Synthetic Modification within the "RPRL" Region of Apelin Peptides: Impact on Cardiovascular Activity and Stability to Neprilysin and Plasma Degradation.
Apelin is an important mammalian peptide hormone with a range of physiological roles, especially in the cardiovascular system. The apelinergic system is a promising target for treatment of disease, but this remains to be realized due to rapid proteolysis of apelin-derived peptides by proteases, including neprilysin (NEP). The synthetic analogues modified within the NEP degradation site ("RPRL" motif) showed improved in vitro proteolytic stability while maintaining receptor-binding affinities, with three candidate peptides retaining full cardiovascular activities for potential therapeutic application. Many such analogues proved physiologically inactive even with relatively conservative modifications, highlighting the importance of this region for full agonist activity of this peptide hormone.


Pharmacokinetic and pharmacodynamic evaluation of linagliptin in African American patients with type 2 diabetes mellitus.
This was an open label, multicentre phase I trial to study the pharmacokinetics and pharmacodynamics of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin in African American patients with type 2 diabetes mellitus (T2DM). Forty-one African American patients with T2DM were included in this study. Patients were admitted to a study clinic and administered 5 mg linagliptin once daily for 7 days, followed by 7 days of outpatient evaluation. Primary endpoints were area under the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax ) and plasma DPP-4 trough inhibition at steady-state. Linagliptin geometric mean AUC was 194 nmol l(-1) h (geometric coefficient of variation, 26%), with a Cmax of 16.4 nmol l(-1) (41%). Urinary excretion was low (0.5% and 4.4% of the dose excreted over 24 h, days 1 and 7). The geometric mean DPP-4 inhibition at steady-state was 84.2% at trough and 91.9% at maximum. The exposure range and overall pharmacokinetic/pharmacodynamic profile of linagliptin in this study of African Americans with T2DM was comparable with that in other populations. Laboratory data, vital signs and physical examinations did not show any relevant findings. No safety concerns were identified. The results of this study in African American patients with T2DM support the use of the standard 5 mg dose recommended in all populations.


Evaluation of cerebellar and cerebral volume in migraine with aura: a stereological study.
Migraine is associated with an increased risk of deep white matter lesions and subclinical posterior circulation infarcts. A significant association between deep white matter hyperintensities and cerebral atrophy is true for various neurological diseases; it was not specifically proven in migraine. The aim of this study was to evaluate the cerebellar and cerebral volume and volume ratios for cerebellum using the Cavalieri principle. We also aimed to examine whether migraine with aura causes cerebellar and cerebral atrophy. Twenty three right-handed patients with migraine with aura diagnosed by means of the International Headache Society criteria and 24 age-matched subjects whose only health problem was headache due to rhinosinusitis and tension type headache were included in the study. Measurements of the cerebellar and cerebral volumes as well as cerebellar/cerebral volume ratios were made using Cavalieri's principle by utilizing the point-counting methods. There were no significant differences between the volumes of cerebrum, cerebellum, and the ratio of cerebellum to cerebrum for males (p = 0.05, p = 0.10, and p = 0.64, respectively) and for females (p = 0.18, p = 0.89, and p = 0.24, respectively). Our results suggest that patients with migraine with aura do not have a significant difference in cerebellar and cerebral volumes and cerebellar/cerebral volume ratios compared to the non-migraine group.


Metastatic Cardiac Tumor from Bronchogenic Carcinoma via Pulmonary Vein: A Case Report.
Metastatic tumors of the heart are more common than the primary cardiac tumors. Bronchogenic carcinoma is one of the common primaries for cardiac metastases. Cardiac metastasis from bronchogenic carcinoma via pulmonary vein is rare occurrence. We present a case of central bronchogenic carcinoma with left atrial tumor thrombus via right superior pulmonary vein.


Low serum 25-hydroxyvitamin D is associated with increased bladder cancer risk: A systematic review and evidence of a potential mechanism.
The development of some cancers is associated with vitamin D deficiency. We suggest that reduced conversion of 25-hydroxyvitamin D (25(OH)D) to 1,25-dihydroxyvitamin D (1,25(OH)2D) and the resulting modification of tissue specific immune responses may be key. Non-muscle-invasive bladder cancer is highly immunoresponsive and stimulation of an inflammatory response by intravesical bacillus Calmette-Guerin (BCG) treatment prevents recurrence. To assess the relationship between serum 25(OH)D and bladder cancer risk we conducted a systematic review. To test our hypothesis, the synthesis of 1,25(OH)2D by human bladder epithelial cell lines (T24/83 and RT4) was examined. Studies were identified from Medline, Web of Science, Embase and Cochrane library (limited to English language, humans and 1990-2018). After removal of duplicates, title and abstract review 6 full papers were appraised. Low vitamin D levels were associated with bladder cancer risk in 5/6 of the studies. Both cell lines express the vitamin D receptor, 25-hydroxyvitamin D 1α-hydroxylase (1α-OHase) and 24-hydroxylase (24-OHase) mRNA, which was induced by 1,25(OH)2D. 24-OHase mRNA was also increased by 25(OH)D indicating 1α-OHase activity. Both cell types expressed TLR1,2,4 and the TLR partners MyD88 and CD14mRNA. Cathelicidin mRNA was undetectable in both cell lines but was induced by 1,25(OH)2D and 25(OH)D in RT4 cells. The systematic review demonstrated that bladder cancer risk correlates with serum 25(OH)D levels. In addition, we have shown that transitional epithelial cells express functional vitamin D signaling and can synthesize sufficient 1,25(OH)2D to stimulate a local immune response. We suggest that in order to maintain optimal immune surveillance within the bladder adequate levels of serum 25(OH)D are required for direct synthesis of 1,25(OH)2D by bladder epithelial cells.


Learned helplessness among families and surrogate decision-makers of patients admitted to medical, surgical, and trauma ICUs.
We sought to determine the prevalence of and clinical variables associated with learned helplessness, a psychologic state characterized by reduced motivation, difficulty in determining causality, and depression, in family members of patients admitted to ICUs. We conducted an observational survey study of a prospectively defined cohort of family members, spouses, and partners of patients admitted to surgical, medical, and trauma ICUs at a large academic medical center. Two validated instruments, the Learned Helplessness Scale and the Perceived Stress Scale, were used, and self-report of patient clinical characteristics and subject demographics were collected. Four hundred ninety-nine family members were assessed. Of these, 238 of 460 (51.7%) had responses consistent with a significant degree of learned helplessness. Among surrogate decision-makers, this proportion was 50% (92 of 184). Characteristics associated with significant learned helplessness included grade or high school education (OR, 3.27; 95% CI, 1.29-8.27; P = .01) and Perceived Stress Scale score > 18 (OR, 4.15; 95% CI, 2.65-6.50; P < .001). The presence of a patient advance directive or do not resuscitate (DNR) order was associated with reduced odds of significant learned helplessness (OR, 0.56; 95% CI, 0.32-0.98; P = .05). The majority of family members of patients in the ICU experience significant learned helplessness. Risk factors for learned helplessness include lower educational levels, absence of an advance directive or DNR order, and higher stress levels among family members. Significant learned helplessness in family members may have negative implications in the collaborative decision-making process.


