Dynamics and directionality in complex networks.
We investigate how we can improve the synchronizability of complex networks simply by changing the link direction while conserving the local link weights and topology. Performing the linear stability analysis of synchronization and numerical simulation of the Kuramoto model in the directed networks, we find that while a random assignment of link directions generally weakens the degree of synchronization, a properly organized directionality can systematically enhance the network synchronization. In this respect, we suggest a simple method of changing the link direction according to the larger residual degree starting from small residual degree nodes. This result provides plausible applications to control the synchronizability of systems in various fields.


[Clinical and ultrasonic diagnosis of hematometra following curettage].
By hands of a case report we describe our diagnostic management in a patient suffering from hematometra 3 months after legal abortion. Sonography plays an important role in such cases to detect and explain the symptoms "metrorrhagy and uterine cramps monthly connected with small inflammatory signs". For curing we did a probing of the uterine cavity to eliminate the residual blood coagulas. 3 months after curing the hematometra the patient was clinically and sonographically without bodily ailments. Hypotheses about etiology and treatment of this rare condition are reviewed.


Less-than-expected variability in evidence for three stages in memory formation.
Gibbs and Ng (1976, 1977) proposed a three-stage model of long-term memory formation on the basis of results from a one-trial-learning passive-avoidance procedure using chicks. Chisquare tests show that much of the evidence for this model (Gibbs & Ng, 1976, 1977, 1979, 1984a, 1984b), involving transient drops in retention and drug effects, is less variable than would be expected by chance. This should reduce belief in the model.


The use of therapeutic drug monitoring in the management of protease inhibitor-related toxicity.
The aim of this project was to determine whether therapeutic drug monitoring (TDM) and subsequent dose modification is effective in the management of protease inhibitor (PI)-associated toxicity. A retrospective case-notes review of patients who had had TDM for suspected antiretroviral drug toxicity from November 2000 to March 2002 was carried out. This identified six symptomatic patients in whom high plasma drug levels of a PI had been found and subsequent dose modification was associated with improvement/resolution of symptoms. In 5/6 patients viral loads were below the level of detection prior to TDM and remained so after dose reduction of PI. TDM-directed dose modification of PI enables patients to continue effective regimens of highly active antiretroviral therapy, thus avoiding the need to switch the regimen.


Minimally Invasive Excision of Lumbar Tophaceous Gout: Case Report.
Symptomatic spinal gout is relatively rare. Open laminectomy, with or without fusion, has been so far the standard treatment for symptomatic spinal gout. We describe here the first case of spinal tophaceus gout treated with minimally invasive surgery. A 60-year-old patient, morbidly obese, with no previous history of gout, presented with neurogenic claudication due to severe lumbar canal stenosis at L3/4. Surgery was performed through a minimally invasive approach, using tubular retractors. During surgery, an extradural mass with a thin capsule and containing white "chalky" partially calcified material, slightly adherent to and compressing the theca, was removed. There were no intra- or perioperative complications. Surgery successfully improved the functional status, with a significant increase in walking distance and no residual leg pain or neurogenic claudication. Histopathology confirmed the diagnosis of spinal tophaceous gout. Although spinal gout is usually responsive to medical treatment, surgery is often the first line treatment, particularly in patients with neurological deficits. Would surgery be indicated, we believe that minimally invasive surgery can be effective in treating symptomatic spinal tophaceous gout. Level of Evidence: Class IV.


Synthesis of semiconducting polymer microparticles as solid ionophore with abundant complexing sites for long-life Pb(II) sensors.
Intrinsically electrically semiconducting microparticles of semiladder poly(m-phenylenediamine-co-2-hydroxy-5-sulfonic aniline) structures containing abundant functional groups, like -NH-, -N=, -NH2, -OH, -SO3H as complexation sites, were efficiently synthesized by chemical oxidative copolymerization of m-phenylenediamine and 2-hydroxy-5-sulfonic aniline. The obtained copolymers were found to be nonporous spherical microparticles that were able to achieve greater π-conjugated structure, smaller particle aggregate size, and stronger interaction with Pb(II) ions than poly(m-phenylenediamine) containing only -NH-, -N=, and -NH2. A potentiometric Pb(II) sensor was fabricated on the basis of the copolymer microparticles as a crucial solid ionophore component within plasticized PVC. The sensor exhibited a Nernstian response to Pb(II) ions over a wide concentration range, together with a fast response, a wide pH range capability, a long lifetime of up to 5 months, and good selectivity over a wide variety of other ions and redox species. The process for synthesizing the microparticles and fabricating the Pb(II)-sensor can be facilely scaled-up for use in the straightforward long-term online monitoring of Pb(II) ions in heavily polluted wastewaters. This study develops an understanding of the facile synthesis of conducting microparticles bearing many functional groups and their structures governing the potentiometric susceptibility toward interaction between Pb(II) ions and the microparticles for fabricating robust long-lived Pb(II)-sensor, signifying the potential suitability of such novel materials for inexpensive sensitive detection of Pb(II) ions.


[Optimal concentration of superparamagnetic iron oxide-short hairpin RNA dual functional molecular probe transfected into ovarian cancer cells in vitro].
To explore the effects of superparamagnetic iron oxide-short hairpin RNA (SPIO-ShRNA) dual functional molecular probes of different concentrations on morphology and biological behavior of ovarian cancer SKOV3 cells in vitro. The dual functional molecular probes at an iron concentration of 5, 15, 30, 45, 75, and 100 mg/L were transfected into SKOV3 cells. The transfection rate of the probe was observed by fluorescence microscope. The distribution and content of iron particles in SKOV3 cells were determined by Prussian blue staining, atomic adsorption spectrometer and electron microscopy. Cell viability was observed by cell counting kit-8 (CCK-8).The apoptosis was detected by flow cytometry. The expression of protein within the cells was detected by Western blot. The changes of the signal intensity were measured by magnetic resonance imaging (MRI). The SPIO-ShRNA dual functional molecular probe was uptaken in aconcentration-dependence manner within a certain range (5-30 mg/L). When the concentration of the probe was 45 mg/L, the labeling rate of the cell was close to 100%; With the increase of the concentration of probe, the cell survival rate decreased gradually. The cell survival rate of each experimental group were 94.626%±1.050%, 93.373%±1.180%, 91.700%±3.122%, 75.100%±4.362%, 72.983%±3.233%, 71.010%±2.910%,5, 15, 30 mg/L cell survival rate was not significantly decreased, the difference was not statistically significant (P=0.226, P=0.068, P=0.475); When the concentration of the probe was greater than or equal to 45 mg/L,the survival rate decreased obviously (P<0.001); Group of 45 mg/L protein expression rate was 68.905%±3.510%, When the concentration of the probe was greater than or equal to 45 mg/L, the inhibition rate of the protein expression level of epidermal growth factor receptor was obviously higher than those of 5, 15, and 30 mg/L groups, the difference was statistically significant (P<0.001, P=0.001, P=0.003, all P<0.01); the MRI displayed that the signal intensity was decreased with increasing concentrations of the probe. The signal intensity of 45 mg/L group was 165.55±4.92, compared with the blank control group(same volume of phosphate buffer saline), normal group (unlabeled ovarian cancer SKOV3 cells), 5, 15, and 30 mg/L groups , the signal intensity of 45 mg/L group decreased significantly (all P<0.001). The dual functional molecular probe can effectively transfect and specifically inhibit the expression of SKOV3 cell lines at the iron concentration of 45 mg/L, and can also be detected by MRI. The role of diagnosis and treatment of the dual functional molecular probe has been initially confirmed.


Cumulative social disadvantage and health-related quality of life: national health interview survey 2013-2017.
Evidence for the association between social determinants of health (SDoH) and health-related quality of life (HRQoL) is largely based on single SDoH measures, with limited evaluation of cumulative social disadvantage. We examined the association between cumulative social disadvantage and the Health and Activity Limitation Index (HALex). Using adult data from the National Health Interview Survey (2013-2017), we created a cumulative disadvantage index by aggregating 47 deprivations across 6 SDoH domains. Respondents were ranked using cumulative SDoH index quartiles (SDoH-Q1 to Q4), with higher quartile groups being more disadvantaged. We used two-part models for continuous HALex scores and logistic regression for poor HALex (< 20th percentile score) to examine HALex differences associated with cumulative disadvantage. Lower HALex scores implied poorer HRQoL performance. The study sample included 156,182 respondents, representing 232.8 million adults in the United States (mean age 46 years; 51.7% women). The mean HALex score was 0.85 and 17.7% had poor HALex. Higher SDoH quartile groups had poorer HALex performance (lower scores and increased prevalence of poor HALex). A unit increase in SDoH index was associated with - 0.010 (95% CI [-0.011, -0.010]) difference in HALex score and 20% higher odds of poor HALex (odds ratio, OR = 1.20; 95% CI [1.19, 1.21]). Relative to SDoH-Q1, SDoH-Q4 was associated with HALex score difference of -0.086 (95% CI [-0.089, -0.083]) and OR = 5.32 (95% CI [4.97, 5.70]) for poor HALex. Despite a higher burden of cumulative social disadvantage, Hispanics had a weaker SDoH-HALex association than their non-Hispanic White counterparts. Cumulative social disadvantage was associated with poorer HALex performance in an incremental fashion. Innovations to incorporate SDoH-screening tools into clinical decision systems must continue in order to accurately identify socially vulnerable groups in need of both clinical risk mitigation and social support. To maximize health returns, policies can be tailored through community partnerships to address systemic barriers that exist within distinct sociodemographic groups, as well as demographic differences in health perception and healthcare experience.


Cellular mechanism of substance P in the regulation of corticosteroid secretion by newt adrenal gland.
In this work, we have studied the effects and the possible cellular mechanism of Substance P (SP) on corticosteroid secretion by the adrenal gland of the urodele crested newt, Triturus carnifex. Adrenals were in vitro superfused with SP, prostaglandin E2 (PGE2), nitric oxide (NO) donor, cyclic GMP (cGMP) analogue, and inhibitors of phospholipase A1, phospholipase A2 (PLA2), phospholipase C, adenylate cyclase (AC), cyclooxygenase (COX), NO synthase (NOS), and soluble guanylate cyclase (sGC). PGE2, corticosterone, and aldosterone release and NOS activity were determined. SP, PGE2, NO donor, and cGMP analogue increased corticosterone and aldosterone; SP and PGE2 increased NOS, and SP increased PGE2. PLA2, AC, COX, NOS, and sGC inhibitors counteracted SP and PGE2 effects, except for PLA2, which did not affect PGE2. These results suggest that SP exhibits a stimulatory role on the corticosteroidogenesis of T. carnifex adrenal gland. In particular SP enhances PLA2 activity, increasing PGE2; this prostaglandin affects AC, which, in turn, enhances NO, and the latter therefore affects sGC, with the consequent corticosteroidogenesis increase.


