intracranial AVMs, including vein of Galen aneurysmal malformation, which were symptomatic at birth or during infancy, extracranial AVM of the face and extremities, and Parkes Weber syndrome (PKWS), previously considered sporadic and nongenetic. These fast-flow lesions can be differed from the other two genetic AVMs seen in hereditary hemorrhagic telangiectasia (HHT) and in phosphatase and tensin homolog (PTEN) hamartomatous tumor syndrome. Finally, some CM-AVM patients had neural tumors reminiscent of neurofibromatosis type 1 or 2. This is the first extensive study on the phenotypes associated with RASA1 mutations, and unravels their wide heterogeneity.


Exploration of the conformational space of oxytocin and arginine-vasopressin using the electrostatically driven Monte Carlo and molecular dynamics methods.
Conformational analysis of the neurohypophyseal hormones oxytocin (OT) and arginine-vasopressin (AVP) has been carried out using two different computational approaches and three force fields, namely by the Electrostatically Driven Monte Carlo (EDMC) method, with the Empirical Conformational Energy Program for Peptides (ECEPP/3) force field or with the ECEPP/3 force field plus a hydration-shell model, and by simulated-annealing molecular dynamics with the Consistent Valence Force Field (CVFF). The low-energy conformations obtained for both hormones were classified using the minimal-tree clustering algorithm and characterized according to the locations of beta-turns in the cyclic moieties. Calculations with the CVFF force field located conformations with a beta-turn at residues 3 and 4 as the lowest energy ones both for OT and for AVP. In the ECEPP/3 force field the lowest energy conformation of OT contained a beta-turn at residues 2 and 3, conformations with this location of the turn being higher in energy for AVP. The latter difference can be attributed to the difference in the size of the side chain in position 3 of the sequences: the bulkier phenylalanine residue of AVP in combination with the bulky Tyr2 residue hinders the formation of a turn at residues 2 and 3. Conformations of OT and AVP with a turn at residues 3,4 were in the best agreement with the x-ray structures of deaminooxytocin and pressinoic acid (the cyclic moiety of vasopressin), respectively, and with the nmr-derived distance constraints. Generally, the low-energy conformations obtained with the hydration-shell model were in a better agreement with the experimental data than the conformations calculated in vacuo. It was found, however, that the obtained low-energy conformations do not satisfy all of the nmr-derived distance constraints and the nuclear Overhauser effect pattern observed in nmr studies can be fully explained only by assuming a dynamic equilibrium between conformations with beta-turns at residues 2,3, 3,4, and 4,5. The low-energy structures of OT with a beta-turn at residues 2,3 have the disulfide ring conformations close to the model proposed recently for a potent bicyclic antagonist of OT [M. D. Shenderovich et al. (1994) Polish Journal of Chemistry, Vol. 25, pp. 921-927], although the native hormone differs from the bicyclic analogue by the conformation of the C-terminal tripeptide. This finding confirms the hypothesis of different receptor-bound conformations of agonists and antagonists of OT.


Effect of phosphodiesterase inhibitors on nitric oxide production by glial cells.
Nitric oxide (NO) is considered to play a crucial role in the development of various pathological processes in the CNS, such as neuronal degeneration, inflammation and demyelination. In order to search for the agents which suppress NO production in the CNS, we examined the effects of one of the agents which elevate cyclic AMP production, phosphodiesterase inhibitors (PDEIs), on NO production by glial cells in vitro. All the types of PDEIs, from type I- to V-specific and non-specific, suppressed the production of NO by mouse microglia and astrocytes stimulated with lipopolysaccharide, in a dose-dependent manner. Suppression of inducible NO synthase by PDEIs was confirmed by the expression of mRNA by RT-PCR. Although it required 10 microM or higher concentration to effectively suppress NO production in vitro, certain combinations of three different PDEIs synergistically suppressed NO production by astrocytes at 1 microM which could be obtained in vivo at usual therapeutic doses. Similary, combinations of three PDEIs at 1 microM synergistically increased intracellular cAMP in astrocytes. The suppressive effects of PDEIs on NO production were abolished by addition of tumor necrosis factor alpha (TNFalpha). Thus, the main suppression mechanism of NO might be indirect through suppression of TNFalpha. Since some PDEIs are reported to pass through the blood-brain-barrier, the combination of three PDEIs may be worth trying in neurological diseases, such as multiple sclerosis, human immunodeficiency virus-related neurological diseases and other neurodegenerative disorders in which NO may play a crucial role.


How do yeast sense mitochondrial dysfunction?
Apart from energy transformation, mitochondria play important signaling roles. In yeast, mitochondrial signaling relies on several molecular cascades. However, it is not clear how a cell detects a particular mitochondrial malfunction. The problem is that there are many possible manifestations of mitochondrial dysfunction. For example, exposure to the specific antibiotics can either decrease (inhibitors of respiratory chain) or increase (inhibitors of ATP-synthase) mitochondrial transmembrane potential. Moreover, even in the absence of the dysfunctions, a cell needs feedback from mitochondria to coordinate mitochondrial biogenesis and/or removal by mitophagy during the division cycle. To cope with the complexity, only a limited set of compounds is monitored by yeast cells to estimate mitochondrial functionality. The known examples of such compounds are ATP, reactive oxygen species, intermediates of amino acids synthesis, short peptides, Fe-S clusters and heme, and also the precursor proteins which fail to be imported by mitochondria. On one hand, the levels of these molecules depend not only on mitochondria. On the other hand, these substances are recognized by the cytosolic sensors which transmit the signals to the nucleus leading to general, as opposed to mitochondria-specific, transcriptional response. Therefore, we argue that both ways of mitochondria-to-nucleus communication in yeast are mostly (if not completely) unspecific, are mediated by the cytosolic signaling machinery and strongly depend on cellular metabolic state.


Novel radiation sensitizers targeting tissue hypoxia.
That hypoxic tissues are more resistant to the effects of radiation than well-oxygenated tissues has been known for many decades, and repeated in vitro demonstrations have confirmed that to achieve the same degree of cytotoxicity, hypoxic cells require about three times the radiation dose that well-oxygenated cells need. Hypoxic cell sensitizers enhance the tissue response to standard radiation, generally by mimicking the effects of oxygen, which induces the formation and stabilization of toxic DNA radicals. Although many hypoxic cell sensitizers like the nitroimidazoles have been evaluated in combination with radiation, these agents have had no or only minimal therapeutic impact due to either their limited potency or their toxicity at biologically relevant concentrations. This article reviews several new modalities that either increase oxygen delivery or sensitize hypoxic tissues. These modalities, all currently in early clinical evaluations, include: (1) tirapazamine, a bioreductive agent; (2) gadolinium texaphyrin, a hypoxic cell sensitizer with biolocalization properties using magnetic resonance imaging; (3) RSR13, an allosteric modifier of hemoglobin; and (4) bovine hemoglobin modified by the attachment of polyethylene glycol polymers.


[Detection of multiple primary malignant tumors in outpatient practice].
The author has studied the occurrence and types of primary-multiple malignant tumors met in the every-day work of the oncological consulting-room of the city hospital. The amount of primary-multiple tumors, the pattern of combinations of malignant lesions in the people subjected to dispensary examination and the efficacy of the prophylactic medical examination are analyzed for the period of 25 years.


Sporadic oral angiomyolipoma. Case report.
Angiomyolipoma (AML) is a rare, benign tumour composed of a variable proportion of lipocytes, smooth muscle and thick-walled blood vessels. AML is part of a family of tumours arising from perivascular epithelioid cells (PEComas), and many cases are associated with tuberous sclerosis, with the kidney being the most frequent site involved. We report a case of sporadic AML in the hard palate of a 52-year-old male, an extremely unusual location for this tumour. Differentiation from other benign and malignant oral mesenchymal lesions depends on recognition of the three histologic components, and immunohistochemical techniques may be helpful. AML occurring in the head and neck do not express HMB-45, an antibody that identifies immature melanosomes, conversely to the usual immunopositivity shown in AMLs from kidney and liver, suggesting that there are differences among them. A wide surgical excision is considered curative, as this tumour usually behaves in a benign fashion.


Immune system-mediated atherosclerosis caused by deficiency of long non-coding RNA MALAT1 in ApoE-/-mice.
The immune system is considered a key driver of atherosclerosis, and beyond proteins and microRNAs (miRs), long non-coding RNAs (lncRNAs) are implicated in immune control. We previously described that lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is involved in cardiac innate immunity in a myocarditis model. Here, we investigated the impact of MALAT1 deficiency upon atherosclerosis development. Heterozygous MALAT1-deficient ApoE-/- mice displayed massive immune system dysregulation and atherosclerosis within 2 months even when kept on normal diet. Aortic plaque area (P < 0.05) and aortic root plaque size (P < 0.001) were increased in MALAT1-deficient vs. MALAT1-wildtype ApoE-/- mice. Serum levels of interferon-γ (IFN-γ), tumour necrosis factor (TNF), and interleukin 6 (IL6) were elevated (P < 0.001) in MALAT1-deficient animals. MALAT1-deficient bone marrow-derived macrophages showed enhanced expression of TNF (P = 0.001) and inducible NO synthase (NOS2) (P = 0.002), suppressed MMP9 (P < 0.001), and impaired phagocytic activity (P < 0.001) upon lipopolysaccharide stimulation. RNA-sequencing revealed grossly altered transcriptomes of MALAT1-deficient splenocytes already at baseline, with massive induction of IFN- γ, TNF, NOS2, and granzyme B; CC and CXC chemokines and CCR8; and innate immunity genes interferon-induced protein with tetratricopeptide repeats (IFIT)1/3, interferon-induced transmembrane protein (IFITM)1/3, ISG15. Multiple miRs were up to 45-fold upregulated. Further, selective ablation of the cytosolic part of the MALAT1 system only, the enzymatically MALAT1-derived mascRNA, resulted in massive induction of TNF (P = 0.004) and IL6 (P = 0.028) in macrophages. Northern analysis of post-myocardial infarction patient vs. control peripheral blood mononuclear cells showed reduced (P = 0.005) mascRNA in the patients. CHART-enriched RNA-sequencing reads at the genomic loci of MALAT1 and neighbouring nuclear enriched abundant transcript (NEAT1) documented direct interaction between these lncRNA transcripts. The data suggest a molecular circuit involving the MALAT1-mascRNA system, interactions between MALAT1 and NEAT1, and key immune effector molecules, cumulatively impacting upon the development of atherosclerosis. It appears reasonable to look for therapeutic targets in this circuit and to screen for anomalies in the NEAT1-MALAT1 region in humans, too, as possible novel disease risk factors.