Amelanotic Melanoma Arising in Filarial Leg: A Report of a Rare Case.
Amelanotic melanoma arising on chronic lymphoedema has not been reported earlier. We reported a case of amelanotic melanoma of right leg developing in a background of chronic lymphoedema of filarial origin in an elderly male of 60 years, who underwent wide local excision of the lesion followed by skin grafting for the same. A histopathological diagnosis of amelanotic melanoma was made. The patient was on follow up when he developed brain metastasis within a period of nine months for which he was operated and is on regular follow up now. We believe this as the first case report of this unusual combination.


Diminished social interaction incentive contributes to social deficits in mouse models of autism spectrum disorder.
One of the core symptoms of autism spectrum disorder (ASD) is impaired social interaction. Currently, no pharmacotherapies exist for this symptom due to complex biological underpinnings and distinct genetic models which fail to represent the broad disease spectrum. One convincing hypothesis explaining social deficits in human ASD patients is amotivation, however it is unknown whether mouse models of ASD represent this condition. Here we used two highly trusted ASD mouse models (male Shank3-deficient [Shank3+/ΔC ] mice modeling the monogenic etiology of ASD, and inbred BTBR mice [both male and female] modeling the idiopathic and highly polygenic pathology for ASD) to evaluate the level of motivation to engage in a social interaction. In the behavioral paradigms utilized, a social stimulus was placed in the open arm of the elevated plus maze (EPM), or the light compartment of the light-dark box (LDB). To engage in a social interaction, mice were thus required to endure innately aversive conditions (open areas, height, and/or light). In the modified EPM paradigm, both Shank3+/ΔC and BTBR mice demonstrated decreased open-arm engagement with a social stimulus but not a novel object, suggesting reduced incentive to engage in a social interaction in these models. However, these deficits were not expressed under the less severe aversive pressures of the LDB. Collectively, we show that ASD mouse models exhibit diminished social interaction incentive, and provide a new investigation strategy facilitating the study of the neurobiological mechanisms underlying social reward and motivation deficits in neuropsychiatric disorders.


Hospitalization before and after gastric bypass surgery.
The use of Roux-en-Y gastric bypass (RYGB) has been reported to be effective in the treatment of obesity and its related comorbidities. Utilization of inpatient services after RYGB is less well understood. To determine the rates and indications for inpatient hospital use before and after RYGB. Retrospective study of Californians receiving RYGB in California hospitals from 1995 to 2004. Hospitalization in the 1 to 3 years after RYGB. In California from 1995 to 2004, 60,077 patients underwent RYGB-11,659 in 2004 alone. The rate of hospitalization in the year following RYGB was more than double the rate in the year preceding RYGB (19.3% vs 7.9%, P<.001). Furthermore, in the subset of patients (n = 24,678) with full 3-year follow-up, a mean of 8.4% were admitted a year before RYGB while 20.2% were readmitted in the year after RYGB, 18.4% in the second year after RYGB, and 14.9% in the third year after RYGB. The most common reasons for admission prior to RYGB were obesity-related problems (eg, osteoarthritis, lower extremity cellulitis), and elective operation (eg, hysterectomy), while the most common reasons for admission after RYGB were complications often thought to be procedure related, such as ventral hernia repair and gastric revision. In multivariate logistic regression models predicting 1-year readmission after RYGB, increasing Charlson Comorbidity Index score, and hospitalization in the 3-year period prior to RYGB were significantly associated with readmission within a year. Increases in hospital use after surgery appear to be related to RYGB. Payers, clinicians, and patients must consider the not-inconsequential rate of rehospitalization after this type of surgery.


Angiotensin Receptor Neprilysin Inhibitors in HFrEF: Is This the First Disease Modifying Therapy Drug Class Leading to a Substantial Reduction in Diuretic Need?
Despite significant advances in disease modifying therapy in heart failure (HF), diuretics have remained the cornerstone of volume management in all HF phenotypes. Diuretics, alongside their definite acute haemodynamic and symptomatic benefits, also possess many possible deleterious side effects. Moreover, questions remain regarding the prognostic impact of chronic diuretic use. To date, few data exist pertaining to diuretic reduction as a result of individual traditional guideline directed medical therapy in HF with reduced ejection fraction (HFrEF). However, diuretic reduction has been demonstrated with sacubitril/valsartan (angiotensin receptor-neprilysin inhibitor [ARNi]) from the PARADIGM study, as well as, post-marketing reports from our own group and others. Whether the ARNi compound represents the dawn of a new era, where effective therapies will have a more noticeable reduction on diuretic need, remains to be seen. The emergence of sodium glucose transport 2 inhibitors and guanylate cyclase stimulators may further exemplify this issue and potentially extend this benefit to HF patients outside of the HFrEF phenotype. In conclusion, emerging new therapies in HFrEF could reduce the reliance on diuretics in the management of this phenotype of HF. These developments further highlight the clinical importance to continually assess an individual's diuretic requirements through careful volume assessment.


Role of the BRAF mutations in the microsatellite instability genetic pathway in sporadic colorectal cancer.
Between 10 and 15% of all cases of colorectal cancer are the result of microsatellite instability (MSI) in the genetic pathway due to an alteration in the DNA repair genes. Tumors with high MSI are characterized by a better prognosis. The BRAF oncogene has been linked to the MSI pathway in tumorogenesis. The objective of this study was to determine whether alterations in BRAF are related to MSI and whether they can result in differences in survival rates. The study cohort comprised 351 patients diagnosed with sporadic colorectal cancer. MSI was determined in accordance with the National Cancer Institute's (NCI) recommendations by means of PCR and sequence analyses. Mutational analysis of the BRAF gene was performed by real-time PCR and subsequent sequencing of the altered samples. The methylation pattern of the hMLH1 gene was determined using methylation-specific PCR analyses of bisulfite-treated DNA and the results confirmed by sequencing. Of the patients tested, 6.9% showed high MSI and 3.7% showed a BRAF gene mutation. hMLH1 methylation was observed in 67.2% of the patients with MSI and/or the BRAF alteration. The BRAF mutation was related to the MSI genetic pathway (P < 0.0001) and with hMLH1 methylation. In the analysis of overall survival only MSI had an independent prognostic value for the risk of death. Patients with the BRAF mutation showed a higher risk of death, although this association was found not to be statistically significant. There is a subgroup of carcinomas which develop via the MSI pathway that carry an alteration of the BRAF gene. This alteration confers a poorer outcome on these patients within the total group of patients with MSI who have a better prognosis. This hypothesis should be further investigated in a larger study population due to the low incidence of BRAF mutations in colorectal cancer.