Treatment of cocaine dependence and depression.
In common with all other classes of substance use disorders, cocaine dependence has been shown to be strongly associated with depression by community and clinical surveys. Diagnosing depression in cocaine abusers can be challenging because it is difficult to distinguish transient symptoms caused by cocaine from enduring depression syndromes. Nonetheless, both "substance-induced" and "independent" depression syndromes require clinical attention, especially when symptoms have been persistent and severe before entering treatment. Use of antidepressant medications for combined cocaine dependence and depression is supported by a preponderance of evidence from 4 randomized clinical trials (RCTs) that prospectively targeted both depression and cocaine dependence and 7 RCTs in which a post hoc analyses demonstrated efficacy in the subgroup of cocaine abusers with comorbid depression. Notably, most negative studies have evaluated SSRIs while positive studies have used agents such as desipramine or buproprion. A substantial clinical trials literature supports the efficacy of behavioral treatments for general populations of cocaine abusers and of patients with depression but few studies have addressed patients with both disorders. Treatment development and research are needed on models of care that truly integrate strategies for addressing both cocaine use and depression. Recent advances have paved the way for a new generation of research. These include validation of efficacious cocaine treatments, improved diagnostic methods, organization of the Clinical Trials Network and development of guidelines for managing methodological challenges posed by high rates of current medication use and polysubstance abuse in treatment entering cocaine abusers.


Testing for the effects and consequences of mid paleogene climate change on insect herbivory.
The Eocene, a time of fluctuating environmental change and biome evolution, was generally driven by exceptionally warm temperatures. The Messel (47.8 Ma) and Eckfeld (44.3 Ma) deposits offer a rare opportunity to take a census of two, deep-time ecosystems occurring during a greenhouse system. An understanding of the long-term consequences of extreme warming and cooling events during this interval, particularly on angiosperms and insects that dominate terrestrial biodiversity, can provide insights into the biotic consequences of current global climatic warming. We compare insect-feeding damage within two middle Eocene fossil floras, Messel and Eckfeld, in Germany. From these small lake deposits, we studied 16,082 angiosperm leaves and scored each specimen for the presence or absence of 89 distinctive and diagnosable insect damage types (DTs), each of which was allocated to a major functional feeding group, including four varieties of external foliage feeding, piercing- and-sucking, leaf mining, galling, seed predation, and oviposition. Methods used for treatment of presence-absence data included general linear models and standard univariate, bivariate and multivariate statistical techniques. Our results show an unexpectedly high diversity and level of insect feeding than comparable, penecontemporaneous floras from North and South America. In addition, we found a higher level of herbivory on evergreen, rather than deciduous taxa at Messel. This pattern is explained by a ca. 2.5-fold increase in atmospheric CO(2) that overwhelmed evergreen antiherbivore defenses, subsequently lessened during the more ameliorated levels of Eckfeld times. These patterns reveal important, previously undocumented features of plant-host and insect-herbivore diversification during the European mid Eocene.


Matrix metalloproteinase 3 is present in the cell nucleus and is involved in apoptosis.
Matrix metalloproteinase (MMP)-3 is a protease involved in cancer progression and tissue remodeling. Using immunofluorescence and immunoelectron microscopy, we identified nuclear localization of MMP-3 in several cultured cell types and in human liver tissue sections. Western blot analysis of nuclear extracts revealed two immunoreactive forms of MMP-3 at 35 and 45 kd, with the 35-kd form exhibiting caseinolytic activity. By transient transfection, we expressed active MMP-3 fused to the enhanced green fluorescent protein (EGFP/aMMP-3) in Chinese hamster ovary cells. We showed that EGFP/aMMP-3 translocates into the nucleus. A functional nuclear localization signal was demonstrated by the loss of nuclear translocation after site-directed mutagenesis of a putative nuclear localization signal and by the ability of the MMP-3 nuclear localization signal to drive a heterologous protein into the nucleus. Finally, expression by Chinese hamster ovary cells of EGFP/aMMP-3 induced a twofold increase of apoptosis rate, compared with EGFP/pro-MMP-3, which does not translocate to the nucleus. Increased apoptosis was abolished by site-directed mutagenesis of the catalytic site of MMP-3 or by using the MMP inhibitor GM6001. This study elucidates for the first time the mechanisms of nuclear localization of a MMP and shows that nuclear MMP-3 can induce apoptosis via its catalytic activity.


Second and third harmonic waves excited by focused Gaussian beams.
Harmonic generation by tightly-focused Gaussian beams is finding important applications, primarily in nonlinear microscopy. It is often naively assumed that the nonlinear signal is generated predominantly in the focal region. However, the intensity of Gaussian-excited electromagnetic harmonic waves is sensitive to the excitation geometry and to the phase matching condition, and may depend on quite an extended region of the material away from the focal plane. Here we solve analytically the amplitude integral for second harmonic and third harmonic waves and study the generated harmonic intensities vs. focal-plane position within the material. We find that maximum intensity for positive wave-vector mismatch values, for both second harmonic and third harmonic waves, is achieved when the fundamental Gaussian is focused few Rayleigh lengths beyond the front surface. Harmonic-generation theory predicts strong intensity oscillations with thickness if the material is very thin. We reproduced these intensity oscillations in glass slabs pumped at 1550nm. From the oscillations of the 517nm third-harmonic waves with slab thickness we estimate the wave-vector mismatch in a Soda-lime glass as Δk(H)= -0.249μm(-1).


Elevated troponin levels associated with hemolysis.
A 75-year-old African American man with a history of gastroesophageal reflux reported chest pain during an episode of intravascular hemolysis. Although the electrocardiogram and echocardiogram were unchanged from baseline, cardiac troponin I was persistently elevated. Cardiac catheterization showed no critical disease, and the elevated troponin was attributed to interference by free hemoglobin and/or bilirubin. Hemoglobinemia and hyperbilirubinemia may produce either false-positive or false-negative troponin levels, depending on the assay used and the form or subunit of troponin measured. In the presence of hemolysis, troponin levels must be interpreted with caution.


Schema change without schema therapy: the role of early maladaptive schemata for a successful treatment of major depression.
Early maladaptive schemata (EMS) have repeatedly been shown to be associated with several psychopathological conditions, including depression. Schema therapy proposes interventions that aim at altering EMS. In the present study, we examined the effect of an integrative psychodynamic inpatient therapy without explicit focus on EMS in a sample with major depression. Forty-seven (38 female, 9 male) patients filled out the Symptom Checklist (SCL-90-R) and the Young Schema Questionnaire (YSQ) at the beginning and end of the treatment. Results revealed that EMS were significantly reduced in three out of five schema domains. Strong endorsement of EMS at the beginning of treatment tended to predict symptom reduction. More importantly, the reduction of symptom distress during treatment was strongly associated with a reduction in EMS of the schema domain Impaired Autonomy/Performance. We discuss that changes in EMS are highly relevant for changes in symptom distress but that EMS can not only be changed by schema therapy but also by other approaches, like psychodynamic therapy.


The interleukin-17 receptor plays a gender-dependent role in host protection against Porphyromonas gingivalis-induced periodontal bone loss.
Interleukin-17 (IL-17) is a proinflammatory cytokine secreted by the newly described CD4(+) Th17 subset, which is distinct from classic Th1 and Th2 lineages. IL-17 contributes to bone destruction in rheumatoid arthritis but is essential in host defense against pathogens that are susceptible to neutrophils. Periodontal disease (PD) is a chronic inflammatory condition initiated by anaerobic oral pathogens such as Porphyromonas gingivalis, and it is characterized by host-mediated alveolar bone destruction due primarily to the immune response. The role of IL-17 in PD is controversial. Whereas elevated IL-17 levels have been found in humans with severe PD, we recently reported that female C57BL/6J mice lacking the IL-17 receptor (IL-17RA(KO)) are significantly more susceptible to PD bone loss due to defects in the chemokine-neutrophil axis (J. J. Yu, M. J. Ruddy, G. C. Wong, C. Sfintescu, P. J. Baker, J. B. Smith, R. T. Evans, and S. L. Gaffen, Blood 109:3794-3802, 2007). Since different mouse strains exhibit differences in susceptibility to PD as well as Th1/Th2 cell skewing, we crossed the IL-17RA gene knockout onto the BALB/c background and observed a similar enhancement in alveolar bone loss following P. gingivalis infection. Unexpectedly, in both strains IL-17RA(KO) female mice were much more susceptible to PD bone loss than males. Moreover, female BALB/c-IL-17RA(KO) mice were defective in producing anti-P. gingivalis immunoglobulin G and the chemokines KC/Groalpha and MIP-2. In contrast, male mice produced normal levels of chemokines and anti-P. gingivalis antibodies, but they were defective in granulocyte colony-stimulating factor upregulation. This study demonstrates a gender-dependent effect of IL-17 signaling and indicates that gender differences should be taken into account in the preclinical and clinical safety testing of anti-IL-17 biologic therapies.


Management of the severe varus and valgus knee using the low contact stress rotating platform.
Many surgeons feel the use of an unconstrained mobile-bearing knee is contraindicated in cases of severe varus and valgus deformity. In the author's opinion the Sigma LCS rotating-platform knee system can be used in virtually every primary knee irrespective of deformity. The key is to maintain flexion stability by not releasing the lateral collateral ligament in a valgus knee or the superficial medial collateral ligament in the varus knee.


Traumatic dislocation of the first metatarsophalangeal joint with entrapment of the flexor hallucis longus tendon.
A case of traumatic dislocation of the first metatarsophalangeal joint with concomitant fibular sesamoid fracture and thoracic vertebral fracture is presented. The first metatarsophalangeal joint was repaired by means of open reduction with collateral ligament repair. At 12 months following the operation, the patient displayed nonpainful and unrestricted first metatarsophalangeal joint motion.


[Dynamics of growth hormone secretion in patients with primary hypothyroidism, before and after treatment with thyroideal hormones].
Growth hormone (GH) secretion was studied in a group of alut controls and a series of patients with primary hypothyroidism before and after treatment with thyroid hormones. Intravenous insulin-induced hypoglycemia was the stimulus used (0,1 UI/kg body weight). It is concluded that in primary hypothyroidism, GH secretion is almost absent due to relative inactivity of the somatotropic cells and/or lack of GH-RH. This decreased secretory response becomes rapidly normal after treatment with physiological doses of thyroid hormones.