Relationship of phosphatidylinositol bisphosphate hydrolysis to calcium mobilization and functional activation in fluoride-treated neutrophils.
Sodium fluoride (20 mM) effected rapid hydrolysis of phosphatidylinositol bisphosphate (PIP2) in human neutrophils. Intracellular free Ca2+ levels increased after PIP2 hydrolysis but before respiratory burst activation. Both the increase in intracellular free Ca2+ levels and the extent of functional activation were dependent on the availability of extracellular Ca2+. The rate of F(-)-stimulated PIP2 hydrolysis, however, was not affected when the rise in cytosolic Ca2+ was severely limited by depletion of extracellular Ca2+. Fluoride caused the specific hydrolysis of PIP2 in isolated neutrophil plasma membranes. This effect occurred in the presence of low levels of available Ca2+ and was accompanied by the release of inositol phosphates. We conclude that PIP2 hydrolysis is an early event in the response of neutrophils to F-. This response is not Ca2+-regulated but may lead to an influx of Ca2+ from the extracellular medium. Activation of a PIP2-specific phospholipase independent of a change in cytosolic free Ca2+ levels may be the initial event in the stimulus-response pathway triggered by fluoride.


Incidence, risk factors, and mortality of atrial fibrillation in breast cancer: a SEER-Medicare analysis.
The national incidence, risk factors, and associated mortality of atrial fibrillation (AF) in breast cancer patients are unknown. Using the Surveillance, Epidemiology, and End Results-Medicare-linked database, we identified females, ≥66 years old, with a new primary diagnosis of breast cancer from 2007 through 2014. These patients were individually matched 1:1 to Medicare enrolees without cancer, and each pair was followed for 1 year to identify a primary outcome of AF. Cumulative incidence was calculated using competing risk survival statistics. Following this, identifying risk factors of AF among breast cancer patients was conducted using the adjusted Cox proportional hazards model. Finally, Kaplan-Meier methods and adjusted Cox proportional hazards modelling were performed to estimate mortality in breast cancer patients with incident and prevalent AF. This study included 85 423 breast cancer patients. Among these 9425 (11.0%) had AF diagnosis prior to the breast cancer diagnosis. New-onset AF was diagnosed in 2993 (3.9%) patients in a 1-year period after the breast cancer diagnosis [incidence 3.3%, 95% confidence interval (CI) 3.0-3.5%, at 1 year; higher rate in the first 60 days (0.6%/month)]. Comparatively, the incidence of new-onset AF in matched non-cancer controls was 1.8% (95% CI 1.6-2.0%). Apart from traditional demographic and cardiovascular risk factors, breast cancer stage was strongly associated with the development of AF [American Joint Committee on Cancer (AJCC) Stage II/III/IV vs. I: adjusted hazard ratio (aHR) 1.51/2.63/4.21, respectively]. New-onset AF after breast cancer diagnosis (aHR 3.00) is associated with increased 1-year cardiovascular mortality. AF incidence is significantly higher in women after a breast cancer diagnosis. Higher breast cancer stages at diagnos are significantly associated with a higher risk of AF. New-onset AF in the new breast cancer diagnosis setting increases 1-year cardiovascular mortality but not breast cancer-related mortality. What are the incidence, prevalence, risk factors and mortality outcomes of atrial fibrillation (AF) in a multi-ethnic representative United States cohort of breast cancer patients? Annual incidence for AF is 3.9% with highest rate in the first 60 days after cancer diagnosis. Cancer stage and grade are the strongest risk factors for AF. New onset AF after breast cancer increases all-cause and cardiovascular mortality. AF incidence is higher in breast cancer patients and is associated with later stage and grade at diagnosis of breast cancer. Involving cardio-oncology in those who develop AF after cancer diagnosis should be encouraged to improve their cardiovascular and overall prognosis.


The induction of the acrosome reaction in guinea-pig sperm by the divalent metal cation ionophore A23187.
The divalent metal cation ionophore A23187 induces an acrosome reaction in guinea-pig sperm which is dependent on external calcium. Examination of this acrosome reaction by electron microscopy shows that it is morphologically normal. The known properties of A23187 and the morphological similarity between the acrosome reaction and the secretory discharges of other secretory cells suggests that the immediate cause of the acrosome reaction is an increase in the cytoplasmic free calcium concentration.


Recovery of Alopecia Universalis with Associated Nail Dystrophy Treated with Tofacitinib: A 6-year-old Child's Case Report.
An emerging treatment modality whose established efficacy in systemic inflammatory diseases is now being actively explored for cutaneous disorders: tofacitinib, an oral Janus kinase inhibitor, is one such treatment. Alopecia universalis has been reported to improve with the use of tofacitinib in various case reports and case series. Nail dystrophy is a diverse skin disorder that has been linked to autoimmune illnesses such as psoriasis and psoriatic arthritis in certain subtypes. Alopecia areata and alopecia universalis are also commonly associated with nail dystrophy. In the present case report, we see that there are also improvements in nail dystrophy in the patient with alopecia universalis who is using tofacitinib.


Activation of SUR2B/Kir6.1 subtype of adenosine triphosphate-sensitive potassium channel improves pressure overload-induced cardiac remodeling via protecting endothelial function.
We sought to explore new strategies targeting SUR2B/Kir6.1, a subtype of adenosine triphosphate (ATP)-sensitive potassium channels (KATP), against pressure overload-induced heart failure. The effects of natakalim, a SUR2B/Kir6.1 selective channel opener, on progression of cardiac remodeling were investigated. Pressure overload-induced heart failure was induced in Wistar rats by abdominal aortic banding. The effects of natakalim (1, 3, and 9 mg·kg⁻¹·d⁻¹ for 10 weeks) on myocardial hypertrophy and heart failure, cardiac histology, vasoactive compounds, and gene expression were assessed. Ten weeks after the onset of pressure overload, natakalim treatment potently inhibited cardiac hypertrophy and prevented heart failure. Natakalim remarkably inhibited the changes of left ventricular hemodynamic parameters and reversed the increase of heart mass index, left ventricular weight index, and lung weight index. Histological examination demonstrated that there was no significant hypertrophy or fibrosis in pressure-overloaded hearts of natakalim-treated rats. Ultrastructural examination of hearts revealed well-organized myofibrils with mitochondria grouped along the periphery of longitudinally oriented fibers in rats from the natakalim group. The content of serum nitric oxide and plasma prostacyclin was increased, whereas that of plasma endothelin-1 and cardiac tissue hydroxyproline and atrial and B-type natriuretic peptide messenger RNA was downregulated in natakalim-treated rats. Natakalim at 0.01-100 µM had no effects on isolated working hearts derived from Wistar rats; however, natakalim had endothelium-dependent vasodilatory effects on the isolated tail artery helical strips precontracted with norepinephrine. These results indicate that natakalim reduces heart failure caused by pressure overloading by activating the SUR2B/Kir6.1 KATP channel subtype and protecting against endothelial dysfunction.


Risk of Salmonella infection with exposure to reptiles in England, 2004-2007.
Non-typhoidal Salmonella infections are a common cause of gastroenteritis in England. Non-Enteritidis, non-Typhimurium Salmonella serotypes have gained in relative importance in recent years, but their modes of transmission are poorly understood. In a large case-case study in England between 2004 and 2007, the association between exposure to reptiles and Salmonella illness was investigated using multivariable logistic regression. Recent reptile exposure was associated with Salmonella illness with an odds ratio of 2.46 (95% confidence interval: 1.57-3.85, p<0.001), with much stronger effects among children under five years of age. The exposure was rare, and a population attributable fraction was estimated as 0.9%. Among the Salmonella serotypes found in people exposed to reptiles, several non-Enteritidis, non-Typhimurium serotypes were strongly associated with exposure. Reptile exposure is a rare but significant risk factor for Salmonella illness in England, with much higher risk in children.


Prokaryotic Capability to Use Organic Substrates Across the Global Tropical and Subtropical Ocean.
Prokaryotes play a fundamental role in decomposing organic matter in the ocean, but little is known about how microbial metabolic capabilities vary at the global ocean scale and what are the drivers causing this variation. We aimed at obtaining the first global exploration of the functional capabilities of prokaryotes in the ocean, with emphasis on the under-sampled meso- and bathypelagic layers. We explored the potential utilization of 95 carbon sources with Biolog GN2 plates® in 441 prokaryotic communities sampled from surface to bathypelagic waters (down to 4,000 m) at 111 stations distributed across the tropical and subtropical Atlantic, Indian, and Pacific oceans. The resulting metabolic profiles were compared with biological and physico-chemical properties such as fluorescent dissolved organic matter (DOM) or temperature. The relative use of the individual substrates was remarkably consistent across oceanic regions and layers, and only the Equatorial Pacific Ocean showed a different metabolic structure. When grouping substrates by categories, we observed some vertical variations, such as an increased relative utilization of polymers in bathypelagic layers or a higher relative use of P-compounds or amino acids in the surface ocean. The increased relative use of polymers with depth, together with the increases in humic DOM, suggest that deep ocean communities have the capability to process complex DOM. Overall, the main identified driver of the metabolic structure of ocean prokaryotic communities was temperature. Our results represent the first global depiction of the potential use of a variety of carbon sources by prokaryotic communities across the tropical and the subtropical ocean and show that acetic acid clearly emerges as one of the most widely potentially used carbon sources in the ocean.


The formulation of the neuron doctrine: the Island of Cajal.
Santiago Ramón y Cajal (1852-1934), Spanish histologist, was the renowned formulator of the "neuron doctrine" and recipient of the 1906 Nobel Prize for Medicine or Physiology for his work on the structure of the nervous system. In contrast to the then well-accepted "reticular theory," which held that the nervous system is arranged and functions as a continuous network of cellular material, Cajal's neuron doctrine envisioned each nerve cell as an autonomous entity, establishing contact--not continuity--with other nerve cells. Cajal's theory is as well a description fitting of Cajal's own temperament, as emerges from his profound memoirs Recuerdos de Mi Vida (Recollections of My Life). The recollections detail the life of the man known from his boyhood as "capricious," the term for the goat who lives alone in the hills. For Cajal, this need for solitude and autonomy was reflected in his choice of the adventurer Robinson Crusoe as a childhood hero. Throughout his life, Cajal's desire for independence formed both his social interactions and his scientific pursuits; in his research, he preferred to remain unfettered by the academic "reticulum" of his time. A close reading of his memoirs reveals that the neuron doctrine, which envisions each nerve cell as "free," is a theory shaped by Cajal's essence, by his solitary nature and unhindered personal spirit.