Circadian patterns of serum insulin-like growth factor (IGF) II and IGF binding protein 3 in growth hormone-deficient patients and age- and sex-matched normal subjects.
Knowledge of the circadian patterns of serum IGF-II and the large molecular weight IGF binding protein, IGFBP-3 might, apart from its physiological relevance, be of clinical interest, inasmuch as measurements of these parameters are being introduced into the evaluation of GH deficiency. We therefore evaluated the 24-h (08.00-08.00 h) patterns of serum IGF-II and IGFBP-3 in 8 GH-deficient patients who were studied during three periods when receiving 1. GH (2 IU) at 20.00 h; 2. GH (2 1U) at 08.00 h and 3. no GH. For comparison, 10 age- and sex-matched untreated healthy subjects were studied once under similar conditions. The serum IGF-II levels of the patients were relatively stable over the 24-h periods, yielding mean levels which were significantly lower during no GH: 553 +/- 78 (evening GH), 554 +/- 54 (morning GH), and 429 +/- 65 micrograms/l (no GH). The mean IGF-II level in the normal subjects was 635 +/- 29 micrograms/l, which was significantly higher than in either patient study. Similarly, stable 24-h levels of IGFBP-3 were recorded in all studies. The mean IGFBP-3 level of the patients was significantly lower when they received no GH, and the mean level in the healthy subjects was higher than in any of the patient studies: 1853 +/- 301 (no GH), 2755 +/- 317 (evening GH), 2904 +/- 269 (morning GH), and 3856 +/- 186 micrograms/l (healthy subjects). However, minute but significant changes over time, characterised by slight decrements at night, were observed for both parameters in several of the studies.(ABSTRACT TRUNCATED AT 250 WORDS)


[Standards, options, and recommendation for external radiotherapy of prostatic cancer: evaluation of the effect of dosage].
The "Standards, Options and Recommendations" (SOR) collaborative project was initiated in 1993 by the Federation of the French Cancer Centres (FNCLCC), with the 20 French Regional Cancer Centres, several French public university and general hospitals, as well as private clinics and medical speciality societies. Its main objective is the development of serviceable clinical practice guidelines in order to improve the quality of health care and the outcome of cancer patients. The methodology is based on a literature review, followed by critical appraisal by a multidisciplinary group of experts. Draft guidelines are produced, then validated by specialists in cancer care delivery. Produce clinical practice guidelines for the radiotherapy of prostate cancer using the methodology developed by the Standards, Options and Recommendations project. The FNCLCC and the French Urology Association (AFU) designated the multidisciplinary group of experts. Available data were collected by a search of Medline and lists selected by experts in the group. A first draft of the guidelines was written, they validated by independent reviewers. The main recommendations are: 1/ a minimal dose of 70 Gy must be used, whatever the prognostic factors; 2/ it appeared that patients with favourable prognostic indicators (stage T1-2, PSA < or = 10 micrograms/L and Gleason score < or = 6) do not benefit from a dose escalation effect for doses over 70-74 Gy; 3/ patients with intermediate prognosis are the ones who benefit most from the dose escalation effect over 74 Gy, provided they receive exclusive radiation therapy; 4/ whenever possible, patients should be included in controlled trials designed to assess the effects of dose escalation and hormonotherapy.


Contribution of nuclear medicine to the diagnosis and management of primary brain tumours.
Positron emission tomography (PET) is a powerful tool that can help physicians manage primary brain tumours at diagnosis and follow-up. In this context, PET imaging is used with three main types of radiotracers: 18F-FDG, amino acid radiotracers, and 68Ga conjugated to somatostatin receptor ligands (SSTRs). At initial diagnosis, 18F-FDG helps to characterize primary central nervous system (PCNS) lymphomas and high-grade gliomas, amino acid radiotracers are indicated for gliomas, and SSTR PET ligands are indicated for meningiomas. Such radiotracers provide information on tumour grade or type, assist in directing biopsies and help with treatment planning. During follow-up, in the presence of symptoms and/or MRI modifications, the differential diagnosis between tumour recurrence and post-therapeutic changes, in particular radiation necrosis, may be challenging, and there is strong interest in using PET to evaluate therapeutic toxicity. PET may also contribute to identifying specific complications, such as postradiation therapy encephalopathy, encephalitis associated with PCNS lymphoma, and stroke-like migraine after radiation therapy (SMART) syndrome associated with glioma recurrence and temporal epilepsy, originally illustrated in this review. This review summarizes the main contribution of PET to the diagnosis, management, and follow-up of brain tumours, specifically gliomas, meningiomas, and primary central nervous system lymphomas.


A study on the evaluation of masticatory ability in osseointegrated implants applied to lower molar region.
Masticatory function was investigated in 7 subjects (5 women and 2 men) with unilateral OIB in their lower molar region. Masticatory movement and myoelectric discharge were analyzed. To examine occlusal contact, the closely occlusal contact area and occluding forces were investigated. The results from the OIB side were compared with the ones from the opposite side. In all subjects, there were no significant differences in the parameters of mandibular movement between chewing the test foods on the OIB side and chewing them on the opposite side. In 6 out of 7 subjects, the closely occlusal area of the interocclusal space differed by less than 1.0 mm between the OIB side and the opposite side in the molar region, and the occluding forces between them were similar. In 6 out of 7 subjects, the masticatory sensations were also similar between the two sides. There were no significant differences between the OIB side and the opposite side in the parameters of mandibular movement, the condition of occlusal contact and the sensation of mastication in patients who were treated with unilateral OIB in the lower molar region. The data seem to suggest that there is little difference between the masticatory ability of OIB and that of natural dentition.


Endoscopic management of migrated biliary stent causing sigmoid perforation.
Endoscopically deployed biliary stents are a well established method for dealing with biliary diseases. Perforation of the gut secondary to migrated biliary stent is reported in less than 1% cases. The authors present the first case of a colonic perforation from migrated biliary stent which was managed endoscopically. An 82-year-old female had a biliary stent for a postcholecystectomy bile leak and presented 6 months later with left iliac fossa pain. Barium enema showed a stent perforating the sigmoid colon. In view of the patient's frailty and absence of peritonitis, an endoscopic retrieval of stent was attempted. Flexible sigmoidoscopy showed a stent partially embedded within the sigmoid diverticulum which was successfully removed and the defect was closed endoscopically using three titanium clips. She had an uncomplicated recovery following the procedure and was discharged home on the second day following the procedure.


Fear of Treatments Surpasses Demographic and Socioeconomic Factors in Affecting Patients With Breast Cancer in Urban South Africa.
Breast cancer is the most common cause of cancer in women in South Africa, and often patients present late. There is little understanding of the psychosocial stresses affecting women with breast cancer in Africa. A questionnaire was distributed to 263 patients with breast cancer at two sites (one government and one private facility) in Johannesburg. Self-reported levels of fear were recorded on summative scales and their relationship to demographic variables assessed through univariable and multivariable modified Poisson regression. Fears related to treatments and prognosis, particularly radiation, loss of hair, and loss of breast, were far stronger than those related to socioeconomic barriers. Relative risk (RR) of most fears was higher in women younger than age 40 years, including treatment affordability (RR, 1.80; 95% CI, 1.26 to 2.56), hair loss (RR, 1.48; 95% CI, 1.12 to 2.95), and surgery (RR, 1.31; 95% CI, 1.02 to 1.68). Difficulty taking time off work predicted fear of job loss (RR, 2.59; 95% CI, 1.59 to 4.21) and missing appointments because of transport (RR, 2.46; 95% CI, 1.52 to 3.96) or family commitments (RR, 2.46; 95% CI, 1.52 to 3.96). Women with dependents and black women were more afraid of dying (RR, 1.73; 95% CI, 1.03 to 2.90; and RR, 1.79; 95% CI, 1.33 to 2.24, respectively); however, socioeconomic status in this sample was a strong confounder of race and explained most of the racial differences in levels of fear. The most significant fears around breast cancer were related to treatment modalities and adverse effects rather than transport, financial, or work concerns. Young age and job insecurity were predictive of increased fears. Education about treatments has a key role to play in improving access to breast cancer care in South Africa.