Prevalence of chronic kidney disease and associated factors among the Chinese population in Taian, China.
This study was designed to assess the prevalence of chronic kidney disease (CKD) and associated risk factors among the Chinese population in Taian, China. A primary care-based cross-sectional study was conducted in Taian, China, from September to December 2012. Participants selected by a multi-stage stratified cluster sampling procedure were interviewed and tested for hematuria, albuminuria, estimated glomerular filtration rate (eGFR) and other clinical indices. Factors associated with CKD were analyzed by univariate and multivariate logistic regression analysis. A total of 14,399 subjects were enrolled in this study. The rates of hematuria, albuminuria and reduced eGFR were 4.20%, 5.25% and 1.89%, respectively. Approximately 9.49% (95% CI: 8.93%-10.85%) of the participants had at least one indicator of CKD, with an awareness of 1.4%. Univariate analyses showed that greater age, body mass index, and systolic and diastolic blood pressure; higher levels of serum creatinine, uric acid, fasting blood glucose, triglycerides, total cholesterol and low-density lipoprotein cholesterol; and lower eGFR were associated with CKD (p < 0.05 each). Multivariate analysis showed that age, female gender, educational level, smoking habits, systolic blood pressure, and history of diabetes mellitus, hyperlipidemia, hypercholesterolemia and hyperuricemia were independent risk factors for CKD. The prevalence of CKD in the primary care population of Taian, China, is high, although awareness is quite low. Health education and policies to prevent CKD are urgently needed among this population.


Primary adenocarcinoma of ileostomy: case report with review of the literature.
Primary adenocarcinoma is a rare and late complication following proctocolectomy and ileostomy for ulcerative colitis, familial adenomatous polyposis, Crohn's disease and multifocal colorectal cancer. We report a case of adenocarcinoma of the ileostomy occurring 48 years after proctocolectomy for ulcerative colitis. A review of the literature suggests that there are 39 cases reported in literature and this case reports the longest interval between formation of ileostomy and diagnosis of ileostomy adenocarcinoma. This case also reports lymph node metastasis to the adjacent mesenteric lymph node. The incidence of lymphnode metastasis is 15 percent as per literature. Onces diagnosis is confirmed by biopsy enblock excision with or without stomal relocation is the main stay of treatment. Patient education and regular surveillance of patients with long-standing ileostomy is recommended for early detection of this unusual cancer.


How Supertough Gels Break.
Fracture of highly stretched materials challenges our view of how things break. We directly visualize rupture of tough double-network gels at >50% strain. During fracture, crack tip shapes obey a x∼y^{1.6} power law, in contrast to the parabolic profile observed in low-strain cracks. A new length scale ℓ emerges from the power law; we show that ℓ scales directly with the stored elastic energy and diverges when the crack velocity approaches the shear wave speed. Our results show that double-network gels undergo brittle fracture and provide a testing ground for large-strain fracture mechanics.


Inducing RNA interference in the arbovirus vector, Culicoides sonorensis.
Biting midges in the genus Culicoides are important vectors of arboviral diseases, including epizootic haemorrhagic disease, bluetongue and most likely Schmallenberg, which cause significant economic burdens worldwide. Research on these vectors has been hindered by the lack of a sequenced genome, the difficulty of consistent culturing of certain species and the absence of molecular techniques such as RNA interference (RNAi). Here, we report the establishment of RNAi as a research tool for the adult midge, Culicoides sonorensis. Based on previous research and transcriptome analysis, which revealed putative small interfering RNA pathway member orthologues, we hypothesized that adult C. sonorensis midges have the molecular machinery needed to perform RNA silencing. Injection of control double-stranded RNA targeting green fluorescent protein (dsGFP), into the haemocoel of 2-3-day-old adult female midges resulted in survival curves that support virus transmission. dsRNA injection targeting the newly identified C. sonorensis inhibitor of apoptosis protein 1 (CsIAP1) orthologue resulted in a 40% decrease of transcript levels and 73% shorter median survivals as compared with dsGFP-injected controls. These results reveal the conserved function of IAP1. Importantly, they also demonstrate the feasibility of RNAi by dsRNA injection in adult midges, which will greatly facilitate studies of the underlying mechanisms of vector competence in C. sonorensis.


Serum cystatin C, determined by a rapid, automated particle-enhanced turbidimetric method, is a better marker than serum creatinine for glomerular filtration rate.
We describe a fully automated particle-enhanced turbidimetric assay for cystatin C in undiluted serum and EDTA-plasma. The throughput is 90 samples per hour and urgent samples can be analyzed in 7 min. The assay range (0.4-14.1 mg/L) covers the concentration range in health and disease. The within- and between-run imprecision is 0.9% and 2.2%, respectively. Analytical recovery of additions of recombinant cystatin C averaged 98%. Rheumatoid factors (< or = 323,000 IU/L), bilirubin (< or = 150 mumol/L), hemoglobin (< or = 1.2 g/L), and triglycerides (< or = 8.5 mmol/L) do not interfere in the assay. In view of the superior (by ROC analysis) diagnostic accuracy of serum concentrations of cystatin C for reduced glomerular filtration rate (GFR) in comparison with creatinine, cystatin C seems an attractive alternative to creatinine for estimation of GFR.


Risk of heart failure associated with dopamine agonists: a nested case-control study.
Recent evidence has emerged that a dopamine agonist, pramipexole, may increase the risk of heart failure among Caucasian patients, but the association has not been examined among Asian patients. The aim of this study was to explore the relationship between use of dopamine agonists and the risk of heart failure. Using data from Taiwan's National Health Insurance research database (NHIRD), we identified a population-based cohort comprising 27,135 patients who were prescribed anti-parkinsonian drugs between 2001 and 2010. We conducted a nested case-control study in which 1,707 cases of newly diagnosed heart failure were matched to 3,414 controls (1:2 matched according to age, gender and cohort entry year) within this cohort. Multivariable conditional logistic regressions were used to estimate the association between use of dopamine agonists and heart failure. An increased risk of heart failure was observed with current use of ergot-derived dopamine agonists (adjusted odds ratio [OR] 1.46, 95 % confidence interval [CI] 1.00-2.12) but not with current use of non-ergot-derived dopamine agonists (adjusted OR 1.24, 95 % CI 0.84-1.82). Among non-ergot-derived dopamine agonists, both pramipexole (adjusted OR 1.40, 95 % CI 0.75-2.61) and ropinirole (adjusted OR 1.22, 95 % CI 0.76-1.95) showed a non-significantly increased heart failure risk. Although the findings of our study were limited by lack of statistical power, a clear pattern of an increased duration of pramipexole use and an increased risk of heart failure were observed. Use of dopamine agonists, including pramipexole, was associated with non-significantly increased risks of heart failure in this population-based study in Taiwan. Further investigation is needed to clarify this potential association.


An unusual cause of gynaecomastia.
Gynaecomastia in adolescents and young adults is a common endocrine disorder with usually benign aetiology. However, gynaecomastia in middle-aged men is uncommon and warrants intensive search to unravel its aetiology. The authors report a 42-year-old male who presented with gynaecomastia due to feminising adrenocortical carcinoma.


Prevalence of internal parasites in beef cows in the United States: Results of the National Animal Health Monitoring System's (NAHMS) beef study, 2007-2008.
During the United States Department of Agriculture (USDA) National Animal Health Monitoring System's (NAHMS) 2007-2008 beef study, 567 producers from 24 US States were offered the opportunity to collect fecal samples from weaned beef calves and have them evaluated for the presence of parasite eggs (Phase 1). Participating producers were provided with instructions and materials for sample collection. Up to 20 fresh fecal samples were collected from each of the 99 participating operations. Fresh fecal samples were submitted to one of 3 randomly assigned laboratories for evaluation. Upon arrival at the laboratories, all samples were processed for the enumeration of strongyle, Nematodirus, and Trichuris eggs using the modified Wisconsin technique. The presence or absence of coccidian oocysts and tapeworm eggs was also noted. In submissions where the strongyle eggs per gram exceeded 30, aliquots from 2 to 6 animals were pooled for DNA extraction. Extracted DNA was subjected to genus level polymerase chain reaction (PCR) identification for the presence of Ostertagia, Cooperia, Haemonchus, Oesophagostomum, and Trichostrongylus. In this study, 85.6% of the samples had strongyle type, Nematodirus, and Trichuris eggs. Among the samples evaluated, 91% had Cooperia, 79% Ostertagia, 53% Haemonchus, 38% Oesophagostomum, 18% Nematodirus, 7% Trichuris, and 3% Trichostrongylus. The prevalence of coccidia and tapeworm eggs was 59.9% and 13.7%, respectively.


Interest of the association clonidine-spironolactone in cirrhotic patients with ascites and activation of sympathetic nervous system.
The aim of this study was to examine the effects of spironolactone, clonidine and the association of clonidine-spironolactone on renin-aldosterone and sympathetic systems, renal function, systemic hemodynamics and mobilization of ascites in 32 alcoholic cirrhotic patients with marked increase in sympathetic system. Measurements were taken before and after an 8-day treatment with spironolactone (200 mg/day), after an 8-day treatment with clonidine (0.150 mg/day) and 10 days after adjunction of spironolactone (200 mg/day) to clonidine. Three patients abandoned the treatment or were excluded because lack of compliance. Spironolactone alone induced an increase in renin-aldosterone and sympathetic systems without any remarkable increase of natriuresis and body weight loss. Given for 8 days, clonidine alone induced a significant decrease in plasma norepinephrine associated with a significant increase in glomerular filtration rate without effect on natriuresis. In contrast, 10 days after adjunction of spironolactone to clonidine, plasma renin and aldosterone significantly decreased, natriuresis increased (from 7.4 +/- 0.7 to 41.6 +/- 3.2 mEq/24 h) and body weight decreased (from 66.03 +/- 2.3 to 63.5 +/- 2.3 kg) without adverse effects. In cirrhotic patients with ascites and marked activation of sympathetic nervous system, spironolactone (200 mg/day) is unable to mobilize ascites. In these patients, after 8 days, clonidine decreases sympathetic activity, increases glomerular filtration rate and after 18 days, decreases plasma renin and aldosterone concentrations allowing a better action of spironolactone. The association clonidine-spironolactone enhances natriuresis and body weight loss.