Effect of slow coronary flow on electrocardiographic parameters reflecting ventricular heterogeneity.
QT interval dispersion reflects regional variations in ventricular repolarization and cardiac electrical instability. Previous studies have showed that QT interval dispersion changes during episodes of myocardial ischemia. Slow coronary flow (SCF) in epicardial coronary arteries is a rare and unique angiographic finding. Whether this pattern of flow is associated with electrocardiographic abnormalities is unknown. Therefore, this study was designed to investigate whether SCF results in electrocardiographic (ECG) changes compared to normal coronary flow. For this aim 24 patients with angiographically proven SCF who had no obstructive coronary lesion (group I) and 25 patients without coronary artery disease (group II) were included in the study. Both groups underwent a routine standard 12-lead surface electrocardiogram recorded at 50 mm/s during rest. QT dispersion (QTd), corrected QT (QTc), and corrected QT dispersion (QTcd) were calculated. Distributions of sex, age, body mass index (BMI), and cardiac risk factors were similar in the 2 groups. Mean heart rate was similar in the 2 groups (74 +/-8 vs 77 +/- 7 p > 0.05). Mean QRS interval durations were similar in the groups (92 +/-7 vs 90 +/-6 ms p > 0.005). In group I, QTd, QTcd, and QTc, were significantly higher than in group II (QTd: 73 +/-14 vs 40 +/-14; QTcd: 71 +/-15 vs 42 +/-9; QTc: 414 +/-14 vs 388 +/-13, respectively p <0.05). In conclusion, SCF was found to be associated with prolonged QT interval and increased QT dispersion. Ischemia in microvascular level and/or altered autonomic regulation of the heart may be responsible mechanisms.


US Health Care Spending by Race and Ethnicity, 2002-2016.
Measuring health care spending by race and ethnicity is important for understanding patterns in utilization and treatment. To estimate, identify, and account for differences in health care spending by race and ethnicity from 2002 through 2016 in the US. This exploratory study included data from 7.3 million health system visits, admissions, or prescriptions captured in the Medical Expenditure Panel Survey (2002-2016) and the Medicare Current Beneficiary Survey (2002-2012), which were combined with the insured population and notified case estimates from the National Health Interview Survey (2002; 2016) and health care spending estimates from the Disease Expenditure project (1996-2016). Six mutually exclusive self-reported race and ethnicity groups. Total and age-standardized health care spending per person by race and ethnicity for each year from 2002 through 2016 by type of care. Health care spending per notified case by race and ethnicity for key diseases in 2016. Differences in health care spending across race and ethnicity groups were decomposed into differences in utilization rate vs differences in price and intensity of care. In 2016, an estimated $2.4 trillion (95% uncertainty interval [UI], $2.4 trillion-$2.4 trillion) was spent on health care across the 6 types of care included in this study. The estimated age-standardized total health care spending per person in 2016 was $7649 (95% UI, $6129-$8814) for American Indian and Alaska Native (non-Hispanic) individuals; $4692 (95% UI, $4068-$5202) for Asian, Native Hawaiian, and Pacific Islander (non-Hispanic) individuals; $7361 (95% UI, $6917-$7797) for Black (non-Hispanic) individuals; $6025 (95% UI, $5703-$6373) for Hispanic individuals; $9276 (95% UI, $8066-$10 601) for individuals categorized as multiple races (non-Hispanic); and $8141 (95% UI, $8038-$8258) for White (non-Hispanic) individuals, who accounted for an estimated 72% (95% UI, 71%-73%) of health care spending. After adjusting for population size and age, White individuals received an estimated 15% (95% UI, 13%-17%; P < .001) more spending on ambulatory care than the all-population mean. Black (non-Hispanic) individuals received an estimated 26% (95% UI, 19%-32%; P < .001) less spending than the all-population mean on ambulatory care but received 19% (95% UI, 3%-32%; P = .02) more on inpatient and 12% (95% UI, 4%-24%; P = .04) more on emergency department care. Hispanic individuals received an estimated 33% (95% UI, 26%-37%; P < .001) less spending per person on ambulatory care than the all-population mean. Asian, Native Hawaiian, and Pacific Islander (non-Hispanic) individuals received less spending than the all-population mean on all types of care except dental (all P < .001), while American Indian and Alaska Native (non-Hispanic) individuals had more spending on emergency department care than the all-population mean (estimated 90% more; 95% UI, 11%-165%; P = .04), and multiple-race (non-Hispanic) individuals had more spending on emergency department care than the all-population mean (estimated 40% more; 95% UI, 19%-63%; P = .006). All 18 of the statistically significant race and ethnicity spending differences by type of care corresponded with differences in utilization. These differences persisted when controlling for underlying disease burden. In the US from 2002 through 2016, health care spending varied by race and ethnicity across different types of care even after adjusting for age and health conditions. Further research is needed to determine current health care spending by race and ethnicity, including spending related to the COVID-19 pandemic.


Effect of prolonged and intermittent treatment on the clinical course of peptic ulcer.
Introduction: The number of patients with peptic ulcer increases annually. According to published data, patients with peptic ulcer constitute about 15% of those hospitalized with gastrointestinal diseases. The aim: That is why we set the task to evaluate the methods of preventive treatment and to choose the most effective one. Materials and methods: For this purpose, we selected 103 patients with peptic ulcer without severe exacerbations and complications from one region (main group) and 101 patients from another region (control group) for observations. Making diagnosis was based on the study of complaints, anamnestic data, physical examination of the patient, evaluation of the functional state of the gastroduodenal system, as well as the X-ray and endoscopic examination. The sources of the study were medical records of outpatients, control cards for dispensary surveillance, registers of temporary disability records, sick leave records and others. Results: Most patients, from both the main and control groups, who were on prophylactic treatment, noticed that they had an increased working capacity, normalized sleep, better appetite and fewer dyspeptic disorders. Patients in the main group for two years were on prolonged prophylactic treatment according to the method that we had developed. by us. Patients in the control group received an intermittent preventive treatment twice a year (in spring and autumn). In the complex of therapeutic measures the following were used: dietary recommendations, antacids, cholinolytics, multivitamins, etc. Conclusions: Prolonged prophylactic treatment is an effective means to combat exacerbations and complications of peptic ulcer and can be recommended for implementation in practice.


Properties of two multifunctional plant fatty acid acetylenase/desaturase enzymes.
The properties of the Delta6 desaturase/acetylenase from the moss Ceratodon purpureus and the Delta12 acetylenase from the dicot Crepis alpina were studied by expressing the encoding genes in Arabidopsis thaliana and Saccharomyces cerevisiae. The acetylenase from C. alpinaDelta12 desaturated both oleate and linoleate with about equal efficiency. The desaturation of oleate gave rise to 9(Z),12(E)- and 9(Z),12(Z)-octadecadienoates in a ratio of approximately 3 : 1. Experiments using stereospecifically deuterated oleates showed that the pro-R hydrogen atoms were removed from C-12 and C-13 in the introduction of the 12(Z) double bond, whereas the pro-R and pro-S hydrogen atoms were removed from these carbons during the formation of the 12(E) double bond. The results suggested that the Delta12 acetylenase could accommodate oleate having either a cisoid or transoid conformation of the C(12)-C(13) single bond, and that these conformers served as precursors of the 12(Z) and 12(E) double bonds, respectively. However, only the 9(Z),12(Z)-octadecadienoate isomer could be further desaturated to 9(Z)-octadecen-12-ynoate (crepenynate) by the enzyme. The evolutionarily closely related Delta12 epoxygenase from Crepis palaestina had only weak desaturase activity but could also produce 9(Z),12(E)-octadecadienoate from oleate. The Delta6 acetylenase/desaturase from C. purpureus, on the other hand, produced only the 6(Z) isomers using C16 and C18 acyl groups possessing a Delta9 double bond as substrates. The Delta6 double bond was efficiently further converted to an acetylenic bond by a second round of desaturation but only if the acyl substrate had a Delta12 double bond and that this was in the Z configuration.


Development of molecular markers linked to the 'Fiesta' linkage group 7 major QTL for fire blight resistance and their application for marker-assisted selection.
A fire blight resistance QTL explaining 34.3%-46.6% of the phenotypic variation was recently identified on linkage group 7 of apple cultivar 'Fiesta' (F7). However, markers flanking this QTL were AFLP and RAPD markers unsuitable for marker-assisted selection (MAS). Two RAPD markers bracketing the QTL have been transformed into SCAR (sequence-characterized amplified region) markers, and an SSR marker specific for the region was developed. Pedigree analysis of 'Fiesta' with these markers enabled tracking of the F7 QTL allele back to 'Cox's Orange Pippin'. Stability of the effect of this QTL allele in different backgrounds was analyzed by inoculating progeny plants of a cross between 'Milwa', a susceptible cultivar, and '1217', a moderately resistant cultivar, and a set of cultivars that carry or lack the allele conferring increased fire blight resistance. Progenies and cultivars that carried both markers were significantly more resistant than those that did not carry both markers, indicating high stability of the F7 QTL allele in different backgrounds. This stability and the availability of reproducible markers bracketing the QTL make this locus promising for use in MAS.


Effects of age, size, and mating history on sex role decision of a simultaneous hermaphrodite.
Contrasting with separate-sexed animals, simultaneous hermaphrodites display unique reproductive strategies as they are male and female at the same time. Simultaneous hermaphrodites that copulate unilaterally, for instance, make a decision to mate as a male or female. Previous studies have demonstrated that sex role preference in hermaphrodites is flexible and is controlled by several, often confounding, factors. We examined the relationship between sex role decisions and 3 life-history traits (age, size, and mating history) in the great pond snail, Lymnaea stagnalis. Based on our field observations, which indicate that adult individuals show overlapping generations and large variation in body size during the breeding season, we performed a sex role choice experiment in the laboratory. We found that young and small snails mate as males first. Both age and size significantly affected sex role decision, with age having a stronger effect. Furthermore, we tested whether L. stagnalis becomes reluctant to inseminate a mate after being inseminated because it is known that after insemination, male investment substantially reduces. Contrary to expectations, our results indicate that the receipt of seminal fluid does not seem to reduce male motivation. In sum, sex role decisions in L. stagnalis are largely determined by age and size but not by having received seminal fluid. This mating pattern, however, does not fully support the size-advantage model because large or old individuals did not perform better as females in our experiment. These results imply a conflicting mating interest, rather than harmonious agreement, between age- and size-different hermaphrodites.