Annexin A1 counteracts chemokine-induced arterial myeloid cell recruitment.
Chemokine-controlled arterial leukocyte recruitment is a crucial process in atherosclerosis. Formyl peptide receptor 2 (FPR2) is a chemoattractant receptor that recognizes proinflammatory and proresolving ligands. The contribution of FPR2 and its proresolving ligand annexin A1 to atherosclerotic lesion formation is largely undefined. Because of the ambivalence of FPR2 ligands, we here investigate the role of FPR2 and its resolving ligand annexin A1 in atherogenesis. Deletion of FPR2 or its ligand annexin A1 enhances atherosclerotic lesion formation, arterial myeloid cell adhesion, and recruitment. Mechanistically, we identify annexin A1 as an endogenous inhibitor of integrin activation evoked by the chemokines CCL5, CCL2, and CXCL1. Specifically, the annexin A1 fragment Ac2-26 counteracts conformational activation and clustering of integrins on myeloid cells evoked by CCL5, CCL2, and CXCL1 through inhibiting activation of the small GTPase Rap1. In vivo administration of Ac2-26 largely diminishes arterial recruitment of myeloid cells in a FPR2-dependent fashion. This effect is also observed in the presence of selective antagonists to CCR5, CCR2, or CXCR2, whereas Ac2-26 was without effect when all 3 chemokine receptors were antagonized simultaneously. Finally, repeated treatment with Ac2-26 reduces atherosclerotic lesion sizes and lesional macrophage accumulation. Instructing the annexin A1-FPR2 axis harbors a novel approach to target arterial leukocyte recruitment. With the ability of Ac2-26 to counteract integrin activation exerted by various chemokines, delivery of Ac2-26 may be superior in inhibition of arterial leukocyte recruitment when compared with blocking individual chemokine receptors.


Assessing prescription writing skills of pre-clerkship medical students in a problem-based learning curriculum.
To audit the acquisition of prescribing skills of pre-clerkship medical students in a problem-based learning (PBL) curriculum that incorporates a prescribing program. Student performance in pharmacotherapy stations included in six out of eight end-of-unit-objective structured practical examinations (OSPE) was evaluated using a rating checklist. Prescription writing skills of 539 students (66.2% female and 33.8% male) were appraised. With the exception of refill element, the other physician-related components including prescriber's identity, date of prescription order, patient's identity, the symbol Rx "Take Thou", and prescriber's signature were written by 96.1% of the students (95% confidence interval (CI) 94.1 - 97.5). However, the drug-related components such as the appropriateness of drug(s) selected, strength, dosage form, quantity to be dispensed and directions for use were written satisfactorily by 50.2% of the students (95% CI 46.0 - 54.4). With respect to prescribing skills, the mean total score of Year 4 students did not significantly differ from that of Year 2 (69.4 (CI 65.7 - 73.1) vs. 66.3 (CI 62.7 to 69.9); p = 0.237). However, the mean scores of individual drug-related components such as appropriateness of drug(s) selected, dosage form, and direction for use were significantly higher in Year 4 than that of Year 2 students (p < 0.05). Of 381 rationally prescribed drugs, 81.1% were written with generic names. This study revealed that the students acquire prescribing skills to a limited extent during the pre-clerkship phase in a PBL program. Prescribing errors and deficits were found to be mainly associated with drug-related components. Further training and assessment of prescribing skills during the clerkship and internship period are needed to achieve mastery of this skill as a terminal competency of graduating physicians.


Estimating the critical duration for temporal summation of standard achromatic perimetric stimuli.
To estimate the critical duration of temporal summation for achromatic Goldmann III stimuli under the conditions of standard automated perimetry (SAP) and quantify response variability for short-duration stimuli. Contrast thresholds were gathered using the method of constant stimuli for seven circular (0.48° diameter) incremental stimuli of varying duration (sum-of-frames equivalent: 8.3-198.3 ms), at an eccentricity of 8.8° along the four principal meridians of the visual field in two healthy, psychophysically experienced observers. Stimuli were presented on a high-resolution cathode ray tube display with a background luminance of 10 cd/m(2). Psychometric functions were fitted using a probit model and nonparametric local-linear analysis. The critical duration was estimated using iterative two-phase regression analysis, the results also being compared with values produced using previously published methods of analysis. The median critical duration estimated using iterative two-phase regression analysis was 27.7 ms (IQR 22.5-29.8). A slight steepening of the psychometric function slope (lower variability) was observed for longer stimulus durations, using both probit and local-linear analysis techniques, but this was not statistically significant. Critical duration estimates in this study are substantially shorter than those previously reported for a Goldmann III stimulus, under the conditions of SAP. Further work is required to firmly establish the relationship between measurement variability and the degree of local temporal and spatial summation.


The effect of serial dilution error on calibration inference in immunoassay.
A common practice in immunoassay is the use of sequential dilutions of an initial stock solution of the antigen of interest to obtain standard samples in a desired concentration range. Nonlinear, heteroscedastic regression models are a common framework for analysis, and the usual methods for fitting the model assume that measured responses on the standards are independent. However, the dilution procedure introduces a propagation of random measurement error that may invalidate this assumption. We demonstrate that failure to account for serial dilution error in calibration inference on unknown samples leads to serious inaccuracy of assessments of assay precision such as confidence intervals and precision profiles. Techniques for taking serial dilution error into account based on data from multiple assay runs are discussed and are shown to yield valid calibration inferences.


Evaluation of PDGF-BB, PDGF-AA, bFGF, IL-1, and EGF dose responses in polyvinyl alcohol sponge implants assessed by a rapid histologic method.
Polyvinyl alcohol sponge implants were used in rats, mice, and guinea pigs to determine dose responses of growth factors. Eight differently treated sponges per rat or guinea pig (4/mouse) were injected with test material on alternate days and evaluated at day 8. Much of the observed response occurred in and around the capsule and was manifest as densely cellular granulation tissue. Including this capsular response in a single histologic slide ranking system provided a more sensitive and faster method of assessing growth factor effects than measurement of connective tissue ingrowth alone. Clear dose responsive effects were seen with recombinant human PDGF-BB, PDGF-AA, bFGF, and IL-1 beta, while EGF gave a lesser response. Lipopolysaccharide did not affect the connective tissue response, alone or in combination with PDGF-BB. PDGF-BB was tested in each species, and the dose response characteristics were qualitatively and quantitatively similar across species.


National Diabetes Plans: can they support changes in health care systems to strengthen diabetes prevention and care?
Healthcare systems do not fit well with the "modern" patient, who has a right to autonomy and self-determination. The services that are designed and delivered in policy contexts are not prone to encourage innovation. National Diabetes Plans, defined as "any formal strategy for improving diabetes policy, services and outcomes that encompass structured and integrated or linked activities which are planned and co-ordinated nationally and conducted at the national, regional, and local level", may hold a great potential not only to improve prevention and care for type 2 diabetes, but also for transforming healthcare delivery. Today, changes to adapt healthcare delivery tend to be implemented within existing provider structures, with limited understanding of specific context, structures, processes and potential for change. National Diabetes Plan can be a diagnostic tool for barriers, can be a driver for planning the change, and can help develop capacities and competences that are needed to strengthen healthcare systems to better address health promotion and chronic diseases.