Primary structure of the lactose permease gene from the yeast Kluyveromyces lactis. Presence of an unusual transcript structure.
The LAC12 gene of Kluyveromyces lactis codes for an inducible lactose permease. We have determined the nucleotide sequence of a DNA fragment which includes the complete LAC12 gene. The 4.7-kilobase (kb) mRNA carrying LAC12 contained two open reading frames, ORFI (1761 bases) and ORFII (1266 bases), separated by a 573-base pair noncoding region. Mung bean and exonuclease VII mapping showed that there was no splicing of the 4.7-kb transcript and thus no intron between the two open reading frames. Chromosomal disruption of ORFI with the URA3 gene destroyed lactose transport activity, suggesting that ORFI codes for a component of the permease. Disruption of ORFII and the noncoding region between the two open reading frames did not affect the lactose permease function, indicating that they do not comprise a part of the permease. We do not know if ORFII is translated, but in either case, the structure of the 4.7-kb mRNA is unusual. We discuss possible origins for it. The peptide predicted from ORFI is hydrophobic as would be expected for a membrane-bound protein. Compared with other membrane proteins, LAC12 (ORFI) protein showed sequence similarity to the human glucose and the Escherichia coli xylose-H+ and arabinose-H+ transporters. No obvious amino acid sequence similarity was found with the lactose permease of E. coli.


KEGG as a reference resource for gene and protein annotation.
KEGG (http://www.kegg.jp/ or http://www.genome.jp/kegg/) is an integrated database resource for biological interpretation of genome sequences and other high-throughput data. Molecular functions of genes and proteins are associated with ortholog groups and stored in the KEGG Orthology (KO) database. The KEGG pathway maps, BRITE hierarchies and KEGG modules are developed as networks of KO nodes, representing high-level functions of the cell and the organism. Currently, more than 4000 complete genomes are annotated with KOs in the KEGG GENES database, which can be used as a reference data set for KO assignment and subsequent reconstruction of KEGG pathways and other molecular networks. As an annotation resource, the following improvements have been made. First, each KO record is re-examined and associated with protein sequence data used in experiments of functional characterization. Second, the GENES database now includes viruses, plasmids, and the addendum category for functionally characterized proteins that are not represented in complete genomes. Third, new automatic annotation servers, BlastKOALA and GhostKOALA, are made available utilizing the non-redundant pangenome data set generated from the GENES database. As a resource for translational bioinformatics, various data sets are created for antimicrobial resistance and drug interaction networks.


Comparative vasoconstrictor effects of angiotensin II, III, and IV in human isolated saphenous vein.
Elevated levels of angiotensin (Ang II) and its degradation products angiotensin III (Ang III) and angiotensin IV (Ang IV) may contribute to the regulation of vascular tone under various clinical circumstances. We investigated the contractile effects of Ang III and Ang IV in endothelium-denuded human saphenous vein (SV) preparations and compared them with those of Ang II. The veins were suspended in organ chambers, and changes in isometric force were recorded. Ang II (0.1-100 nM), Ang III (1 nM-3 microM), and Ang IV (0.3 microM-0.1 mM) caused concentration-dependent contractions with comparable maximal responses (Emax). Ang III was 16 times less active than Ang II, whereas Ang IV was approximately 2,700-fold less potent than Ang II. In the presence of the aminopeptidase-A and -M inhibitor amastatin (10 microM), the potencies of Ang III and Ang IV were increased by approximately 16 and 12 times, respectively, although no changes of Ang II potency were observed. The AT1-selective Ang II receptor antagonist losartan (10 and 100 nM) but not the AT2-selective antagonist PD123177 (1 microM), shifted the concentration-response curves (CRC) for the angiotensin peptides to the right in a parallel manner. Preincubation with indomethacin (10 microM), a cyclooxygenase inhibitor, did not influence the CRCs for any of the angiotensin peptides studied. Tachyphylaxis was investigated by constructing a second series of CRCs for the angiotensin peptides after an interval of 60 min. Ang II showed strong tachyphylaxis (the Emax value of the second Ang II CRC was approximately 50% of the first), whereas Ang III and Ang IV did not. Our results indicate that in endothelium-denuded human SV, both Ang III and Ang IV are less potent but similarly efficacious vasoconstrictor agents compared with Ang II. Endogenous aminopeptidase activity may counteract the effects of the angiotensin peptides. The contractile responses to all three peptides are mediated via AT1-receptors but not AT2-receptors.


Differential effects of ureteral obstruction on rat kininogen gene family.
The precursors of kinins, K-kininogens and T-kininogens (KG), are encoded by separate genes that display 90% nucleotide sequence homology. Despite their homology, K-KG and T-KG genes are differentially regulated. The K-KG gene is expressed constitutively and encodes high- and low-molecular-weight KG, the precursors of the vasoactive nonapeptide bradykinin. In contrast, the T-KG gene is inducible, and its protein is a potent thiol-protease inhibitor. Given their potential role in the regulation of blood pressure, renal hemodynamics, and the response to inflammation and tissue injury, K-KG and T-KG gene expression in rats subjected to chronic (1 or 5 wk) unilateral ureteral obstruction (UUO), a maneuver that suppresses renal kallikrein synthesis to 25% of controls, has been examined. Northern and slot blots of total liver and kidney RNA were probed with oligonucleotides complementary to either T-KG or K-KG mRNA under high-stringency conditions. Steady-state levels of hepatic T-KG mRNA were increased in the UUO compared with sham-operated rats--2.7-fold at 1 wk and 4.1-fold at 5 wk (P < 0.05). Western blot analysis revealed that the 68-kd T-KG protein was up-regulated 2.5- to 3-fold in the liver of UUO rats (P < 0.05). In marked contrast, the abundance of high (2.3-kb)- and low (1.6-kb)-molecular-weight splicing transcripts of hepatic pre-K-KG mRNA was not altered at either time after UUO.(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of alcohol consumption on cardiovascular events in male patients with healed myocardial infarction.
In Western countries, many studies have shown that among healthy people moderate drinkers have a lower incidence of cardiovascular events than abstainers and heavy drinkers. However, it is not clear whether this is true in patients with a healed myocardial infarction (MI). In the present study cardiovascular events were defined as cardiac events or strokes. Male patients only were included because the incidence of cardiovascular events is low in females. In patients younger than 65 years, the incidence of cardiovascular events was 34.6 persons per year (54 cases: 3.9%) of abstainers, 17.4 persons per year (20 cases: 1.9%) of moderate drinkers (p<0.01 vs abstainers) and 30.3 s persons per year (18 cases: 3.2%) of heavy drinkers. However, in those aged 65 years or older, the incidence was 47.8 persons per year (24 cases: 4.5%) of abstainers, 58.4 persons per year (14 cases: 5.6%) of moderate drinkers, and 314.8 persons per year (12 cases: 19.7%) of heavy drinkers. In this age group, cardiovascular events were significantly higher in heavy drinkers than in the other 2 groups (p<0.01), and the incidence was not lower in the moderate drinkers than in abstainers as shown in the younger group. In patients younger than 65 years with a healed MI, drinking limited less than 30 ml/day (moderate intake) reduces the incidence of cardiovascular events, but not in those aged 65 years or older.


Congenital muscular dystrophies: 1997 update.
The congenital muscular dystrophies (CMDs) comprise a heterogeneous group of muscle disorders with onset in utero or during the first year of life. Several forms of CMD show various types of brain involvement in addition to a muscular dystrophy. Two forms are defined at the molecular level: merosin deficient-CMD caused by mutations in the LAMA2-gene on chromosome 6q2. Fukuyama congenital muscular dystrophy (FCMD) is prevalent in Japan and caused by an as yet unidentified gene on chromosome 9q31. At least two further forms of CMD with brain involvement are nosologically well defined: Walker--Warburg-CMD is characterized by lissencephaly type 11, eye dysgenesis and muscular dystrophy. This autosomal recessive disorder is fatal or results in complete lack of development. A similar but much milder phenotype with pachygyria of the brain, various degrees of eye changes and milder muscular dystrophy that is compatible with achievement of simple motor milestones has been described under the name of muscle-eye-brain disease (MEB) in Finland. A number of nosologically less distinct forms of muscular dystrophy have been outlined such as 'pure' CMD without brain involvement, CMD with cerebellar hypoplasia or CMD type Ullrich with hyperelasticity of the distal joints. Several other CMD phenotypes are known, some of which are suggestive of more distinctly separate nosological entities due to their occurrence in siblings or due to a characteristic pattern of clinical, histopathological and imaging features, and await further clarification.


Pinning Control of Lag-Consensus for Second-Order Nonlinear Multiagent Systems.
Lag consensus means that the corresponding state vectors of the followers are behind the leader with a lag time. In this paper, Lyapunov functional and matrix theory are applied to analyze pinning-controlled lag consensus of second-order nonlinear multiagent systems. The focus is twofold: 1) to find out which agents should be pinned and 2) to determine what the coupling strength should be, so that the multiagent systems can reach lag consensus. Moreover, the practical problem in a noisy environment is considered. Finally, an illustrative example is provided to demonstrate the effectiveness of the proposed pinning control protocol.


Implementation lessons for school food policies and marketing restrictions in the Philippines: a qualitative policy analysis.
The school environment can enhance children's skills, knowledge and behaviours in relation to healthy eating. However, in many countries, unhealthy foods are commonly available in schools, and children can be exposed to aggressive marketing by the food industry. Taking the perspective of policymakers, this study aimed to identify barriers and enablers to effective school food policy development and implementation in the Philippines. In May 2016, semi-structured interviews were conducted with 21 policymakers and stakeholders involved in school food policymaking and implementation in the Philippines. The Health Policy Analysis Triangle was used to identify interview questions and to guide the thematic analysis. These included the political and socio-environmental context, strengths and limitations of existing policy content, roles and behaviours of actors, implementation processes, policy outcomes, and opportunities to improve policy coherence. The Department of Education's policy 'Orders' represented a relatively strong policy framework for the education sector of the Philippines. However, a lack of human and financial resources for implementation, planning, and policy enforcement limited the impact of the policy on the healthiness of school food provision. Ambiguity in policy wording allowed a wide interpretation of the foods eligible to be provided in schools, and led to difficulties in effective monitoring and enforcement. Food companies used existing relationships with schools to promote their brands and compromise the establishment of a stronger food policy agenda. We found a motivated group of actors engaging in policy-oriented learning and advocating for a stronger policy alternative so as to improve the school food environment. The adoption of policy mechanisms being used to promote healthy dietary practices in the school setting will be strengthened by more robust implementation planning processes, and resources to support implementation and enforcement. Policymakers should ensure policy language clearly and unequivocally promotes healthier food and beverage options. Steps should be taken to achieve policy coherence by ensuring the objectives of one agency or institution are not undermining that of any others. Where there is reliance on the private sector for school resources, safeguards should be established to protect against conflicts of interest.