Development of a Boron Nitride-Filled Dental Adhesive System.
There is a dearth of adhesive systems capable of forming stable bonds between restorative materials and tooth surfaces. To address the concern, this study determined the effects of using methacrylate-functionalized boron nitride nanosheets (BNNSs) in a polymeric dental adhesive system. The bisphenol A glycidyl dimethacrylate (BisGMA):2 hydroxyethyl methacrylate (HEMA) (60:40) adhesive monomer blend with a photoinitiator was filled with 0 wt% (control), 0.1 wt%, and 1 wt% BNNSs and light cured. Fourier transform infrared spectroscopy was performed to determine the conversion degree of monomer double bonds (DoC). Water absorption and solubility were measured. Flexural strength and Youngs's modulus were evaluated to determine the mechanical properties of the composite adhesive system. Finally, dentin bond strength degradation and fracture mode were quantified with a microtensile bond test to confirm the bonding ability of the developed adhesive system. Results showed that the incorporation of BNNSs increased DoC (9.8% and 5.4% for 0.1 and 1 wt%, respectively), but it did not affect water sorption (101.9-119.72 (µg/mm3)), solubility (2.62-5.54 (µg/mm3)), Young's modulus (529.1-1716.1 MPa), or microtensile bond strength (46.66-54.72 MPa). Further studies are needed with varying BNNS loading percentages from 0.1 wt% to 1 wt% in order to more comprehensively determine the effect of BNNSs on dental adhesives.


Effects of ginger (Zingiber officinale) supplementation on testicular histology, semen characteristic, blood plasma parameters and reproductive performance in aged broiler breeder roosters.
Higher long-chain polyunsaturated fatty acids contents in roosters' sperm plasma membrane along with age-related decrease in antioxidant defense make the spermatozoa very susceptible to lipid peroxidation. Ginger root contains abundant amounts of gingerol, shogaols, gingerdiol and other active compounds, which known as antioxidant compounds to enhance semen quality. The goal of the study was to evaluate the effect of dietary supplementation of ginger root on semen quality, blood chemistry, immune response, testicular histology and reproductive performance of Ross-308 breeder roosters from 47 to 60 weeks of age. The feeding of ginger root resulted in an increase in parameters related to sperm forward motility and seminal total antioxidant capacity (TAC), and following there was a tendency to increase and decrease in seminal superoxide dismutase activity and malondialdehyde concentration, respectively; however, sperm concentration was not affected. There was an increase and tendency to increase in blood total protein and TAC in the supplemented group respectively. The roosters fed ginger supplemented diet had a higher spermiation index; and following there was tendency to increase seminal tubes spermatozoids number (p = 0.056) and repopulation index (p = 0.058). Despite the improved seminal antioxidant status and a tendency to lower embryonic mortality in the ginger-received group, the fertility and hatchability rate of roosters were statistically insignificant. Supplementations of ginger root in ageing rooster's diet had a beneficial effect on sperm motility, seminal antioxidant status and testicular spermiation index.


Clinicopathologic Characteristics of Thyroid Nodules Positive for the THADA-IGF2BP3 Fusion on Preoperative Molecular Analysis.
Background: Thyroid adenoma-associated (THADA)-IGF2BP3 fusions have been identified as an oncogenic event in thyroid neoplasms. However, the prevalence of this gene fusion and associated phenotypical and clinical features are not well defined. The aim of this study was to characterize thyroid nodules positive for THADA-IGF2BP3 fusions on preoperative molecular analysis, review surgical outcomes, and explore potential impact of the fusion detection on patient management. Methods: Thyroid nodules positive for THADA-IGF2BP3 fusion on ThyroSeq v3 genomic classifier (GC) testing of fine needle aspiration (FNA) (n = 30) samples from November 2017 to August 2019 were identified. Demographic and clinical data were obtained by retrospective chart review; pathology slides were re-examined. Results: Thirty nodules positive for THADA-IGF2BP3 fusion on FNA were identified, representing ∼2% of 1280 nodules that underwent molecular analysis. Of the 27 nodules with available cytology diagnosis data, 22 (81%) were diagnosed as atypia of undetermined significance, 3 (11%) as follicular neoplasm, and 1 (4%) each were benign, and suspicious for malignancy. No additional mutations or gene fusions were identified in any of the nodules. Of the 24 cases with available clinical data, 22 (92%) THADA-IGF2BP3-positive nodules were managed surgically, 14 (64%) by thyroid lobectomy, and 8 (36%) by total thyroidectomy. Of the patients who had initial lobectomy, 3 (21%) had completion surgery. On surgical pathology, 7 (32%) THADA-IGF2BP3-positive nodules were malignant (six encapsulated follicular variant papillary thyroid carcinomas (EFVPTC), one minimally infiltrative FVPTC), 10 (45%) noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), and 5 (23%) follicular adenomas (FA). THADA-IGF2BP3-positive malignancies were intrathyroidal, without aggressive histology. Nodule size was similar between malignant nodules, NIFTP, and FA (2.6, 2.7, and 2.3 cm, respectively; p = 0.77). On limited follow-up (mean, 18 months) available for six patients with malignant fusion-positive nodule and 4 patients with NIFTP, no tumor recurrences were found. Conclusions: In this series of patients, 77% of THADA-IGF2BP3 fusion-positive thyroid nodules were thyroid tumors requiring surgery, either papillary carcinoma or NIFTP. However, all cancers were low risk, predominantly encapsulated FVPTCs and thus can likely be adequately treated with lobectomy.


Quantum non-Gaussianity certification of photon number-resolving detectors.
We report on direct experimental certification of the quantum non-Gaussian character of a photon number-resolving detector. The certification protocol is based on an adaptation of the existing quantum non-Gaussianity criteria for quantum states to quantum measurements. In our approach, it suffices to probe the detector with a vacuum state and two different thermal states to test its quantum non-Gaussianity. The certification is experimentally demonstrated for the detector formed by a spatially multiplexed array of ten single-photon avalanche photodiodes. We confirm the quantum non-Gaussianity of POVM elements Π^m associated with the m-fold coincidence counts, up to m = 7. The experimental ability to certify from the first principles the quantum non-Gaussian character of Π^m is for large m limited by low probability of the measurement outcomes, especially for vacuum input state. We find that the injection of independent Gaussian background noise into the detector can be helpful and may reduce the measurement time required for reliable confirmation of quantum non-Gaussianity. In addition, we modified and experimentally verified the quantum non-Gaussianity certification protocol employing a third thermal state instead of a vacuum to speed up the whole measurement. Our findings demonstrate the existence of efficient tools for the practical characterization of fundamental non-classical properties and benchmarking of complex optical quantum detectors.


Severe tetanus: its complications and management.
When phenothiazines and barbiturates fail to control the spasms of tetanus, total paralysis induced by muscle relaxants may be the only way of keeping the patient alive. The hazards of this technique are illustrated in this report of a patient with severe tetanus who was totally paralyzed for 26 days. Cardiac arrest, ileus, atelectasis, anemia, and limb contractures were among the problems dealt with. Devoted nursing care, an experienced medical team, respirators, minute ventilation meters, an airway pressure alarm, a hypothermia unit, a cardiac monitor pacemaker and facilities for determining blood-gas tensions were all necessary in the successful treatment of this patient. It is suggested that patients with severe tetanus should be transferred, under anesthesia and artificially ventilated, to hospitals possessing all these facilities.


Blowout fracture in a 3-year-old.
A 3-year-old patient was referred to the oral and maxillofacial department with a fracture of the orbital floor. Due to the lack of clinical symptoms, a conservative approach was chosen. After 3 weeks, an enophthalmos developed. The orbital floor reconstruction was successfully performed through a transconjunctival approach. This case highlights the rarity of pure blowout fractures in young children. The specific presentation and diagnostics of orbital floor fractures in children and the related surgical planning and intervention are discussed.


The Effect of PDE5 Inhibitors on the Male Reproductive Tract.
The therapeutic range of cyclic nucleotide phosphodiesterase 5 inhibitors (PDE5) inhibitors is getting wider in the last years. This review study focuses on the potential employment of PDE5 inhibitors as an adjunct tool for the therapeutic management of male infertility. The literature tends to suggest a beneficial effect of PDE5 inhibitors on Leydig and Sertoli cells secretory function. It also appears that PDE5 inhibitors play a role in the regulation of the contractility of the testicular tunica albuginea and the epididymis. Moreover, scientific data suggest that PDE5 inhibitors enhance the prostatic secretory function leading to an improvement in sperm motility. Other studies additionally demonstrate the role of PDE5 inhibitors in the regulation of the sperm capacitation process. Placebo-controlled, randomized, blind studies are necessary to unambiguously incorporate PDE5 inhibitors as an adjunct tool for the pharmaceutical treatment of semen disorders and male infertility.


Exposure to extrinsic stressors, social defeat or bisphenol A, eliminates sex differences in DNA methyltransferase expression in the amygdala.
Chemical and psychological stressors can exert long lasting changes in brain function and behaviour. Changes in DNA methylation have been shown to be an important mechanism mediating long lasting changes in neural function and behaviour, especially for anxiety-like or stress responses. In the present study, we examined the effects of either a social or chemical stressor on DNA methyltransferase (DNMT) gene expression in the amygdala, an important brain region modulating stress responses and anxiety. In adult California mice (Peromyscus californicus) that were naïve to social defeat, females had higher levels of Dnmt1 expression in punch samples of the central amygdala (CeA) than males. In addition, mice that underwent social defeat stress showed reduced Dnmt1 and Dnmt3a expression in the CeA of females but not males. A second study using more anatomically specific punch samples replicated these effects for Dnmt1. Perinatal exposure (spanning from periconception through lactation) to bisphenol A or ethinyl oestradiol (oestrogens in birth control pills) also abolished sex differences in Dnmt1 expression in the CeA but not the basolateral amygdala. These findings identify a robust sex difference in Dnmt1 expression in the CeA that is sensitive to both psychological and chemical stressors. Future studies should aim to examine the impact of psychological and chemical stressors on DNA methylation in the CeA and also investigate whether Dnmt1 may have an underappreciated role in plasticity in behaviour.