[Photogrammetric studies on the degree of swelling in the inflamed gingiva].
A photographic method was described with which changes in the swelling of the gingiva can be objectively determined. During exposure of the film, the flash device projects vertical lines on the teeth and gingiva. These lines are photographed with a compact camera which the subject holds with his teeth over a separate occlusion template. Increased swelling of the gingiva was demonstrated in eight subjects during an observation period of 21 days in which no oral hygiene was carried out.


Filament displacement image analytics tool for use in investigating dynamics of dense microtubule networks.
The fate and motion of cells is influenced by a variety of physical characteristics of their microenvironments. Traditionally, mechanobiology focuses on external mechanical phenomena such as cell movement and environmental sensing. However, cells are inherently dynamic, where internal waves and internal oscillations are a hallmark of living cells observed under a microscope. We propose that these internal mechanical rhythms provide valuable information about cell health. Therefore, it is valuable to capture the rhythms inside cells and quantify how drugs or physical interventions affect a cell's internal dynamics. One of the key dynamical entities inside cells is the microtubule network. Typically, microtubule dynamics are measured by end-protein tracking. In contrast, this paper introduces an easy-to-implement approach to measure the lateral motion of the microtubule filaments embedded within dense networks with (at least) confocal resolution image sequences. Our tool couples the computer vision algorithm Optical Flow with an anisotropic, rotating Laplacian of Gaussian filtering to characterize the lateral motion of dense microtubule networks. We then showcase additional image analytics used to understand the effect of microtubule orientation and regional location on lateral motion. We argue that our tool and these additional metrics provide a fuller picture of the active forcing environment within cells.


Can people feel happy and sad at the same time?
The authors investigated whether people can feel happy and sad at the same time. J. A. Russell and J. M. Carroll's (1999) circumplex model holds that happiness and sadness are polar opposites and, thus, mutually exclusive. In contrast, the evaluative space model (J. T. Cacioppo & G. G. Berntson, 1994) proposes that positive and negative affect are separable and that mixed feelings of happiness and sadness can co-occur. The authors both replicated and extended past research by showing that whereas most participants surveyed in typical situations felt either happy or sad, many participants surveyed immediately after watching the film Life Is Beautiful, moving out of their dormitories, or graduating from college felt both happy and sad. Results suggest that although affective experience may typically be bipolar, the underlying processes, and occasionally the resulting experience of emotion, are better characterized as bivariate.


Transcultural adaptation and validation of a Korean version of the Oxford Ankle Foot Questionnaire for children.
The purpose of this study was to translate and transculturally adapt the original English version of the Oxford Ankle Foot Questionnaire (OAFQ) into a Korean version, and to evaluate its psychometric properties. A Korean OAFQ for children was developed according to established guidelines. To test validity, 169 consecutive patients with foot and ankle problems and their caregivers each completed the OAFQ. The children also completed a Korean version of the KIDSCREEN-52 health related quality of life questionnaire (KIDSCREEN-52 HRQOL). To validate the Korean version of the OAFQ, reliability (child-parent agreement and internal consistency), feasibility (floor and ceiling effects), and construct validity were evaluated, and factor analysis was performed. In terms of reliability, Cronbach's α values were > 0.7 in all subscales of the OAFQ (0.765 to 0.901). Child-parent agreement was confirmed by high intraclass correlation coefficients for all subscales (0.791 to 0.863). In terms of construct validity, there were moderate correlations between the subscales of the OAFQ and the subscales of the KIDSCREEN-52 HRQOL. Factor analysis revealed a three-component solution for both the child/adolescent and parent-proxy version, by combining the school and play, and footwear items into one subscale. In terms of feasibility, no floor effects were found for all subscales. However, ceiling effects were observed for the school and play, and emotional subscales for child/adolescent and parent-proxy versions. The OAFQ was successfully translated and transculturally adapted into the Korean language; the Korean version of the OAFQ represents a reliable and valid instrument for evaluating children's foot or ankle problems. However, factor analysis suggested the use of a three-subscale questionnaire.


Levan enhanced the NF-κB suppression activity of an oral nano PLGA-curcumin formulation in breast cancer treatment.
Chemoresistance (CR) is one of the reasons why chemotherapy agents like Gemcitabine (GMC) remain insufficient in healing breast cancer. Activation of Nuclear Factor-kappa B (NF-κB) during chemotherapy is known as an important factor in the development of CR. The hydrophobic polyphenol curcumin is shown to inhibit NF-κB and hence CR. The aim of this work was to increase the poor bioavailability of curcumin by loading it into the nano-micelles made of Poly (Lactide-co-Glycolide) (PLGA) and levan, where levan as a natural fructose homopolymer makes the nano-micelle more stable and increases its uptake using the fructose moieties. In this study, a PLGA-levan-curcumin formulation (PLC) was designed and characterized. The size was measured as 154.16 ± 1.45 nm with a 67.68% encapsulation efficiency (EE%). The incorporation between the components was approved. Levan made the nano-micelles stable for at least three months, increased their uptake, and led to a 10,000-fold increase in the solubility of curcumin. The enhanced bioavailability of curcumin reduced the NF-κB levels elevated by GMC, both in vitro and in vivo. The PLC showed a complete tumor treatment, while GMC only showed a rate of 52%. These point to the great potential of the PLC to be used simultaneously with chemotherapy.


Potent and Orally Bioavailable Inverse Agonists of RORγt Resulting from Structure-Based Design.
Retinoic acid receptor related orphan receptor γt (RORγt), has been identified as the master regulator of TH17-cell function and development, making it an attractive target for the treatment of autoimmune diseases by a small-molecule approach. Herein, we describe our investigations on a series of 4-aryl-thienyl acetamides, which were guided by insights from X-ray cocrystal structures. Efforts in targeting the cofactor-recruitment site from the 4-aryl group on the thiophene led to a series of potent binders with nanomolar activity in a primary human-TH17-cell assay. The observation of a DMSO molecule binding in a subpocket outside the LBD inspired the introduction of an acetamide into the benzylic position of these compounds. Hereby, a hydrogen-bond interaction of the introduced acetamide oxygen with the backbone amide of Glu379 was established. This greatly enhanced the cellular activity of previously weakly cell-active compounds. The best compounds combined potent inhibition of IL-17 release with favorable PK in rodents, with compound 32 representing a promising starting point for future investigations.


Ficus carica latex-mediated synthesis of silver nanoparticles and its application as a chemophotoprotective agent.
The present work provides scientific support on the use of latex of Ficus carica to synthesize stable silver nanoparticles (AgNPs). AgNPs synthesized immediately after the addition of latex to silver nitrate solution at room temperature. Synthesized nanoparticles were of spherical shape with average size of 163.7 nm. Fourier transform infrared spectroscopy analysis revealed capping of proteins and phenolic compound on AgNPs, while X-ray diffraction analysis confirmed the fcc nature of AgNPs. Particles formed were stable for a long time (6 months). It was found that incorporation of AgNPs with 2 and 4% concentration exhibits synergistic increase in sun protection factor of commercial sunscreen and natural extracts ranging from 01 to 12,175% than control. Further characterization of latex and AgNPs revealed total phenolic content of 98.75 and 94.88 μg/ml. The ferric ion reduction potentials of latex and AgNPs were 79.69 and 18.79%. Reduction potential of ascorbic acid was synergistically increased after cumulative preparation of ascorbic acid with latex and AgNPs and found to be 106.76 and 101.50% for ascorbic acid + latex and ascorbic acid + AgNPs, respectively.