Evidence for concerted kinetic oxidation of progesterone by purified rat hepatic cytochrome P-450g.
Purified cytochrome P-450g, a male-specific rat hepatic isozyme, was observed to metabolize progesterone to two primary metabolites (6 beta-hydroxyprogesterone and 16 alpha-hydroxyprogesterone), two secondary metabolites (6 beta,16 alpha-dihydroxyprogesterone and 6-ketoprogesterone), and one tertiary metabolite (6-keto-16 alpha-hydroxyprogesterone). The Km,app for the formation of these products from progesterone was determined to be approximately 0.5 microM, while the Km,app for metabolism of 6 beta- and 16 alpha-hydroxyprogesterone was found to be 5-10 microM. The ratio of primary to secondary metabolites did not change significantly at progesterone concentrations from 6 to 150 microM, and a lag in formation of secondary metabolites was not observed in 1-min incubations. Concerted oxidation of progesterone to secondary products without the intermediate products leaving the active site was suggested by these results and confirmed by isotopic dilution experiments in which little or no dilution of metabolically formed 6 beta,16 alpha-dihydroxyprogesterone and 6-keto-16 alpha-hydroxyprogesterone was observed in incubations containing a mixture of radiolabeled progesterone and unlabeled 6 beta-hydroxyprogesterone or 16 alpha-hydroxyprogesterone. Incubation of 6 beta-hydroxyprogesterone with a reconstituted system in an atmosphere of 18O2 resulted in greater than 90% incorporation of 18O in the 16 alpha-position of 6 beta,16 alpha-dihydroxyprogesterone but no incorporation of 18O into 6-ketoprogesterone, even though the reaction was dependent upon enzyme and O2, and not inhibited by mannitol, catalase, or superoxide dismutase. Factors which characterize the metabolism of progesterone by cytochrome P-450g in terms of active-site constraints and the catalytic competence of the enzyme in microsomes were also explored.


Three-dimensional optical transfer function in differential confocal microscopy.
To reveal the fundamental characteristics of differential confocal microscopy (DCM), its imaging properties were analysed by studying the 3D optical transfer function (OTF). The zero transfer at zero frequency along the axial direction in DCM, which has not been well understood and is considerably different from the transfer behaviour in conventional confocal microscopy (CM), was elucidated. The integral expressions of the OTFs for CM and DCM and the subsequent simulation results showed that DCMs have higher transfer capability than CM in the axial direction at medium and high frequencies. Conventionally, the relative optimal defocusing amount in DCMs are determined through calculations of the gradient of the point spread functions in the spatial domain. In contrast, in this study, the OTF performances were compared and the optimal defocusing amount was found to be between 5 and 7.


Progressive decline in stroke mortality in Brazil from 1980 to 1982, 1990 to 1992, and 2000 to 2002.
We describe the trends in stroke mortality in Brazil during 3 decades and investigate their differences according to regional disparities, sex, and age distributions. Official data on mortality and population estimates were retrieved to calculate standardized mortality rates (with the 1980 Brazilian population as a reference) in 6 age strata and in the 5 political regions for the initial period (3 first years) of the 1980, 1990, and 2000 decades. Data were corrected for undefined causes of death. The Poisson model was used to estimate risk reduction during the 3 decades and to study the interaction between those rates and sex, age strata, and regions. The stroke standardized mortality rate decreased consistently in the last 20 years, from 68.2 to 40.9 per 100,000 habitants. This reduction paralleled a decrease in total cardiovascular mortality rates in the same period, from 208.2 to 126.1 per 100,000 habitants. The reduction in stroke standardized mortality rate was detected in men and women and in all age strata. The reduction was evident in all geopolitical regions of the country, with the wealthiest regions' exhibiting higher initial rates and more marked standardized mortality rate reductions. The risk of dying of stroke in the period 2000 to 2002 was 0.45 (95% CI, 0.44 to 0.45) of that found in the period 1980 to 1982. The risk of dying of stroke in Brazil declined dramatically between the initial period in the early 1980s and the early 2000s. The decline was especially marked in the most developed regions and may reflect an improvement in general health conditions during the study period.


Anti-proliferative Effect of a Novel Anti-oxidative Peptide in Hanwoo Beef on Human Colorectal Carcinoma Cells.
The present study aimed to characterise anti-oxidant peptides from water-soluble protein extracts of Hanwoo beef and evaluate their anti-proliferative effect on human colorectal carcinoma cells (HCT116). Antioxidant peptides were purified from the low-molecular-weight fraction (<3 kDa) of Hanwoo beef extract. Antioxidant activity of peptide fractions was determined using the oxygen radical absorbance capacity (ORAC) assay. Purified peptide (P3) displayed higher ORAC activity than the low-molecular-weight fraction (202.66 μM TE/g vs 167.38 μM TE/g of dry matter, respectively) (p<0.05). The peptide sequence of P3 was Cys-Cys-Cys-Cys-Ser-Val-Gln-Lys (888.30 Da). The novel peptide P3, at 250 μg/mL, also significantly inhibited HCT116 cell proliferation up to 25.24% through phosphorylation of ERK, JNK, and p38 kinase (p<0.05). Hence, antioxidant peptide P3 from Hanwoo beef extract can be used as an antioxidative and anti-cancer agent in the functional food industry.


Machine-learned dynamic disorder of electron transfer coupling.
Electron transfer (ET) is a fundamental process in chemistry and biochemistry, and electronic coupling is an important determinant of the rate of ET. However, the electronic coupling is sensitive to many nuclear degrees of freedom, particularly those involved in intermolecular movements, making its characterization challenging. As a result, dynamic disorder in electron transfer coupling has rarely been investigated, hindering our understanding of charge transport dynamics in complex chemical and biological systems. In this work, we employed molecular dynamic simulations and machine-learning models to study dynamic disorder in the coupling of hole transfer between neighboring ethylene and naphthalene dimer. Our results reveal that low-frequency modes dominate these dynamics, resulting primarily from intermolecular movements such as rotation and translation. Interestingly, we observed an increasing contribution of translational motion as temperature increased. Moreover, we found that coupling is sub-Ohmic in its spectral density character, with cut-off frequencies in the range of 102 cm-1. Machine-learning models allow direct study of dynamics of electronic coupling in charge transport with sufficient ensemble trajectories, providing further new insights into charge transporting dynamics.


Angiotensin receptor blocker selectivity at the AT1- and AT2-receptors: conceptual and clinical effects.
The advent of specific angiotensin II (Ang II) receptor blockers (ARBs) some ten years ago has provided substantial information on the specific actions of the AT1- and AT2-receptors. Most of the early research concentrated on the AT1-receptor, and the actions and biological roles of the AT2-receptor are much less well characterised. The AT2-receptor is involved in the inhibition of cell proliferation, and in cell differentiation and development, regeneration and apoptosis. By raising local Ang II concentrations at the AT2-receptor, selective blocking of the AT1-receptor may therefore have beneficial effects. This concept may be important for antihypertensive therapy and in cardiovascular disease in general.


"If we can show that we are helping adolescents to understand themselves, their feelings and their needs, then we are doing [a] valuable job": counselling young people on sexual health in the Brook Advisory Centre (1965-1985).
First opened in 1964 in London, the Brook Advisory Centres (BAC) were the first centres to provide contraceptive advice and sexual counselling to unmarried people in postwar Britain. Drawing on archival materials, medical articles published by BAC members and oral history interviews with former counsellors, this paper looks at tensions present in sexual health counselling work between progressive views on young people's sexuality and moral conservatism. In so doing, this paper makes two inter-related arguments. First, I argue that BAC doctors, counsellors and social workers simultaneously tried to adopt a non-judgmental listening approach to young people's sexual needs and encouraged a model of heteronormative sexual behaviours that was class-based and racialised. Second, I argue that emotional labour was central in BAC staff's attempt to navigate and smooth these tensions. This emotional labour and the tensions within it is best illustrated by BAC's pyschosexual counselling services, which on the one hand tried to encourage youth sexual pleasure and on the other taught distinctive gendered sexual roles that contributed to pathologising teenage sexual behaviours and desire.In all, I contend that, in resorting to an emotionally orientated counselling, BAC members reconfigured for the young the new form of sexual subjectivity that had been in the making since the interwar years, that is, the fact that individuals regarded themselves as sexual beings and expressed feelings and anxieties about sex. BAC's counselling work was as much a rupture with the interwar contraceptive counselling tradition-since it operated in a new climate, stressed a non-judgmental listening approach and catered for the young-as it was a continuity of some of the values of the earlier movement.


Effect of Casein Phosphopeptide-Amorphous Calcium Phosphate and Three Calcium Phosphate on Enamel Microhardness.
This study aims to investigate the effect of casein phos-phopeptide-amorphous calcium phosphate and three calcium phosphate (CPP-ACP and TCP) on increasing the microhardness of human enamel after induction of erosion. A total of 26 healthy human-impacted third molar teeth were chosen, and their hardness measured using a microhardness testing machine. The samples were immersed in Coca Cola (pH = 4.7) for 8 minutes. Then, micro-hardness was measured again, and these samples were randomly divided into four groups (two control groups and two experimental groups). (1) Negative control group: Artificial saliva was used for 10 minutes, (2) positive control group: Fluoride gel was used for 10 minutes, (3) β-TCP group: TCP was used for 10 minutes, (4) CCP-ACP group: CCP-ACP was used for 10 minutes. The final microhardness of those samples was measured, and the changes in microhardness of teeth within group and between groups were analyzed using the paired and analysis of variance tests respectively. Results were considered statistically significant at a level of p < 0.05. No significant difference was observed in microhard-ness between CPP-ACP group and TCP group (p = 0.368) during the time microhardness significantly dropped after soaking in soda. Casein phosphopeptide-amorphous calcium phosphate and TCP increased the microhardness of teeth. The increase in hardness in the TCP group was higher than in the CPP-ACP group, but this difference was not significant (p = 0.36). Casein phosphopeptide-amorphous calcium phosphate and TCP can affect the remineralization of erosive lesions.


Type III CRISPR-Cas systems produce cyclic oligoadenylate second messengers.
In many prokaryotes, type III clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated (Cas) systems detect and degrade invasive genetic elements by an RNA-guided, RNA-targeting multisubunit interference complex. The CRISPR-associated protein Csm6 additionally contributes to interference by functioning as a standalone RNase that degrades invader RNA transcripts, but the mechanism linking invader sensing to Csm6 activity is not understood. Here we show that Csm6 proteins are activated through a second messenger generated by the type III interference complex. Upon target RNA binding by the interference complex, its Cas10 subunit converts ATP into a cyclic oligoadenylate product, which allosterically activates Csm6 by binding to its CRISPR-associated Rossmann fold (CARF) domain. CARF domain mutations that abolish allosteric activation inhibit Csm6 activity in vivo, and mutations in the Cas10 Palm domain phenocopy loss of Csm6. Together, these results point to an unprecedented mechanism for regulation of CRISPR interference that bears striking conceptual similarity to oligoadenylate signalling in mammalian innate immunity.