Notes from "Pavlov's Wednesdays": Pavlov's law of effect.
Pavlov's Wednesday seminars indicate that he adopted homeostatic balance as a law of effect in order to deal with Konorski's experiments on omission and avoidance training; he did not, as is often thought, completely assimilate instrumental conditioning into his classical framework. He saw the 'new' type of conditioning as the basis of voluntary behavior in higher animals and devoted considerable attention to it in 1930-1933.


Age-related changes in the integration of gaze direction and facial expressions of emotion.
Gaze direction influences younger adults' perception of emotional expressions, with direct gaze enhancing the perception of anger and joy, while averted gaze enhances the perception of fear. Age-related declines in emotion recognition and eye-gaze processing have been reported, indicating that there may be age-related changes in the ability to integrate these facial cues. As there is evidence of a positivity bias with age, age-related difficulties integrating these cues may be greatest for negative emotions. The present research investigated age differences in the extent to which gaze direction influenced explicit perception (e.g., anger, fear and joy; Study 1) and social judgments (e.g., of approachability; Study 2) of emotion faces. Gaze direction did not influence the perception of fear in either age group. In both studies, age differences were found in the extent to which gaze direction influenced judgments of angry and joyful faces, with older adults showing less integration of gaze and emotion cues than younger adults. Age differences were greatest when interpreting angry expressions. Implications of these findings for older adults' social functioning are discussed.


Primary health care use and health care accessibility among adolescents in the United Arab Emirates.
This study examined primary health care use and accessibility among adolescents living in the United Arab Emirates. In a cross-sectional study, we collected health care use, sociodemographic and residential data for a sample of 6363 adolescents. Logistic regression modelling was used to examine predictors of health care use. The most-consulted health professionals were dentists or orthodontists, family doctors and eye specialists. Local adolescents were more likely to attend public clinics/hospitals than private facilities, while the opposite was true for expatriates. In the previous 12 months 22.6% of the participants had not obtained the health care they needed and 19.5% had not had a routine health check-up. Common reasons for not obtaining care were busy schedules, dislike/fear of doctors and long waiting times. Predictors of not obtaining needed care included nationality and income, while those for having a routine check-up were mother's education and car ownership. Improvements to the health care sector may increase health care accessibility among adolescents.


A mitochondria-targeted fluorescent probe for hypochlorite sensing and its application in bioimaging.
A coumarin-diaminomaleonitrile derivative (C-DAN) was designed and prepared. Upon addition of hypochlorite (OCl-), the fluorescence emission peak of C-DAN at 475 nm was gradually enhanced with a rapid response (within 5 s); meanwhile, the color of the solution changed from dark red to bright yellow which can be observed with the naked eye. Furthermore, owing to its advantages including high selectivity, sensitivity, and low toxicity, our C-DAN probe has been applied for detecting OCl- in living cells and zebrafish, indicating it is an ideal tool for biological applications.


Anti-inflammatory effect as a mechanism of effectiveness underlying the clinical benefits of pelotherapy in osteoarthritis patients: regulation of the altered inflammatory and stress feedback response.
The purpose of the present investigation was to evaluate whether an anti-inflammatory effect together with an improvement of the regulation of the interaction between the inflammatory and stress responses underlies the clinical benefits of pelotherapy in osteoarthritis (OA) patients. This study evaluated the effects of a 10-day cycle of pelotherapy at the spa centre 'El Raposo' (Spain) in a group of 21 OA patients diagnosed with primary knee OA. Clinical assessments included pain intensity using a visual analog scale; pain, stiffness and physical function using the Western Ontario and McMaster Universities Arthritis Index; and health-related quality of life using the EuroQol-5D questionnaire. Serum inflammatory cytokine levels (IL-1β, TNF-α, IL-8, IL-6, IL-10 and TGF-β) were evaluated using the Bio-Plex® Luminex® system. Circulating neuroendocrine-stress biomarkers, such as cortisol and extracellular 72 kDa heat shock protein (eHsp72), were measured by ELISA. After the cycle of mud therapy, OA patients improved the knee flexion angle and OA-related pain, stiffness and physical function, and they reported a better health-related quality of life. Serum concentrations of IL-1β, TNF-α, IL-8, IL-6 and TGF-β, as well as eHsp72, were markedly decreased. Besides, systemic levels of cortisol increased significantly. These results confirm that the clinical benefits of mud therapy may well be mediated, at least in part, by its systemic anti-inflammatory effects and neuroendocrine-immune regulation in OA patients. Thus, mud therapy could be an effective alternative treatment in the management of OA.


The Role of Trust as a Mediator Between System Characteristics and Response Behaviors.
The purpose of the current work was to clarify how subjective trust determines response behavior when interacting with a signaling system. In multiple theoretical frameworks, trust is acknowledged as a prime mediator between system error characteristics and automation dependence. Some researchers have operationally defined trust as the behavior exhibited. Other researchers have suggested that although trust may guide operator responses, trust does not completely determine the behavior. Forty-four participants interacted with a primary flight simulation task and a secondary signaling system task. The signaling system varied in reliability (90%, 60%) and error bias (false alarm, miss prone). Trust was measured halfway through the experimental session to address the criterion of temporal precedence in determining the effect of trust on behavior. Analyses indicated that trust partially mediated the relationship between reliability and agreement rate. Trust did not mediate the relationship between reliability and reaction time. Trust also did not mediate the relationships between error bias and reaction time or agreement rate. Analyses of variance generally supported specific behavioral and trust hypotheses, indicating that the paradigm employed produced similar effects on response behaviors and subjective estimates of trust observed in other studies. These results indicate that strong assumptions of trust acting as the prime mediator between system error characteristics and response behaviors should be viewed with caution. Practitioners should consider assessing factors other than trust to determine potential operator response behaviors, which may be more predictive.


High Verdet constants and diamagnetic responses of GeS2-In2S3-PbI2 chalcogenide glasses for integrated optics applications.
Chalcogenide glasses as kind of diamagnetic magneto-optical materials have promising applications in the field of integrated optics and optical communication systems due to their excellent properties, such as easy to be processed into waveguide and temperature independence of the Verdet constants. For clarifying the influence factors following the compositional variation on Faraday effect and finding a glass with a large Verdet constant, novel pseudo-ternary chalcogenide glass system, GeS2 - In2S3 - PbI2, was prepared and investigated. The composition, wavelength and temperature dependences on the Verdet constants were systematically investigated at the wavelengths of 635, 808, 980 and 1319 nm. PbI2 was confirmed to have positive contribution to the Verdet constant and the Becquerel rule was proved to be an effective guidance for predicting the Verdet constant in chalcogenide glasses. The 60GeS2·15In2S3·25PbI2 glass was found to possess the largest Verdet constant (V = 0.215 min·G-1·cm-1, @808nm), which is great larger than that of commercial diamagnetic glasses. These glasses also possess good glass-forming ability and VIS-IR transmittance, therefore be a good candidate for next-generation integrated optical isolator and other magneto-optical devices.


Who will volunteer? Analysing individual and structural factors of volunteering in Swiss sports clubs.
This article analyses the conditions influencing volunteering in sports clubs. It focuses not only on individual characteristics of volunteers but also on the corresponding structural conditions of sports clubs. It proposes a model of voluntary work in sports clubs based on economic behaviour theory. The influences of both the individual and context levels on the decision to engage in voluntary work are estimated in different multilevel models. Results of these multilevel analyses indicate that volunteering is not just an outcome of individual characteristics such as lower workloads, higher income, children belonging to the sports club, longer club memberships, or a strong commitment to the club. It is also influenced by club-specific structural conditions; volunteering is more probable in rural sports clubs whereas growth-oriented goals in clubs have a destabilising effect.


[Vibration massage in the prevention of postresection complications and in the clinical rehabilitation of patients with pulmonary tuberculosis after surgical interventions].
A new procedure has been developed for prevention of early postresectional complications and for clinical rehabilitation of patients with tuberculosis after surgical interventions. The procedure is based on a 13-14-day course of regional and systemic physiotherapy applied to a patient's respiratory organs and chest after surgery in a certain order with the use of tuberculostatic agents. Regional physiotherapy includes local massage of the root of the contralateral operated lung with a light vibromassage apparatus; systemic physiotherapy involves electric vibroacupressure of the whole circumference of the chest with a special device. Early postresection complications were significantly less frequently observed in the study group (n = 60) than in the control group (n = 50) (p < 0.01). The procedure reduces the likelihood of development of a number of pleuropulmonary events (atelectasis, non-specific pneumonia, residual postresection pleural cavity, bronchial fistulas) and promotes functional rehabilitation in patients.


Dendritic spines detection based on directional morphological filter and shortest path.
Dendritic spines are membranous protrusions from neuron's dendrites. They play a very important role in the nervous system. They are very small and have various shapes; hence it is very challenging to detect them in neuron images. This paper presents a novel method for detecting dendritc spines in 2D images. A new dendrite backbone or centerline extraction method is introduced herein which is based on an iterative process between smoothing and extraction. The proposed method iteratively refines the extraction result using both directional morphological filtering and improved Hessian filtering until a satisfactory extraction result is obtained. A shortest path method is applied along a backbone to extract the boundary of the dendrites. Spines are then segmented from the dendrites outside the extracted boundary. The proposed algorithm has been tested with many images and good results are achieved.