Association between advanced practice nursing and 30-day mortality in mechanically ventilated critically ill patients: A retrospective cohort study.
Little is known about the association between advanced practice nursing and mortality. The aim of this study was to evaluate whether the presence of advanced practice nurses (APN), that is, certified nurse (CN) and certified nurse specialist (CNS) in intensive care, is associated with 30-day mortality for mechanically ventilated critically ill patients. Using a Japanese national in-patient database, we identified 45,620 patients who were admitted to an intensive care unit (ICU) and received mechanical ventilation within 2 days of hospital admission between 1 April 2014 and 31 March 2015. We assessed the association between the number of CN/CNSs per 10 adult ICU beds and 30-day mortality. We examined 8955 patients in 134 hospitals without CN/CNSs and 36,665 in 284 hospitals with CN/CNSs. Overall, the number of CN/CNSs per 10 adult ICU beds ranged from 0 to 7.5. In the multivariable analysis, the number of CN/CNSs per 10 adult ICU beds was significantly associated with a reduction in 30-day mortality (adjusted odds ratio 0.97; 95% confidence interval, 0.94-1.00; P=0.023). Our findings show that APNs may play an important role in improving patient outcome in the adult ICU.


[Effect of Shenfu injection on expression of lipopolysaccharide --induced microRNA-146a in alveolar macrophages].
To study the effects of Shenfu injection (SF) on the expression of lipopolysaccharide(LPS)-induced microRNA-146a (miR-146a) in rat alveolar macrophages (AMs), and to extrapolate its potential anti-inflammatory mechanisms. In vitro cultured rat AMs (NR8383 cells) were randomly divided into control group, LPS stimulation group, and SF stimulation group. The LPS stimulation group was challenged with a final concentration of 1 mg/L LPS, and to the control group an equal volume of phosphate buffer solution (PBS) was added instead. For SF treated group, SF in different concentrations (1 ml/L or 10 ml/L) was used during incubation of AMs for half an hour, and then LPS was added (1 mg/L final concentration). After 6 hours, the cells and were collected. MiRNA-146a expression [reverse transcription-polymerase chain reaction (RT-PCR)] in cells and tumor necrosis factor-α (TNF-α ) content [enzyme-linked immunosorbent assay (ELISA)] in culture supernatant were determined for each group. Both the expression of miR-146a and TNF-α content in LPS stimulation group were significantly elevated compared with control group [miR-146a (expression folds): 5.92 + 1.57 vs. 1.04 +0.38; TNF-α (ng/L): 636.93 _ 30.21 vs. 20.46 + 2.81; both P<0.05]. Compared with LPS stimulation group, the expression of miR-146a was significantly upregulated in cells in both 1 ml/L and 10 ml/L SF stimulation groups, but TNF- α content was significantly reduced in the supernatant [miR-146a (expression folds): 7.02 + 0.91, 8.11 ± 1.07 vs. 5.92 -1.57; TNF-α (ng/L): 447.24 +21.29, 357.83 +19.73 vs. 636.93 +30.21, all P<0.05] in a dose-dependent manner (both P<0.05). SF could up-regulate miR-146a expression in AMs in a dose-dependent manner, and it was speculated that miR-146a might be involved in the anti-inflammatory processes with SF treatment.


Nursery outbreak of neonatal fungal arthritis treated with fluconazole.
Eight preterm infants with mean gestational age of 31.6 +/- 1.16 weeks and a mean birth weight of 1310 +/- 201.7 g presented at a mean postnatal age of 26 +/- 11.4 days with knee joint swellings and pedal oedema. There was no other clinical, haematological or microbiological evidence of bacterial sepsis. Fungal cultures yielded growth of Candida spp. from blood in five, from urine in four, from cerebrospinal fluid in one, and from all the three babies in whom the joints were aspirated. Radiographic changes of metaphysitis of the involved joints were noted in all. All infants had received prior antibiotic therapy. No infant had received total parenteral nutrition or had central lines inserted. All infants were treated with fluconazole in doses of 7.5 mg/kg/day for 6 weeks. Six of eight were thriving well at 3 months of age without any evidence of residual joint disease. One infant succumbed to disseminated disease and one was lost to follow-up. Candidial arthritis is an uncommon presentation of neonatal candidiasis. Fluconazole therapy proved effective.


Simple triage and rapid decontamination of mass casualties with colored clothes pegs (STARDOM-CCP) system against chemical releases.
The efficiency and speed with which first responders, paramedics, and emergency physicians respond to an event caused by the release of a chemical is an important concern in all modern cities worldwide. A system for the initial triage and decontamination of victims of a chemical release was developed using colored clothes pegs of the following seven colors: red, yellow, green, black, white, and blue. Red indicates the need for emergency care, yellow for semi-emergency care, green for non-emergency care, black for expectant, white for dry decontamination, and blue for wet decontamination. The system can be employed as one of the techniques directed at improving the efficiency of decontamination in countries where there is a risk of chemical releases. It is recommended that this system should be adopted internationally and used for both drills and actual events.


Scaled quantum chemical force fields for 1,1-difluorocyclopropane and the influence of vibrational anharmonicity.
Potential functions and harmonic (omega(i)) and anharmonic (nu(i)) fundamental frequencies have been calculated for 1,1-difluorocyclopropane (DFCP) and its d4 and d2 isotopomers using the program Gaussian 03. B3LYP and MP2 models were employed, each with the bases 6-311++G** and cc-pVTZ. Anharmonicity corrections Delta(i) = omega(i) - nu(i) are listed and shown to be different for symmetric and antisymmetric CH stretching modes in situations where Fermi resonance appears to be absent. The same effect is missing in C2H4, for which similar calculations were made. The quadratic force fields for DFCP have been scaled in symmetry coordinate space with 15 scale factors both to observed frequencies nu(obsd)and also to omega (obsd), where omega(obsd) = nu(obsd) + Delta. With nu(obsd) especially, different scale factors are needed for the symmetric and antisymmetric CH stretching force constants due to their differing anharmonicities. The source of the latter in the quartic and cubic force field is explored. MP2 calculations of valence interaction force constants involving the stretching of bonds on a common carbon atom are preferred to those from a B3LYP model. In either model, scaling to omega(obsd) rather than to nu(obsd) does not remove the necessity of varying scale factors for differing types of motion in the same group. Theoretical values of the five quartic centrifugal distortion constants are listed for the normal species and compared with new experimental data. The predictions are sufficiently good to be useful in fitting pure rotational transitions. A weakness is identified in the current Gaussian 03 code for the calculation of vibration-rotation quantities, and limitations are noted in the manner in which Fermi resonance is handled.