Gynecological surgery in adulthood imparts cognitive and brain changes in rats: A focus on hysterectomy at short-, moderate-, and long-term intervals after surgery.
Premenopausal hysterectomy is associated with a greater relative risk of dementia. We previously demonstrated cognitive impairments in adult rats six weeks after hysterectomy with ovarian conservation compared with intact sham-controls and other gynecological surgery variations. Here, we investigated whether hysterectomy-induced cognitive impairments are transient or persistent. Adult rats received sham-control, ovariectomy (Ovx), hysterectomy, or Ovx-hysterectomy surgery. Spatial working memory, reference memory, and anxiety-like behavior were tested either six-weeks post-surgery, in adulthood; seven-months post-surgery, in early middle-age; or twelve-months post-surgery, in late middle-age. Hysterectomy in adulthood yielded spatial working memory deficits at short-, moderate-, and long-term post-surgery intervals. Serum hormone levels did not differ between ovary-intact, but differed from Ovx, groups. Hysterectomy had no significant impact on healthy ovarian follicle or corpora lutea counts for any post-surgery timepoint compared with intact sham-controls. Frontal cortex, dorsal hippocampus, and entorhinal cortex were assessed for activity-dependent markers. In entorhinal cortex, there were alterations in FOSB and ΔFOSB expression during the early middle-age timepoint, and phosphorylated ERK1/2 levels at the adult timepoint. Collectively, results suggest a primary role for the uterus in regulating cognition, and that memory-related neural pathways may be modified following gynecological surgery. This is the first preclinical report of long-term effects of hysterectomy with and without ovarian conservation on cognition, endocrine, ovarian, and brain assessments, initiating a comprehensive framework of gynecological surgery effects. Translationally, findings underscore critical needs to decipher how gynecological surgeries, especially those involving the uterus, impact the brain and its functions, the ovaries, and overall aging from a systems perspective.


Are Sleep Problems a Risk Factor for the Onset of Musculoskeletal Pain in Children and Adolescents? A Systematic Review.
Musculoskeletal pain is a major burden on the society. Adults with sleep problems are at higher risk of musculoskeletal pain onset, but there is no evidence for this relationship in children and adolescents. This study aimed to systematically review prospective studies on the risk of musculoskeletal pain onset in children and adolescents with sleep problems. Five databases (MEDLINE, PsycINFO, AMED, EMBASE, and HMIC) were systematically searched to identify prospective studies that investigated if children and adolescents (aged 6-19 years) with sleep problems are at higher risk of musculoskeletal pain onset. Included studies were assessed for study quality and a best evidence synthesis was carried out on extracted data. Thirteen prospective studies were identified. Overall, evidence indicates that sleep problems (quality, quantity, and day time tiredness) are not risk factors for musculoskeletal pain onset. Further analysis on specific body regions shows strong evidence that sleep problems are a risk factor for neck pain onset (only in girls) and that sleep problems are not a risk factor for the onset of widespread pain. Overall, sleep problems are not a risk factor for musculoskeletal pain onset in children and adolescents. Increased risk was found for some specific body regions and subgroups, but the evidence base was less strong and generally inconsistent. This review found a lack of quality in research methodology compared to research in adults, and further research with improved methodology is required.


Influence of acetylator phenotype of the leprosy patient on the emergence of dapsone resistant leprosy.
The half time of disappearance of dapsone and monoacetyl dapsone and the acetylator phenotype of the leprosy patients who harboured dapsone sensitive and dapsone resistant M. leprae was assessed in 27 subjects. Sixteen patients were rapid acetylators, five were slow and six were intermediate acetylators. The mean T 1 1/2 lives of dapsone (30.26 +/- 11.0) and monoacetyl dapsone (31.11 +/- 12.0) were also studied in the above patients. The percentage of different acetylators in both resistant and sensitive groups were similar showing no correlation between the emergence of drug resistance and the phenotype of the patient. The mean time of disappearance of DDS and MAD in the different acetylators did not show significant difference. The ratios of MAD/DDS in an individual at 3, 6 or 24 hours after the dose were similar. The mean T 1 1/2 lives of DDS and MAD in resistant and sensitive patients also showed no difference. Neither T 1 1/2 lives of DDS or MAD nor the acetylator phenotype seem to influence the emergence of dapsone resistance.


Combination chemotherapy with cyclophosphamide, doxorubicin, and bleomycin for metastatic transitional cell carcinoma of the urinary tract.
Twenty-three patients with metastatic transitional cell carcinoma of the urinary tract received at least two courses of the combination of cyclophosphamide, doxorubicin, and bleomycin. Eight patients (35%) achieved partial remission and an additional six (26%) had stable disease. Duration of survival was significantly longer for the partial responders (median, 30 weeks) than the remaining patients (median, 18 weeks). Principal morbidity (mucositis, fever, and pulmonary toxicity) was due to bleomycin. These results are not superior to single-agent chemotherapy and reinforce the need for further careful evaluation of new combination programs containing cis-diamminedichloroplatinum(II). The failure of bleomycin to improve responses and its considerable toxicity suggest that its continued systemic use in this disease is not warranted.


Covering the uninsured: how much would it cost?
To provide benchmarks for evaluating the costs of alternative proposals to provide insurance coverage for the uninsured, this study presents two sets of cost estimates derived from medical spending patterns of lower- or middle-income people with private insurance plans and those of people with public insurance coverage during 1996-1998. The analysis suggests that the uninsured would use dollar 33.9-dollar 68.7 billion (in 2001 dollars) in additional medical care if they were fully insured. An increase in medical spending of this range would increase total health care spending by 3-6 percent and would raise health care's share of GDP by less than one percentage point.


Social cognition in patients following surgery to the prefrontal cortex.
Impaired social cognition, including emotion recognition, may explain dysfunctional emotional and social behaviour in patients with lesions to the ventromedial prefrontal cortex (VMPFC). However, the VMPFC is a large, poorly defined area that can be sub-divided into orbital and medial sectors. We sought to investigate social cognition in patients with discrete, surgically circumscribed prefrontal lesions. Twenty-seven patients between 1 and 12 months post-neurosurgery were divided into groups based on Brodmann areas resected, determined by post-surgical magnetic resonance imaging. We hypothesised that patients with lesions to the VMPFC (n=5), anterior cingulate cortex (n=4), orbitofrontal cortex (n=7) and dorsolateral prefrontal cortex (DLPFC, n=11) would perform worse than a control group of 26 extra-cerebral neurosurgery patients on measures of dynamic facial emotion recognition, theory of mind (ToM) and empathy. Results indicated the VMPFC-lesioned group performed significantly worse than the control group on the facial emotion recognition task overall, and for fear specifically, and performed worse on the ToM measure. The DLPFC group also performed worse on the ToM and empathy measures, but DLPFC lesion location was not a predictor of performance in hierarchical multiple regressions that accounted for other variables, including the reduced estimated verbal IQ in this group. It was concluded that isolated orbital or medial prefrontal lesions are not sufficient to produce impairments in social cognition. This is the first study to demonstrate that it is the combination of lesions to both areas that affect social cognition, irrespective of lesion volume. While group sizes were similar to other comparable studies that included patients with discrete, surgically circumscribed lesions to the prefrontal cortex, future large, multi-site studies are needed to collect larger samples and confirm these results.


Staging of malignant lymphoma with three-station black-blood fast short-inversion time inversion recovery (STIR).
The purpose of this study was to assess the usefulness of three-station black-blood fast short-inversion time inversion recovery (STIR) imaging in detecting and staging malignant lymphoma. Seventeen patients with malignant lymphoma were examined with a 1.5T imager. The findings and stagings determined with three-station black-blood fast STIR imaging were compared with reference standards (e.g., computed tomography [CT] findings and clinical stagings). Three-station black-blood fast STIR imaging provided a fat-suppressed T2-weighted imaging contrast with fewer flow artifacts and revealed nodal involvement as well as bone marrow and spleen involvement to an extent comparable with CT. Especially notable was the excellent specificity (94%) of this imaging technique. Regarding disease staging, significant agreement was observed between clinical staging (k=0.60) and staging as evaluated by three-station black-blood fast STIR, although the detection of lymphadenopathy in the thorax was relatively poor. The average time required for this imaging was approximately 30 min. Three-station black-blood fast STIR MR imaging may be useful as a staging tool for malignant lymphoma because this imaging technique reveals lymphoma lesions, which determine the staging, without radiation exposure or the use of contrast agents.


Concomitant Atrial Fibrillation Procedures During Cardiac Surgery in a UK Center: Reflection of Worldwide Practice?
Guidelines recommend concomitant atrial fibrillation (AF) ablation during cardiac surgery to restore normal sinus rhythm (NSR). The study determines, to what extent patients with AF undergoing cardiac surgery at our institution received a concomitant AF procedure, what these procedures entailed, and short-term outcomes. A retrospective study of 2,984 patients undergoing cardiac surgery over 18 months. Patients who were in preoperative AF were identified and those who underwent a concomitant AF procedure (Group 1) were compared with those who did not (Group 2). Three hundred and thirteen (10.5%) patients had pre-operative AF; paroxysmal (19.5%), persistent (11.8%), longstanding (63%), unknown (5.8%). 116/313 (37.1%) patients had a concomitant AF procedure: 7.7% patients had a concomitant AF ablation and 29.4% had only a Left Atrial Appendage Occlusion (LAAO). Fewer patients with paroxysmal and persistent AF underwent concomitant AF procedures compared with the ones who had no AF procedures (6.7 vs. 12.8% and 17.6 vs. 31%, respectively). Greater in-hospital survival (99.1 vs. 93.9%, p = 0.025) and survival at a mean follow up of 6 weeks (97.4 vs. 89.3%, p = 0.09) was probably determined by patient's preoperative comorbidities. There were no differences in readmission rates, permanent pacemaker insertion, cerebral events or NSR at discharge or follow-up, between groups. In our center, concomitant AF ablation is performed only in 7.7% of cases, 29.4% had only an LAAO performed at the time of surgery. There was no difference in restoring NSR, cerebral events, or readmission rates compared with patients who had nothing done for their preoperative AF.