The pathogenesis of gastrointestinal bacterial overgrowth.
The normal indigenous intestinal microflora consists of about 10(15) bacteria that under physiological conditions reside mainly in the lower gastrointestinal tract. Bacterial overgrowth implies abnormal bacterial colonization of the upper gut, resulting from failure of specific defense mechanisms restricting colonization under physiological conditions. At present two types of bacterial overgrowth with defined pathogenesis can be distinguished: (1) gastric overgrowth with upper respiratory tract microflora resulting from selective failure of the gastric acid barrier, and (2) gastrointestinal overgrowth with Gram-negative bacilli (enteric bacteria) resulting from failure of intestinal clearance. Helicobacter pylori-induced gastritis of the oxyntic mucosa is the main cause of acquired failure of the gastric acid barrier, which is common among the healthy elderly. Intestinal clearance may fail as the result of impaired intestinal peristalsis or anatomical abnormalities that alter luminal flow. Impaired peristalsis is associated with conditions interfering with intestinal neuromuscular function including myopathic, neuropathic, autoimmune, infectious, inflammatory, metabolic, endocrine, and neoplastic diseases. Anatomical abnormalities are mainly the result of gastrointestinal surgery, intestinal diverticula or fistula. Combined failure of intestinal clearance and the gastric acid barrier results in more severe colonization with Gram-negative bacilli. Gram-negative bacilli are uncommon in the upper gut of otherwise healthy individuals with gastric hypochlorhydria, being acquired (H. pylori) or drug-induced. Significant bacterial overgrowth with Gram-negative bacilli is a rational in the search for an explanation to optimize clinical management. The clinical significance of colonization with upper respiratory tract microflora remains unclear. Translocation of live bacteria, their metabolic products, or antigens from a small bowel colonized by Gram-negative bacilli play a role in the pathogenesis of spontaneous bacterial peritonitis in hepatic disease and in certain types of sepsis, indicating that further studies can point to new patient populations with potential benefit from medical treatment.


No association of PTPN22 R620W gene polymorphism with rheumatic heart disease and systemic lupus erythematosus.
Rheumatic heart disease (RHD) or acute rheumatic fever (ARF) develops as a consequence of an exaggerated immune response to Group A beta haemolytic streptococci causing pharyngitis. The molecular mimicry appears between human cardiac myosin and M protein of group A streptococcal membranes. The polymorphism of the protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene, which encodes an important negative regulator of T cell activation, has been reported to be associated with susceptibility to several autoimmune diseases such as SLE and RA. The objective of this study was to investigate whether PTPN22 R620W polymorphism confers susceptibility to RHD in Turkish population. PTPN 22 R620W (rs2476601, A/G) polymorphism was genotyped by PCR-RFLP in 121 patients with RHD who fulfilling the revised classification criteria of Jones, and 160 healthy control (HC), and also 137 SLE as a diseased-control. The frequency of GG and AG genotypes were found to be 94% (114), 6% (7) in RHD, respectively and 96% (153) and 4% (7) in HC, respectively. The homozygous AA genotype was not present in RHD and HC. There was no statistically significant difference between RHD and HC according to the frequency of AG heterozygote genotype (P = 0.831; OR = 1.13; 95% CI 0.37-3.46). The frequency of the rare allele A was also very similar in RHD patients and HC (3, 2% respectively). A similar result was also found between SLE and HC. Our results demonstrated that the PTPN22 R620W polymorphism is not associated with RHD nor with SLE in Turkish population.


Progress toward measles elimination--Eastern Mediterranean Region, 2008-2012.
In 1997, the 22 countries in the World Health Organization (WHO) Eastern Mediterranean Region (EMR) adopted a goal of measles elimination by 2010. To achieve this goal, the WHO Regional Office for the Eastern Mediterranean Region (EMRO) developed a four-pronged strategy: 1) achieve ≥ 95% vaccination coverage of children with the first dose of measles-containing vaccine (MCV1) in every district of each country through routine immunization services, 2) achieve ≥ 95% vaccination coverage with the second dose of measles-containing vaccine (MCV2) in every district of each country either through a routine 2-dose vaccination schedule or through supplementary immunization activities (SIAs), 3) conduct high-quality, case-based surveillance in all countries, and 4) provide optimal clinical case management, including supplementing diets with vitamin A. Although significant progress was made toward measles elimination in the EMR during 1997-2007, the measles elimination goal was not reached by the target date of 2010, and the date was revised to 2015. This report updates previous reports and summarizes the progress made toward measles elimination in EMR during 2008-2012. From 2008 to 2012, large outbreaks occurred in countries with a high incidence of measles, and reported annual measles cases in EMR increased from 12,186 to 36,456. To achieve measles elimination in EMR, efforts are needed to increase 2-dose vaccination coverage, especially in countries with high incidence of measles and in conflict-affected countries, and to implement innovative strategies to reach populations at high risk in areas with poor access to vaccination services or with civil strife.


Do Knee Pain Phenotypes Have Different Risks of Total Knee Replacement?
Pain is the main impetus for osteoarthritis (OA) patients to seek healthcare including joint replacement. The pain experience in OA is heterogeneous and affected by factors across multiple domains-peripheral, psychological, and neurological. This indicates the existence of homogenous subgroups/phenotypes within OA patients with pain. We recently identified three pain phenotypes using a wide spectrum of pain-related factors, including structural damage on magnetic resonance imaging (MRI), emotional problems, number of painful sites, sex, body mass index, education level and comorbidities (i.e., Class 1: high prevalence of emotional problems and low prevalence of structural damage (25%); Class 2: low prevalence of emotional problems and high prevalence of structural damage (20%); Class 3: low prevalence of emotional problems and low prevalence of structural damage (55%)). This study was to examine whether the total knee replacement (TKR) risk over 12 years was different among these three pain phenotypes. Data on 963 participants (mean age 62.8 ± 7.4 years) from a population-based cohort study were utilised. Data on socio-demographic, psychological and comorbidities were collected. MRI of the right knee structural pathology was performed. TKR history was ascertained by linking to the Australian Orthopedic Association National Joint Replacement Registry. Latent class analysis and the Cox proportional hazards model were applied for the analysis. During the follow-up period, 41 right and 44 left TKRs in 67 participants were identified. In multivariable analyses, participants in Class 1 and 2 had a higher risk of having a TKR (Class 1 vs. Class 3, HR (hazard ratio) 4.81, 95%CI (confidence interval) 2.33-9.93; Class 2 vs. Class 3, HR 9.23, 95%CI 4.66-18.30). These associations were stronger in the imaged right knee but were also significant in the left knee. Participants within distinct pain phenotypes have different risks of TKR, suggesting that the identified phenotypes reflect distinct clinical subgroups with different prognoses. The risk for TKR was higher in Class 1 than that in Class 3, suggesting that pain/emotional status is a stronger driver for TKR than structural damage, and that selecting patients for TKR needs to be optimized in clinical practice.


Differential MCMI-III psychopathological profiles between intimate partner violence perpetrators with and without childhood family violence.
This study explored the differential prevalence of personality disorders (PD) and clinical syndromes between male perpetrators of intimate partner violence (IPV) with and without a history of childhood family violence (CFV). A sample of 981 perpetrators of IPV was assessed with the Millon Clinical Multiaxial Inventory-III (MCMI-III). Comparisons of sociodemographic characteristics and MCMI-III scales' scores between perpetrators with (n = 293) and without (n = 688) CFV were carried out. Results showed that IPV perpetrators with CFV had a lower level of education, were less frequently employed, and had higher rates of previous psychiatric history than perpetrators without CFV. Statistically significant differences between groups in almost all the MCMI-III scales were found. Perpetrators with CFV presented with higher scores on most of the evaluated scales and showed a more severe psychopathological profile than perpetrators without CFV. The multivariate analysis showed that the main MCMI-III domains related to CFV were higher scores on the disclosure and alcohol dependence scales and lower scores on the passive-aggressive scale. These findings reveal that CFV is associated with a more severe psychopathological profile in perpetrators of IPV. In order to develop tailored interventions, the presence of CFV and psychopathological symptoms should be assessed in IPV perpetrators.


Methyl donor supplementation suppresses the progression of liver lipid accumulation while modifying the plasma triacylglycerol lipidome in periparturient Holstein dairy cows.
Co-supplementation of methyl donors may lower hepatic lipid content in transition cows. To define the ability of methyl donor supplementation (MDS) to reduce hepatic lipid content and modify the plasma lipidome, 30 multiparous Holstein cows (2.04 ± 0.69 lactations; 689 ± 58 kg of body weight; 3.48 ± 0.10 units of body condition score) were fed a ration with or without rumen-protected methyl donors (22 g/d of Met, 10 g/d of choline chloride, 3 g/d of betaine, 96 mg/d of riboflavin, and 1.4 mg/d of vitamin B12) from d -28 before expected calving through d 14 postpartum. Cows were randomly enrolled based on predefined selection criteria (body condition score and parity). Base diets without MDS were formulated for gestation (15.4% crude protein with a predicted Lys-to-Met ratio of 3.25; 1.44 Mcal of net energy for lactation/kg of dry matter) and lactation (16.6% crude protein with a predicted Lys-to-Met ratio of 3.36; 1.64 Mcal of net energy for lactation/kg of dry matter). Blood sampling occurred from d -28 relative to expected calving through d 14 postpartum. Liver tissue was biopsied at d -28 relative to expected calving and on d 5 and 14 postpartum. In addition to routine analyses, serum AA concentrations on d 10 and 12 were quantified using mass spectrometry. Plasma triacylglycerol (TAG) and cholesteryl esters (CE) were qualitatively measured using time-of-flight mass spectrometry. Data were analyzed using a mixed model with repeated measures. Dry matter intake and milk yield were not modified by MDS. The transition from d -28 relative to expected parturition to d 14 postpartum was characterized by increased plasma fatty acid (0.15 to 0.71 mmol/L) and β-hydroxybutyrate (0.34 to 0.43 mmol/L) levels and liver lipid content (3.91 to 9.16%). Methyl donor supplementation increased the serum Met level by 26% and decreased the serum Lys-to-Met ratio by 21% on d 10 and 12, respectively. Moreover, the increase in hepatic lipid content from d 5 through 14 postpartum was suppressed with MDS relative to control (3.57 vs. -0.29%). Dietary MDS modified the TAG and CE lipidome. For example, MDS increased plasma TAG 46:3 (carbon number:double bond) by 116% relative to control cows on d 5 postpartum. Moreover, MDS tended to increase plasma CE 34:6. In contrast, MDS lowered plasma TAG 54:8 by 39% relative to control cows on d 5 postpartum. We concluded that in the absence of gains in dry matter intake and milk and milk protein yields, dietary MDS slows the progression of hepatic lipid accumulation and modifies the plasma TAG lipidome in transition cows.