15 cm-1 to 12 000 cm-1 spectral coverage without changing optics: Diamond beam splitter adaptation of an FTIR spectrometer.
In order to facilitate IR absorption measurements, we have upgraded our Bruker IFS66v/S Fourier-transform infrared (FTIR) spectrometer. A synthetic diamond beam splitter without compensator plate and UHV diamond viewports was installed. We have also modified the IR detector chamber to allow measurements with 5 different detectors. As a result we can now obtain FT absorption spectra from 12 000 cm-1 to 15 cm-1 with the same sample held under ultrahigh vacuum conditions, simply by switching between appropriate IR detectors. We demonstrate the performance of the upgraded FTIR spectrometer by presenting measurements of matrix isolated fullerene ions and an adhesive tape.


Redundancy and error resilience in Boolean networks.
We consider the effect of noise in sparse Boolean networks with redundant functions. We show that they always exhibit a nonzero error level, and the dynamics undergoes a phase transition from nonergodicity to ergodicity, as a function of noise, after which the system is no longer capable of preserving a memory of its initial state. We obtain upper bounds on the critical value of noise for networks of different sparsity.


Impaired exercise capacity and skeletal muscle function in a mouse model of pulmonary inflammation.
Pulmonary TNFα has been linked to reduced exercise capacity in a subset of patients with moderate to severe chronic obstructive pulmonary disease (COPD). We hypothesized that prolonged, high expression of pulmonary TNFα impairs cardiac and skeletal muscle function, and both contribute to exercise limitation. Using a surfactant protein C promoter-TNFα construct, TNFα was overexpressed throughout life in mouse lungs (SP-C/TNFα+). TNFα levels in wild-type (WT) female serum and lung were two- and threefold higher than in WT male mice. In SP-C/TNFα+ mice, TNFα increased similarly in both sexes. Treadmill exercise was impaired only in male SP-C/TNFα+ mice. While increases in lung volume and airspace size induced by TNFα were comparable in both sexes, pulmonary hypertension along with lower body and muscle mass were evident only in male mice. Left ventricular (LV) function (cardiac output, stroke volume, LV maximal pressure, and LV maximal pressure dP/dt) was not altered by TNFα overexpression. Fatigue measured in isolated soleus and EDL was more rapid only in soleus of male SP-C/TNFα+ mice and accompanied by a loss of oxidative IIa fibers, citrate synthase activity, and PGC-1α mRNA and increase in atrogin-1 and MuRF1 expression also only in male mice. In situ gastrocnemius fatigue resistance, reflecting both oxygen availability and contractility, was decreased similarly in female and male SP-C/TNFα+ mice. These data indicate that male, but not female, mice overexpressing pulmonary TNFα are susceptible to exercise limitation, possibly due to muscle wasting and loss of the oxidative muscle phenotype, with protection in females possibly due to estrogen.


Highly enantioselective copper-catalyzed electrophilic trifluoromethylation of β-ketoesters.
Enantioselective Cu-catalyzed trifluoromethylation of β-ketoesters using commercially available trifluoromethylating reagents is reported. A number of α-CF(3) β-ketoesters are obtained with up to 99% ee. The trifluoromethylated products were then transformed diastereoselectively to α-CF(3) β-hydroxyesters with two adjacent quaternary stereocenters via a Grignard reaction.


Rapid detection of cytomegalovirus using immune scanning electron microscopy.
Monoclonal antibodies specific for human cytomegalovirus were conjugated to latex microspheres that were already labelled with rabbit anti-mouse immunoglobulin. The beads were incubated with serum or urine from patients, and then collected on a filter surface, which was analyzed in a scanning electron microscope. Size, immunological specificity, and relative quantity of virus particles were determined within 2 h after serum or urine collection by the visualization of virus particles specifically bound to the latex bead surface. No such binding of virus particles were detected in the various controls. This method was compared with conventional virus isolation by tissue culture. It enables identification of viruses within a few hours in different body fluids. Even without specific antibodies, the filtration method may permit the rapid detection of particles and the determination of their size in various body fluids.


Process of Change in Pain-Related Fear: Clinical Insights From a Single Case Report of Persistent Back Pain Managed With Cognitive Functional Therapy.
Study Design Single case report with repeated measures over 18 months. Background Management of persistent low back pain (PLBP) associated with high pain-related fear is complex. This case report aims to provide clinicians with insight into the process of change in a person with PLBP and high bending-related fear, who was managed with an individualized behavioral approach of cognitive functional therapy. Case Description A retired manual worker with PLBP believed that his spine was degenerating, that bending would hurt him, and that avoidance was the only form of pain control. At baseline, he presented high levels of pain-related fear on the Tampa Scale of Kinesiophobia (score, 47/68) and a high-risk profile on the Örebro Musculoskeletal Pain Questionnaire (score, 61/100). Unhelpful beliefs and behaviors led to a vicious cycle of fear and disengagement from valued life activities. Guided behavioral experiments were used to challenge his thoughts and protective responses, indicating that his behavior was modifiable and the pain controllable. Using a multidimensional clinical-reasoning framework, cognitive functional therapy management was tailored to target key drivers of PLBP and delivered over 6 sessions in a 3-month period. Outcomes Over an 18-month clinical journey, he demonstrated improvements in bending-related fear, pain expectancy, and pain experience, and substantial changes in pain-related fear (Tampa Scale of Kinesiophobia: 33/68; change, -14 points) and risk profile (Örebro Musculoskeletal Pain Questionnaire: 36/100; change, -25 points). Clinical interviews at 6 and 18 months revealed positive changes in mindset, understanding of pain, perceived pain control, and behavioral responses to pain. Discussion This case report provides clinicians with an insight to using a multidimensional clinical-reasoning framework to identify and target the key drivers of the disorder, and to using cognitive functional therapy to address unhelpful psychological and behavioral responses to pain in a person with PLBP and high pain-related fear. Level of Evidence Therapy, level 5. J Orthop Sports Phys Ther 2017;47(9):637-651. Epub 13 Jul 2017. doi:10.2519/jospt.2017.7371.


Bradykinin induces translocation of the protein kinase C isoforms alpha, epsilon, and zeta.
Bradykinin exerts a broad spectrum of cellular effects on different tissues. It is believed that these effects are predominantly mediated by the recently cloned B2 receptor. The mechanism of post-receptor signal transduction is not known in detail. Involvement of protein kinase C (PKC) was suggested and activation of the classical PKC isoforms alpha and beta was recently demonstrated. The aim of the present study was to investigate whether the B2 receptor also activates new (delta, epsilon) and atypical (zeta) PKC isoforms. To investigate this, chinese hamster ovary (CHO) cells, stably transfected with human B2 receptor, were used. In these cells the PKC isoforms alpha, delta, epsilon and zeta were detected by immunoblotting with specific antibodies. To monitor hormone-induced PKC translocation plasma membranes were prepared. Stimulation of the cells with bradykinin resulted in a rapid (30-60 s) translocation of the PKC isoforms alpha, epsilon, and zeta. Translocation of PKC delta was not detected. The effect of bradykinin was reduced by simultaneous addition of the receptor antagonist HOE 140, a bradykinin-related decapeptide. The data show that the B2 receptor in this cell model is able to activate, in addition to the classical PKC isoform alpha, the new PKC isoform epsilon and the atypical PKC isoform zeta. To test whether these effects are as well observed in a non-transfected cell, the experiments were repeated in human foreskin fibroblasts which naturally express high levels of B2 receptors. In this cell system similar results on PKC alpha, epsilon, and zeta were observed, suggesting that all three PKC isoforms are involved in signal transduction of the B2 receptor.