Comprehensive genomic profiling of recurrent endometrial cancer: Implications for selection of systemic therapy.
To assess whether comprehensive genomic profiling (CGP) in the setting of routine clinical care allows molecular classification of recurrent endometrial cancer (EC) into the four Cancer Genome Atlas (TCGA) categories: POLE ultramutated, microsatellite instable, copy-number low, and copy-number high and whether this approach can identify genomic alterations (GAs) which inform treatment decisions. Archival tissues from 74 patients diagnosed with recurrent EC were prospectively analyzed using hybrid-capture-based genomic profiling. Tumor mutational burden and microsatellite instability were measured. Clinically relevant GAs (CRGAs) were defined as GAs associated with targeted therapies available on-label or in mechanism-driven clinical trials. Using POLE mutational analysis, mismatch repair status, and p53 mutational analysis as surrogate for 'copy-number' status CGP segregated all cases into four TCGA molecular subgroups. While recurrent serous ECs were predominantly copy-number high, we found no clear prevalence of a specific molecular subtype in endometrioid, clear cell or undifferentiated tumors. Every tumor sample had at least one GA and 91% (67/74) had at least one CRGA. In this series 32% (24/74) of patients received a matched therapy based on the results of CGP. Objective responses to the matched therapy were seen in 25% (6/24) of patients with an additional 37.5% (9/24) achieving stable disease leading to a clinical benefit rate of 62.5% with a median treatment duration of 14.6 months (range 4.3-69 months). CGP allows molecular classification of EC into four TCGA categories and allows identification of potential biomarkers for matched therapy in the setting of routine clinical care.


[Lung transplantation for treatment of pulmonary cystic fibrosis: report of one case].
A right single lung transplantation was performed in a 17-year-old female patient with end-stage cystoid pulmonary fibrosis and without cardiopulmonary bypass in June 2003. The donor lung was perfused with cold UW solution with a cold ischemic time of 280 min. The patient weaned from ventilator on the next day of operation (18 h later) and was able to walk at the fourth day postoperatively. Immunosuppression included methylprednisolone used before FK 506, mycophenolate mofetil and prednisone dosed after operation. The patient remains well a month after operation with significant improvement of the lung function and enjoys normal life.


Consequences of metamorphosis for the locomotor performance and thermal physiology of the newt Triturus cristatus.
During metamorphosis, most amphibians undergo rapid shifts in their morphology that allow them to move from an aquatic to a more terrestrial existence. Two important challenges associated with this shift in habitat are the necessity to switch from an aquatic to terrestrial mode of locomotion and changes in the thermal environment. In this study, I investigated the consequences of metamorphosis to the burst swimming and running performance of the European newt Triturus cristatus to determine the nature and magnitude of any locomotor trade-offs that occur across life-history stages. In addition, I investigated whether there were any shifts in the thermal dependence of performance between life-history stages of T. cristatus to compensate for changes in their thermal environment during metamorphosis. A trade-off between swimming and running performance was detected across life-history stages, with metamorphosis resulting in a simultaneous decrease in swimming and increase in running performance. Although the terrestrial habitat of postmetamorphic stages of the newt T. cristatus experienced greater daily fluctuations in temperature than the aquatic habitat of the larval stage, no differences in thermal sensitivity of locomotor performance were detected between the larval aquatic and postmetamorphic stages. The absence of variation across life-history stages of T. cristatus may indicate that thermal sensitivity may be a conservative trait across ontogenetic stages in amphibians, but further studies are required to investigate this assertion.


A case of bullous Sézary syndrome.
Sézary syndrome is a rare leukemic subtype of cutaneous T cell lymphoma that is characterized by erythroderma, lymphadenopathy, and malignant T cells in the peripheral blood. Poor prognostic factors of Sézary syndrome include advanced disease stage, older age at onset, and large cell transformation. Presentation with bullous lesions, though rare, has been reported in a few patients. We present an elderly woman with bullous Sézary syndrome who presented with a two-month history of progressive rash. Upon admission, the patient had pruritic, erythematous, edematous plaques with overlying flaccid bullae and erosions involving the scalp, neck, torso, and extremities. Despite treatment, the patient died two months after presentation. Although rare, bullous lesions associated with Sézary syndrome may indicate poor prognosis.


Enhanced Security and Privacy via Fragmented Federated Learning.
In federated learning (FL), a set of participants share updates computed on their local data with an aggregator server that combines updates into a global model. However, reconciling accuracy with privacy and security is a challenge to FL. On the one hand, good updates sent by honest participants may reveal their private local information, whereas poisoned updates sent by malicious participants may compromise the model's availability and/or integrity. On the other hand, enhancing privacy via update distortion damages accuracy, whereas doing so via update aggregation damages security because it does not allow the server to filter out individual poisoned updates. To tackle the accuracy-privacy-security conflict, we propose fragmented FL (FFL), in which participants randomly exchange and mix fragments of their updates before sending them to the server. To achieve privacy, we design a lightweight protocol that allows participants to privately exchange and mix encrypted fragments of their updates so that the server can neither obtain individual updates nor link them to their originators. To achieve security, we design a reputation-based defense tailored for FFL that builds trust in participants and their mixed updates based on the quality of the fragments they exchange and the mixed updates they send. Since the exchanged fragments' parameters keep their original coordinates and attackers can be neutralized, the server can correctly reconstruct a global model from the received mixed updates without accuracy loss. Experiments on four real data sets show that FFL can prevent semi-honest servers from mounting privacy attacks, can effectively counter-poisoning attacks, and can keep the accuracy of the global model.


Maternal and neonatal outcomes in patients with hepatitis C and intrahepatic cholestasis of pregnancy: The sum of the parts.
Hepatitis C virus and intrahepatic cholestasis of pregnancy (ICP) are well-known independent risk factors for adverse outcomes in pregnancy. In addition, it is well-established that there is an association between Hepatitis C and ICP. This study's objective was to describe the impact of having both Hepatitis C and ICP on maternal and obstetric outcomes compared to patients having either Hepatitis C or ICP. We conducted a retrospective cohort study of the Nationwide Readmissions Database, an all-payor sample of discharges from approximately 60% of US hospitalizations. Deliveries at 24-42+ weeks between 10/2015 and 12/2020 were included. Diagnosis of Hepatitis C and ICP, and outcomes related to severe maternal morbidity were identified using International Classification of Disease-10 codes. Patients were categorized based on Hepatitis C and ICP status. Weighted logistic and negative binomial regression analyses were used to evaluate the association between Hepatitis C and ICP status and outcomes, adjusting for patient and hospital characteristics. The primary outcome was any severe maternal morbidity; secondary outcomes included acute respiratory distress syndrome, acute kidney injury, sepsis, gestational diabetes, cesarean delivery, preterm birth, and hospital length of stay. We modeled interaction terms between ICP and Hepatitis C to assess whether there was a greater or lesser effect from having both conditions on outcomes than we would expect from additive combination of the individual components (i.e., synergy or antagonism). A total of 10,040,850 deliveries between 24-42+ weeks were identified. Of these, 45,368 had Hepatitis C only; 84,582 had ICP only; and 1,967 had both Hepatitis C and ICP. Patients with both Hepatitis C and ICP had 1.5-fold higher odds of developing severe maternal morbidity compared to having neither. There was an also an increased odds of severe maternal morbidity in patients with both Hepatitis C and ICP compared to patients with only Hepatitis C or ICP. Having both was also associated with higher odds of preterm birth and length of stay compared to having only Hepatitis C, only ICP, or neither (preterm birth: aOR 5.09, 95% CI 4.87-5.33 vs. neither; length of stay: 46% mean increase, 95% CI 35-58% vs. neither). Associations were additive-no significant interactions between hepatitis C and cholestasis were found on rates of severe maternal morbidity, acute respiratory distress syndrome, acute kidney injury, sepsis, cesarean section, or preterm birth (all p>0.05), and was minimal for gestational diabetes and length of stay. Hepatitis C and ICP are independent, additive risk factors for adverse maternal and obstetric outcomes. Despite physiologic plausibility, no evidence of a synergistic effect of these two diagnoses on outcomes was noted. These data may be useful in counseling patients regarding their increased risk of adverse outcomes when ICP presents in association with Hepatitis C versus ICP alone.


Creatine supplementation enhances anti-tumor immunity by promoting adenosine triphosphate production in macrophages.
Creatine is an indispensable organic compound utilized in physiological environments; however, its role in immunity is still poorly understood. Here, we show that creatine supplementation enhances anti-tumor immunity through the functional upregulation of macrophages by increasing adenosine triphosphate (ATP) production. Creatine supplementation significantly suppressed B16-F10-originated tumor growth in mice compared with the control treatment. Under these conditions, intratumor macrophages polarized towards the M1 phenotype rather than the M2 phenotype, and there was an increase in tumor antigen-specific CD8+ T cells in the mice. The cytokine production and antigen-presenting activity in the macrophages were enhanced by creatine supplementation, resulting in a substantial increase in tumor antigen-specific CD8+ T cells. ATP upregulation was achieved through the cytosolic phosphocreatine (PCr) system via extracellular creatine uptake, rather than through glycolysis and mitochondrial oxidative phosphorylation in the macrophages. Blockade of the creatine transporter (CrT) failed to upregulate ATP and enhance the immunological activity of macrophages in creatine supplementation, which also impaired CD8+ T cell activity. Consequently, CrT blockade failed to suppress tumor growth in the creatine-supplemented mice. Thus, creatine is an important nutrient that promotes macrophage function by increasing ATP levels, ultimately contributing to enhanced anti-tumor immunity orchestrated by CD8+ T cells.


Giant seminoma in an undescended testicle metastasizing to the neck and liver.
Germ cell tumors account for 98% of all testicular malignancies. Delays in seeking treatment are unfortunately common and may lead to metastatic spread. The present study reported a case of a 24-year-old man with a giant 12×10 cm left inguinal mass and a left neck mass that had grown rapidly during recent months. Computed tomography confirmed that the mass measured 12.1×9.4 cm and was a left undescended testicle malignancy, and also revealed widespread metastasis to the liver and a large retroperitoneal mass (12.6×8.2 cm). Immunohistochemical staining confirmed seminoma. The patient was treated with chemotherapy with the VIP protocol (cisplatin, etoposide and ifosfamide). Following courses of chemotherapy, the patient received complete clinical remission and was disease-free at the 6 month follow-up.