Applications of CRISPR/Cas9 for the Treatment of Duchenne Muscular Dystrophy.
Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive neuromuscular disease prevalent in 1 in 3500 to 5000 males worldwide. As a result of mutations that interrupt the reading frame of the dystrophin gene (DMD), DMD is characterized by a loss of dystrophin protein that leads to decreased muscle membrane integrity, which increases susceptibility to degeneration. CRISPR/Cas9 technology has garnered interest as an avenue for DMD therapy due to its potential for permanent exon skipping, which can restore the disrupted DMD reading frame in DMD and lead to dystrophin restoration. An RNA-guided DNA endonuclease system, CRISPR/Cas9 allows for the targeted editing of specific sequences in the genome. The efficacy and safety of CRISPR/Cas9 as a therapy for DMD has been evaluated by numerous studies in vitro and in vivo, with varying rates of success. Despite the potential of CRISPR/Cas9-mediated gene editing for the long-term treatment of DMD, its translation into the clinic is currently challenged by issues such as off-targeting, immune response activation, and sub-optimal in vivo delivery. Its nature as being mostly a personalized form of therapy also limits applicability to DMD patients, who exhibit a wide spectrum of mutations. This review summarizes the various CRISPR/Cas9 strategies that have been tested in vitro and in vivo for the treatment of DMD. Perspectives on the approach will be provided, and the challenges faced by CRISPR/Cas9 in its road to the clinic will be briefly discussed.


A randomized controlled trial of cognitive remediation in schizophrenia.
Individuals with schizophrenia have consistently been found to exhibit cognitive deficits, which have been identified as critical mediators of psychosocial functional outcomes. Recent reviews of cognitive remediation (CRT) have concluded that these deficits respond to training. This multi-site community study examined 40 individuals with schizophrenia who underwent cognitive remediation using the Neuropsychological Educational Approach to Remediation(1) (NEAR). Assessments using the same neuropsychological tests and measures of psychosocial outcome were made at four time points: baseline, before start of active intervention, end of active intervention and 4 months after end of active intervention. Dose of antipsychotic medication remained constant throughout the study period. After participating in NEAR, individuals showed significant improvements in verbal and visual memory, sustained attention and executive functioning. This effect persisted 4 months after the treatment ceased. The average effect size was mild to moderate. Social and occupational outcomes also improved from baseline to post-treatment, which persisted 4 months later. Our findings replicate those of previous studies that suggest that NEAR is effective in improving cognition in individuals with schizophrenia in a naturalistic and ecologically valid setting. Further it extends such findings to show a generalisation of effects to social/occupational outcomes and persistence of effects in the short term.


Radié: visualizing taxon properties and parsimonious mappings using a radial phylogenetic tree.
A phenotypic character has a convex mapping to a given phylogenetic tree if each character state can be assigned a single point of origin in the tree. However, phenomena such as convergent evolution and lateral genetic transfer can lead to intermingling of character states and a consequent non-convex mapping. The phylogenetic heterogeneity of different characters can identify subsets of states that are non-randomly associated or which may have been transferred from one lineage to another. We have developed Radié, an interactive 3D Java application for mapping character states to the leaves and internal edges of a radial phylogenetic tree. In Radié each state of a given character is associated with a unique color, and internal edges with many descendant character states can be represented in a number of different ways to illustrate the diversity within each group. Radié is freely available for download at http://kiwi.cs.dal.ca/~beiko/software-and-data/radie; source code is available upon request from the authors.


Accuracy of pedicle screw placement for lumbar fusion using anatomic landmarks versus open laminectomy: a comparison of two surgical techniques in cadaveric specimens.
We determined whether the accuracy of lumbar pedicle screw placement is optimized by performing a laminectomy before screw placement with screw entry point and trajectory being guided by pedicle visualization and palpation (Technique 1). This technique was compared with a technique using anatomic landmarks for pedicle screw placement (Technique 2). The biomechanical stability of the instrumented constructs, in the absence and presence of a laminectomy, was also compared. Twelve L1-L3 specimens were harvested from fresh cadavers. The intact laminectomy and instrumented spines were biomechanically tested in flexion and extension, lateral bending, and axial rotation. Laminectomies were performed in six of the 12 specimens before pedicle screw placement using Technique 1. The remaining six specimens underwent pedicle screw and rod fixation using Technique 2. Computed tomographic images were obtained for all instrumented specimens. Deviation of the screws from the ideal entry point or trajectory was analyzed to quantitatively compare the two techniques. Computed tomographic analysis of the specimens showed that all screw placements were within the pedicles. Scatter plot analysis demonstrated that screws placed using Technique 2 were more likely to have the combination of entry points and trajectories medial to the ideal entry point and trajectory. Laminectomy did not weaken the final pedicle screw and rod-fixated constructs. All screw placements were grossly within the confines of the pedicles, regardless of technique, as evidenced by computed tomographic analysis. Furthermore, the anatomic landmark technique and the open laminectomy technique yielded biomechanically equivalent pedicle screw and rod-fixated constructs.


Decreased expression of manganese superoxide dismutase in transformed cells is associated with increased cytosine methylation of the SOD2 gene.
Tumor cells express lower levels of manganese superoxide dismutase (MnSOD) than their normal counterparts. Enforced expression of MnSOD reverses the malignant phenotype of many transformed cells, suggesting that SOD2 is a tumor suppressor. The SOD2 gene contains a large CpG island spanning > 3.5 kb that starts near the 5' edge of the promoter and extends into intron 2. We hypothesized that the difference in SOD2 expression between tumor cells and their normal cell counterparts might be secondary to differences in their cytosine methylation patterns in this CpG island. To test this hypothesis, we analyzed the methylation status of the SOD2 gene in two cell line models that show differential MnSOD expression between normal and SV40-transformed cells: WI38 and MRC5 and their SV40-transformed variants, WI38-VA and MRC5-VA. We subdivided the SOD2 gene CpG island into 10 individual regions for analysis by bisulfite genomic sequencing. A region located in intron 2 displayed a significant increase in cytosine methylation in both transformed cell lines that expressed low levels of MnSOD mRNA compared with their normal cell counterparts. Recent studies by others have shown that SOD2 intron 2 is a potent transcriptional enhancer. The association between increased cytosine methylation of the SOD2 intron 2 region and decreased MnSOD expression in transformed cells compared with their normal counterparts suggests that an epigenetic mechanism contributes to the differential SOD2 gene expression between these normal and SV40-transformed cells.


Single-stage bilateral conversion arthroplasty for hip fusion via direct anterior approach in a patient with severe ankylosing spondylitis and kyphoscoliosis: a case report.
Severe ankylosing spondylitis (AS) frequently involves hip joints and, occasionally, presents with concurrent spinal deformities, such as kyphoscoliosis, creating complex challenges for surgical management. We present a 26-year-old Persian male with a history of AS and severe kyphoscoliosis, leading to bilateral hip fusion and immobility. Following spinal deformity correction, a one-stage bilateral conversion to total hip arthroplasty (THA) was conducted through the direct anterior approach. Primary correction of spinal deformities allows for extended surgical procedures under general anesthesia. Single stage bilateral hip conversion arthroplasty via the direct anterior approach enhances postoperative mobilization, reduce the risk of re-ankylosis, and improve the overall quality of life for AS patients with this unique presentation.


The Cth2 ARE-binding protein recruits the Dhh1 helicase to promote the decay of succinate dehydrogenase SDH4 mRNA in response to iron deficiency.
Iron is an essential nutrient that participates as a redox co-factor in a broad range of cellular processes. In response to iron deficiency, the budding yeast Saccharomyces cerevisiae induces the expression of the Cth1 and Cth2 mRNA-binding proteins to promote a genome-wide remodeling of cellular metabolism that contributes to the optimal utilization of iron. Cth1 and Cth2 proteins bind to specific AU-rich elements within the 3'-untranslated region of many mRNAs encoding proteins involved in iron-dependent pathways, thereby promoting their degradation. Here, we show that the DEAD box Dhh1 helicase plays a crucial role in the mechanism of Cth2-mediated mRNA turnover. Yeast two-hybrid experiments indicate that Cth2 protein interacts in vivo with the carboxyl-terminal domain of Dhh1. We demonstrate that the degradation of succinate dehydrogenase SDH4 mRNA, a known target of Cth2 on iron-deficient conditions, depends on Dhh1. In addition, we localize the Cth2 protein to cytoplasmic processing bodies in strains defective in the 5' to 3' mRNA decay pathway. Finally, the degradation of trapped SDH4 mRNA intermediates by Cth2 supports the 5' to 3' directionality of mRNA turnover. Taken together, these results suggest that Cth2 protein recruits the Dhh1 helicase to ARE-containing mRNAs to promote mRNA decay.


A Promising Future for Precision Epigenetic Therapy for Follicular and Diffuse Large B-Cell Lymphoma?
Epigenetic mechanisms such as DNA hypermethylation or histone deacetylation normally silence gene expression that regulates numerous cellular activities. Germinal center-derived lymphomas such as follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL) are characterized by frequent mutations of histone-modifying genes. EZH2 is essential to the formation of germinal center in the secondary lymphoid tissue (eg, lymph nodes and spleen) and is one of the most frequently mutated histone-modifying genes in human lymphomas. EZH2 encodes a histone methyltransferase, mediates transcriptional repression and acts as an oncogene that promotes the development and progression of a variety of human malignancies, including FL and DLBCL. Thus, recurrent mutations in the EZH2 and other non-histone epigenetic regulators represent important targets for therapeutic interventions. Recently, an orally active inhibitor of EZH2, tazemetostat, has received regulatory approval for patients with mutated EZH2 relapsed or refractory FL after ≥2 prior systemic therapies. It is also approved for those with relapsed or refractory FL who have no satisfactory alternative treatment options, regardless of their mutational status of EZH2. Currently, tazemetostat and its combination therapies for patients with relapsed or refractory germinal center-derived lymphomas, as well as frontline therapies for previously untreated patients, are in various phases of clinical investigations. Despite the promise of epigenetic therapies, potential pitfalls such as target selectivity, risk of oncogenic activation, risk of secondary malignancies associated with epigenetic therapies must be carefully monitored. Future applications of epigenetic approach that incorporate clinical and genomic features are needed to determine how individualized treatments can be used for these hematologic malignancies.