Glycerol-preserved corneal tissue in emergency corneal transplantation: An alternative for fresh corneal tissue in COVID-19 crisis.
Due to the COVID-19 pandemic, most of the eye banks have limited/stopped corneal collection, as this is a highly contagious disease. This has led to shortage of donor corneas worldwide. Glycerol preservation of tissue remains a viable option in this scenario. The objective is to compare fresh corneal tissue (FCT) with glycerol-preserved cornea (GPC) in emergency corneal transplantation. This was a retrospective cohort study conducted in a tertiary care centre of Uttarakhand. Medical records of the patients who underwent therapeutic penetrating keratoplasty (TPK) were reviewed. FCT group included patients who underwent TPK with fresh corneal tissue and GPC group included patients who underwent TPK with glycerol preserved cornea. The indications and outcomes of TPK in the terms of therapeutic success were analysed and compared between both the groups. A total of 94 eyes of 91 patients underwent TPK from October 2011 to August 2017. FCT group included 60 eyes of 57 patients and GPC group included 34 eyes of 34 patients. The primary indication of TPK was infectious keratitis in both the groups (FCT-81.6%; GPC - 91.2%) There was no significant difference in the therapeutic success in both the groups (P = 0.741, Odds ratio- 1.59 with 95% CI- 0.39-6.44). Complications included glaucoma (FCT-21.7%; GPC- 35.2%) graft infection (FCT- 18.33% GPC- 2.9%); graft rejection (FCT-11.66%, GPC- 0%); and graft failure (FCT-88.33%, GPC-100%). The GPC is comparable to FCTs in therapeutic transplant and can be a useful interim procedure in saving the eyes in cases of infective keratitis in the time of crisis.


Bacterial cyanide oxygenase is a suite of enzymes catalyzing the scavenging and adventitious utilization of cyanide as a nitrogenous growth substrate.
Cyanide oxygenase (CNO) from Pseudomonas fluorescens NCIMB 11764 catalyzes the pterin-dependent oxygenolytic cleavage of cyanide (CN) to formic acid and ammonia. CNO was resolved into four protein components (P1 to P4), each of which along with a source of pterin cofactor was obligately required for CNO activity. Component P1 was characterized as a multimeric 230-kDa flavoprotein exhibiting the properties of a peroxide-forming NADH oxidase (oxidoreductase) (Nox). P2 consisted of a 49.7-kDa homodimer that showed 100% amino acid identity at its N terminus to NADH peroxidase (Npx) from Enterococcus faecalis. Enzyme assays further confirmed the identities of both Nox and Npx enzymes (specific activity, 1 U/mg). P3 was characterized as a large oligomeric protein (approximately 300 kDa) that exhibited cyanide dihydratase (CynD) activity (specific activity, 100 U/mg). Two polypeptides of 38 kDa and 43 kDa were each detected in the isolated enzyme, the former believed to confer catalytic activity based on its similar size to other CynD enzymes. The amino acid sequence of an internal peptide of the 43-kDa protein was 100% identical to bacterial elongation factor Tu, suggesting a role as a possible chaperone in the assembly of CynD or a multienzyme CNO complex. The remaining P4 component consisted of a 28.9-kDa homodimer and was identified as carbonic anhydrase (specific activity, 2,000 U/mg). While the function of participating pterin and the roles of Nox, Npx, CynD, and CA in the CNO-catalyzed scavenging of CN remain to be determined, this is the first report describing the collective involvement of these four enzymes in the metabolic detoxification and utilization of CN as a bacterial nitrogenous growth substrate.


Spontaneous decrease in the size of a residual thoracic intradural lipoma.
Intradural spinal lipomas of thoracic cord are quite rare. It is known that lipomas are hamartomas, which change their size with alterations of body fat. An 18-year-old male patient, with a thoracic intradural lipoma showing spontaneous decrease in the size of a residual lipoma and tethering of the cord 4 years after surgery, is presented in this report.


Optimization of adeno-associated virus vector-mediated gene transfer to the respiratory tract.
An efficient adeno-associated virus (AAV) vector was constructed for the treatment of respiratory diseases. AAV serotypes, promoters and routes of administration potentially influencing the efficiency of gene transfer to airway cells were examined in the present study. Among the nine AAV serotypes (AAV1-9) screened in vitro and four serotypes (AAV1, 2, 6, 9) evaluated in vivo, AAV6 showed the strongest transgene expression. As for promoters, the cytomegalovirus (CMV) early enhancer/chicken β-actin (CAG) promoter resulted in more robust transduction than the CMV promoter. Regarding delivery routes, intratracheal administration resulted in strong transgene expression in the lung, whereas the intravenous and intranasal administration routes yielded negligible expression. The combination of the AAV6 capsid and CAG promoter resulted in sustained expression, and the intratracheally administered AAV6-CAG vector transduced bronchial cells and pericytes in the lung. These results suggest that AAV6-CAG vectors are more promising than the previously preferred AAV2 vectors for airway transduction, particularly when administered into the trachea. The present study offers an optimized strategy for AAV-mediated gene therapy for lung diseases, such as cystic fibrosis and pulmonary fibrosis.


Caffeine Biodegradation by Cytochrome P450 1A2. What Determines the Product Distributions?
Caffeine is a natural compound found in plant seeds that after consumption by humans effects the central nervous system as well as the cardiovascular system. In general, the cytochrome P450 enzymes in the liver are involved in the biodegradation of caffeine, which gives paraxanthine, theobromine and theophylline products. There has been debate for many years why multiple products are obtained and how their distributions are determined. To this end we performed a high-level computational study using a combination of molecular dynamics and quantum mechanical approaches. A series of quantum chemical cluster models on the mechanism of caffeine activation by P450 model complexes give hydrogen atom abstraction barriers that predicts the correct ordering and statistical distribution of products. Our studies highlight that second-coordination sphere effects and thermochemical properties of the substrate determine the product distributions.


Oxamate Enhances the Anti-Inflammatory and Insulin-Sensitizing Effects of Metformin in Diabetic Mice.
Metformin (MET) is the first-line drug for treating type 2 diabetes mellitus (T2DM). However, MET increases blood lactate levels in patients with T2DM. Lactate possesses proinflammatory properties and causes insulin resistance (IR). Oxamate (OXA), a lactate dehydrogenase inhibitor, can decrease tissue lactate production and blood lactate levels. This study was conducted to examine the effects of the combination of OXA and MET on inflammation, and IR in diabetic db/db mice. Supplementation of OXA to MET led to lowered tissue lactate production and serum lactate levels compared to MET alone, accompanied with further decreased tissue and blood levels of pro-inflammatory cytokines, along with better insulin sensitivity, beta-cell mass, and glycemic control in diabetic db/db mice. These results show that OXA enhances the anti-inflammatory and insulin-sensitizing effects of MET through the inhibition of tissue lactate production in db/db mice.


Different patterns of genealogical relationships found in the two major QTLs causing reduction of seed shattering during rice domestication.
The three quantitative trait loci (qSH1, qSH3, and qSH4) causing reduction of seed shattering were investigated to examine their relative importance during rice domestication. The qSH1 and qSH4 loci showed a distinct effect on the reduction of shattering, compared with the qSH3 locus. Fine mapping and sequence analysis strongly suggested that the qSH1 and qSH4 loci are the same as the recently reported genes. A non-shattering allele at qSH1 drastically changed the shattering phenotype to a non-shattering phenotype even in the presence of shattering alleles at the qSH3 and qSH4 loci, showing that qSH1 is genetically epistatic to the other loci. The level of the reduction in sequence diversity was compared between the qSH1 and qSH4 regions. The sequence diversity was severely reduced in the qSH1 region of Oryza sativa subsp. japonica compared with that of O. sativa subsp. indica, despite that the level of diversity was similarly reduced at the qSH4 region in the 2 subspecies. Phylogenetic reconstruction based on the combined sequences of the flanking sites showed different patterns in the 2 subspecies. The 2 subspecies formed a single clade with respect to qSH4, whereas they were separated into different lineages with respect to qSH1, suggesting that these loci had different histories during rice domestication.


Survival after coronary revascularization in the elderly.
Elderly patients with ischemic heart disease are increasingly referred for coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI). However, reports of poor outcomes in the elderly have led to questions about the benefit of these strategies. We studied survival by prescribed treatment (CABG, PCI, or medical therapy) for patients in 3 age categories: <70 years, 70 to 79 years, and > or =80 years of age. The Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (APPROACH) is a clinical data collection and outcome monitoring initiative capturing all patients undergoing cardiac catheterization and revascularization in the province of Alberta, Canada, since 1995. Characteristics and long-term outcomes of a cohort of >6000 elderly patients with ischemic heart disease were compared with younger patients. In 15 392 patients >70 years of age, 4-year adjusted actuarial survival rates for CABG, PCI, and medical therapy were 95.0%, 93.8%, and 90.5%, respectively. In 5198 patients 70 to 79 years of age, survival rates were 87.3%, 83.9%, and 79.1%, respectively. In 983 patients > or = 80 years of age, survival was 77.4% for CABG, 71.6% for PCI, and 60.3% for medical therapy. Absolute risk differences in comparison to medical therapy for CABG (17.0%) and PCI (11.3%) were greater for patients > or =80 years of age than for younger patients. Elderly patients paradoxically have greater absolute risk reductions associated with surgical or percutaneous revascularization than do younger patients. The combination of these results with a recent randomized trial suggests that the benefits of aggressive revascularization therapies may extend to subsets of patients in older age groups.


Growth hormone: important role in muscular exercise in adults.
Measurement by radio-immunoassay of growth hormone in the plasma of adults showed consistently low concentrations in subjects in bed in the morning. Exercise caused marked increases except when the subjects ingested carbohydrate during the exercise.


Protein engineering of protein kinase A catalytic subunits results in the acquisition of novel inhibitor sensitivity.
Analysis of the role of specific protein kinases in signal transduction networks has relied heavily on ATP analog inhibitors. Currently used agents, however, often do not distinguish between kinase family members. Genetic approaches can also be used to inactivate a specific kinase, but these techniques do not afford the rapid kinetics possible with pharmacological inhibitors. To circumvent this problem, modification of the structure of a particular protein kinase can be performed to engineer a drug-target interaction of choice. We have used this method to create protein kinase A (PKA) catalytic subunits with modifications that confer sensitivity to novel ATP analog inhibitors. Mutation of methionine 120 to alanine or glycine in either the Calpha or Cbeta subunits of PKA induces sensitivity to a series of C-3 derivatized pyrazolo[3,4-d]pyrimidine-based inhibitors. Modification of threonine 183 enhances this inhibitor sensitivity. The IC(50) values in cell culture of the most broadly effective agent, 1-NM, ranged from 25 to 200 nm depending upon the combination of modified amino acids and were significantly higher than the potencies observed with H-89. Despite their high sequence conservation, Cbeta enzymes with inhibitor-sensitive amino acids at position 120 showed a substantial loss of overall catalytic activity when used to induce reporter gene transcription in transfected cells. Conversion of position 46 (lysine to isoleucine) rescued the ability of position 120 mutated Cbeta enzymes to induce gene transcription. Application of this combined genetic and pharmacological approach should allow analysis of the specific roles of PKA isoforms in cell culture and in vivo.