Partial characterization of an enzymatic extract from Bentong ginger (Zingiber officinale var. Bentong).
Extraction of protease from a local ginger rhizome (Zingiber officinale var. Bentong) was carried out. The effect of extraction pH (6.4, 6.8, 7.0, 7.2, 7.6, 8.0, 8.4, and 8.8) and stabilizers (0.2% ascorbic acid, 0.2% ascorbic acid and 5 mM EDTA, or 10 mM cysteine and 5 mM EDTA) on protease activity during extraction was examined. pH 7.0 potassium phosphate buffer and 10 mM cysteine in combination with 5 mM EDTA as stabilizer were found to be the most effective conditions. The extraction procedure yielded 0.73% of Bentong ginger protease (BGP) with a specific activity of 24.8±0.2 U/mg protein. Inhibitory tests with some protease inhibitors classified the enzyme as a cysteine protease. The protease showed optimum activity at 60 °C and pH 6-8, respectively. The enzyme was completely inhibited by heavy metal cations such as Cu2+, and Hg2+. SDS stimulated the activity of enzyme, while emulsifiers (Tween 80 and Tween 20) slightly reduced its activity. The kinetic analysis showed that the protease has Km and Vmax values of 0.21 mg mL-1 and 34.48 mg mL-1 min-1, respectively. The dried enzyme retained its activity for 22 months when stored at -20 °C.


Is diet flexibility an adaptive life trait for relictual and peri-urban populations of the endangered primate Macaca sylvanus?
Habitat loss, fragmentation and urban expansion may drive some species to marginal habitats while others succeed in exploiting urban areas. Species that show dietary flexibility are more able to take advantage of human activities to supplement their diet with anthropogenically abundant and accessible resources. The Barbary macaque (Macaca sylvanus) is an endangered species due to the loss of its habitat, and human pressure. The population of Gouraya National Park (Algeria) lives in a relictual habitat that constitutes about 0.6% of the species range. In addition, this population is a unique case where urban expansion favours contact zones between Barbary macaque habitats and a big city (Bejaia). We quantified the dietary composition of Gouraya macaques over an annual cycle with the objective to understand how diet flexibility of this species may help it adapt to a relictual habitat or cope with urban expansion. We recorded the phenology of plant species every month. This study shows that Gouraya macaques, compared to those living in other forest types of the distribution area, are under lower seasonal constraints. They consume a greater amount of fruit and seeds that are available throughout much of the year, and a lesser amount of costly to find and extract subterranean foods. Therefore the Gouraya relictual habitat appears as a favourable environment compared to other major habitats of that species. This study also shows that colonizing peri-urban zones increases the availability and species richness of diet resources for Barbary macaques as they consume more human foods and exotic plants than in farther sites. Adult males eat more human foods than adult females and immatures do. The exploitation of high-energy anthropogenic food could favour macaque population growth and expansion towards the city center associated with human/macaque conflicts. We recommend applying management actions to restore macaques back to their natural habitat.


Serum CDC42 reflects the exacerbation risk and severity, Th1/2 cell imbalance and inflammation in asthmatic children.
Aim: To explore the clinical implication of serum CDC42 in asthmatic children. Materials & methods: Serum CDC42 from 80 asthmatic children experiencing exacerbation, 80 asthmatic children in remission and 40 healthy controls was detected by ELISA. Results: CDC42 was highest in asthmatic children experiencing exacerbation followed by asthmatic children in remission and healthy controls (p < 0.001). Among asthmatic children experiencing exacerbation, CDC42 positively correlated with exacerbation severity (p = 0.011), Th2 (p = 0.017), TNF-α (p < 0.001), IL-6 (p = 0.009) and IL-8 (p = 0.008) and negatively correlated with Th1/Th2 ratio (p = 0.028). In asthmatic children in remission, CDC42 correlated with lower Th1/Th2 ratio (p = 0.028) and higher TNF-α (p = 0.026). In healthy controls, CDC42 showed no correlation with Th1/2 or inflammatory cytokines. Conclusion: Circulating CDC42 reflects exacerbation risk, Th1/2 imbalance and inflammation in asthmatic children.


Which patients initiate cognitive processing therapy and prolonged exposure in department of veterans affairs PTSD clinics?
The United States Department of Veterans Affairs (VA) provides Cognitive Processing Therapy (CPT) and Prolonged Exposure therapy (PE) for PTSD at all of its facilities, but little is known about systematic differences between patients who do and do not initiate these treatments. VA administrative data were analyzed for 6,251 veterans receiving psychotherapy over one year in posttraumatic stress disorder (PTSD) specialty clinics at nine VA medical centers. CPT and PE were initiated by 2,173 (35%) patients. Veterans' probability of initiating either CPT or PE (considered together) was 29% lower (adjusted odds ratio = .61) if they had a psychiatric hospitalization within the same year, and 15% lower (AOR = .78) if they had service-connected disability for PTSD. Veterans' probability of starting CPT or PE was 19% lower (AOR = .74) if they were Hispanic or Latino, 10% lower (AOR = .84), if they were male rather than female, and 9% lower (AOR = .87) if they were divorced, separated or widowed rather than currently married. Probability of receiving CPT or PE was also lower if verans had more co-occurring psychiatric diagnoses (AOR per diagnosis = .88), were older (AOR per every five years = .95), or lived further away from the VA clinic (AOR per every ten miles = .98). Nonetheless, most patients initiating CPT or PE had two or more comorbidities and were service-connected for PTSD. Observed gender, age and ethnic differences in initiation of CPT and PE appear unrelated to clinical suitability and warrant further study.


Detection of urinary drug metabolite (xenometabolome) signatures in molecular epidemiology studies via statistical total correlation (NMR) spectroscopy.
Western populations use prescription and nonprescription drugs extensively, but large-scale population usage is rarely assessed objectively in epidemiological studies. Here we apply statistical methods to characterize structural pathway connectivities of metabolites of commonly used drugs detected routinely in 1H NMR spectra of urine in a human population study. 1H NMR spectra were measured for two groups of urine samples obtained from U.S. participants in a known population study. The novel application of a statistical total correlation spectroscopy (STOCSY) approach enabled rapid identification of the major and certain minor drug metabolites in common use in the population, in particular, from acetaminophen and ibuprofen metabolites. This work shows that statistical connectivities between drug metabolites can be established in routine "high-throughput" NMR screening of human samples from participants who have randomly self-administered drugs. This approach should be of value in considering interpopulation patterns of drug metabolism in epidemiological and pharmacogenetic studies.


Enthalpy-entropy compensation in biomolecular halogen bonds measured in DNA junctions.
Interest in noncovalent interactions involving halogens, particularly halogen bonds (X-bonds), has grown dramatically in the past decade, propelled by the use of X-bonding in molecular engineering and drug design. However, it is clear that a complete analysis of the structure-energy relationship must be established in biological systems to fully exploit X-bonds for biomolecular engineering. We present here the first comprehensive experimental study to correlate geometries with their stabilizing potentials for fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) X-bonds in a biological context. For these studies, we determine the single-crystal structures of DNA Holliday junctions containing halogenated uracil bases that compete X-bonds against classic hydrogen bonds (H-bonds), estimate the enthalpic energies of the competing interactions in the crystal system through crystallographic titrations, and compare the enthalpic and entropic energies of bromine and iodine X-bonds in solution by differential scanning calorimetry. The culmination of these studies demonstrates that enthalpic stabilization of X-bonds increases with increasing polarizability from F to Cl to Br to I, which is consistent with the σ-hole theory of X-bonding. Furthermore, an increase in the X-bonding potential is seen to direct the interaction toward a more ideal geometry. However, the entropic contributions to the total free energies must also be considered to determine how each halogen potentially contributes to the overall stability of the interaction. We find that bromine has the optimal balance between enthalpic and entropic energy components, resulting in the lowest free energy for X-bonding in this DNA system. The X-bond formed by iodine is more enthalpically stable, but this comes with an entropic cost, which we attribute to crowding effects. Thus, the overall free energy of an X-bonding interaction balances the stabilizing electrostatic effects of the σ-hole against the competing effects on the local structural dynamics of the system.


Coma following ECT and intravenous droperidol: case report.
A 60-year-old man with psychotic depression became comatose following the administration of intravenous droperidol given for post-ECT delirious agitation. The differential diagnosis, which included neuroleptic malignant syndrome and the possibility that droperidol may have uniquely detrimental effects in the context of post-ECT delirium, are discussed. In light of recent publications advocating droperidol as the pharmacologic treatment of choice for severe agitation, this case illustrates a need for greater caution in its use for the treatment of post-ECT delirium.


Zolpidem, a novel nonbenzodiazepine hypnotic. II. Effects on cerebellar cyclic GMP levels and cerebral monoamines.
The effect of zolpidem, a novel nonbenzodiazepine short-acting hypnotic, on cerebellar cyclic GMP (cGMP) and biochemical indices of cerebral norepinephrine, serotonin and dopamine metabolism has been investigated in the rat and mouse. Zolpidem diminished the levels of cerebellar cGMP in the rat markedly (ED50 = 0.7 mg/kg i.p.). This effect was antagonized, in a competitive manner, by the benzodiazepine antagonist Ro 15-1788. The zolpidem-induced decrease of cerebellar cGMP levels was rapid in onset and of short duration (less than 1 hr). When given in combination with muscimol (in a dose which by itself did not alter cerebellar cGMP content) zolpidem potentiated the diminution of the cyclic nucleotide levels induced by the gamma-aminobutyric acid mimetic. Zolpidem (up to 30 mg/kg i.p.) failed to alter the rate of utilization of norepinephrine or the levels of total 3,4-dihydroxyphenylethyleneglycol or 3-methoxy, 4-hydroxyphenylethyleneglycol sulfate in the rat brain. However, the compound (10-30 mg/kg) diminished serotonin synthesis in the hippocampus, striatum and frontal cortex. At high doses (30-100 mg/kg i.p.), zolpidem also decreased the rate of utilization of dopamine and 3,4-dihydroxyphenylacetic acid levels in the rat striatum. Moreover, zolpidem (10 mg/kg i.p.) prevented partially the haloperidol-induced increase in 3,4-dihydroxyphenylacetic acid concentrations in both striatum and frontal cortex. Finally, zolpidem prevented the increase in 3,4-dihydroxyphenylacetic acid levels in the frontal cortex induced by electric footshock stress in rats (ED50 = 2 mg/kg i.p.) and BALB/C mice. This effect was antagonized by coadministration of Ro 15-1788.