D-Cycloserine Ameliorates Autism-Like Deficits by Removing GluA2-Containing AMPA Receptors in a Valproic Acid-Induced Rat Model.
Valproic acid (VPA)-exposed rat offspring have demonstrated autism spectrum disorder (ASD) phenotypes and impaired N-methyl-D-aspartate receptor (NMDAR)-dependent long-term depression (LTD) in the lateral nucleus of the amygdala. NMDAR partial agonist D-cycloserine (DCS) has been reported to act as a cognitive enhancer by increasing the NMDAR response to improve autistic-like phenotypes in animals. However, the mechanism of DCS in alleviating the ASD is still unknown. Using combined behavioral, electrophysiological, and molecular approaches, we found that DCS administration rescued social interaction deficits and anxiety/repetitive-like behaviors observed in VPA-exposed offspring. In the amygdala synapses, DCS treatment reversed the decreased paired pulse ratio (PPR) and the impaired NMDAR-dependent LTD, increased the frequency and amplitude of miniature excitatory post-synaptic currents (mEPSCs), and resulted in a higher dendritic spine density at the amygdala synapses in the VPA-exposed offspring. Moreover, we found that DCS facilitated the removal of GluA2-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (GluA2/AMPARs) by inducing NMDAR-dependent LTD in the VPA-exposed offspring. We further established that the effects of DCS treatment, including increased GluA2/AMPAR removal and rescues of impaired social behavior, were blocked by Tat-GluA23Y, a GluA2-derived peptide that disrupted regulation of AMPAR endocytosis. These results provided the first evidence that rescue of the ASD-like phenotype by DCS is mediated by the mechanism of GluA2/AMPAR removal in VPA-exposed rat offspring.


Are prothrombin fragment 1 + 2 and thrombin-antithrombin complexes useful in the management of oral anticoagulant therapy?
We investigated the behavior of prothrombin fragment F1 + 2 and thrombin-antithrombin complexes in 70 patients treated with chronic anticoagulant therapy. Moreover, in a longitudinal study 37 patients were evaluated twice and 16 patients three times. Twenty-eight age- and sex-matched healthy subjects were also studied as a control group. Prothrombin fragment F1 + 2 or thrombin-antithrombin values among patients with different International Normalized Ratios, nor in the same patients studied two or three times. Our results confirm that oral anticoagulant treatment can effectively reduce thrombin activity. However, strong anticoagulation does not induce a further significant decrease in fragment F1 + 2 values. Therefore, we feel measurement of fragment F1 + 2 might be less useful than thought in optimizing oral anticoagulant therapy.


A pilot survey of inmate preferences for on-site, visiting consultant, and telemedicine psychiatric services.
To assess inmate preferences for in-prison mental health services, outside psychiatric consultants, and telemedicine psychiatric consultation for 16 mental health services. Structured interviews were conducted of the service modality preferences of 28 inmates who received psychiatric telemedicine consultations in New York State Department of Corrections facilities. For five of the 16 mental health services assessed, a significantly larger proportion of inmates preferred delivery of mental services by their on-site mental health team to an outside psychiatric consultant, whether visiting or using telemedicine. For another eight services, inmate preferences were approximately equal. For three services (treatment progress, evaluation of childhood sexual abuse, and sexual concerns), inmates reported a trend toward preference for outside consultation (visiting and telemedicine combined). For no service did inmates prefer telemedicine to a visiting consultant. Although inmates prefer the use of on-site mental health professionals for many mental health services, some inmates prefer visiting or telemedicine consultants for the evaluation of safety and sexual issues. Because telemedicine is efficient and readily available, its role in these areas requires further evaluation.


NUCLEO-CYTOPLASMIC MALE STERILITY AND ALTERNATIVE ROUTES TO DIOECY.
Population-genetic models of nucleo-cytoplasmic gynodioecy are shown to allow invasion of males and conversion to dioecy in a single cytotype. Pleiotropic effects of restorer alleles on fertility through male or female function can maintain a cytoplasmic polymorphism in a population that prevents evolution to dioecy regardless of the pollen fertility of males. However, a cytoplasmic polymorphism has little effect on, and may even reduce, the minimum pollen fertility required for the spread of males into an equilibrium gynodioecious population. Where the thresholds for dioecy are similar, the presence of males during a transient preequilibrium high frequency of females can accelerate evolution to dioecy by more than 50 times relative to nuclear male sterility. However, the appearance of a nonrestorable male-sterile cytotype generally eliminates males from both subdioecious and dioecious populations, converting them to purely cytoplasmic gynodioecy. These models contradict the previously suggested notion that nucleo-cytoplasmic gynodioecy represents a "stable" intermediate breeding system and instead show that such gynodioecy can generally evolve to subdioecy, and often to dioecy, as easily as nuclear gynodioecy.


Elastic energy of protein-DNA chimeras.
We present experimental measurements of the equilibrium elastic energy of protein-DNA chimeras, for two different sets of attachment points of the DNA "molecular spring" on the surface of the protein. Combining these with measurements of the enzyme's activity under stress and a mechanical model of the system, we determine how the elastic energy is partitioned between the DNA and the protein. The analysis shows that the protein is mechanically stiffer than the DNA spring.


Syntheses and analytical characterizations of novel (2-aminopropyl)benzo[b]thiophene (APBT) based stimulants.
Two groups of amphetamine-like drugs with psychostimulant properties that were first developed during the course of scientific studies and later emerged as new psychoactive substances (NPS) are based on the (2-aminopropyl)indole (API) and (2-aminopropyl)benzofuran (APB) structural scaffolds. However, sulfur-based analogs with a benzo[b]thiophene structure (resulting in (2-aminopropyl)benzo[b]thiophene (APBT) derivatives) have received little attention. In the present investigation, all six racemic APBT positional isomers were synthesized in an effort to understand their structure-activity relationships relative to API- and APB-based drugs. One lesson learned from the NPS phenomenon is that one cannot exclude the appearance of such substances on the market. Therefore, an in-depth analytical characterization was performed, including various single- and tandem mass spectrometry (MS) and ionization platforms coupled to gas chromatography (GC) and liquid chromatography (LC), nuclear magnetic resonance spectroscopy (NMR), and solid phase and GC condensed phase infrared spectroscopy (GC-sIR). Various derivatizations have also been explored; it was found that all six APBT isomers could be differentiated during GC analysis after derivatization with heptafluorobutyric anhydride and ethyl chloroformate (or heptafluorobutyric anhydride and acetic anhydride) under non-routine conditions. Discriminating analytical features can also be derived from NMR, GC-EI/CI- single- and tandem mass spectrometry, LC (pentafluorophenyl stationary phase), and various infrared spectroscopy approaches (including GC-sIR). Availability of detailed analytical data obtained from these novel APBT-type stimulants may be useful to researchers and scientists in cases where forensic and clinical investigations are warranted.


The effect of in situ/in vitro three-dimensional quantitative computed tomography image voxel size on the finite element model of human vertebral cancellous bone.
Quantitative computed tomography-based finite element modeling technique is a promising clinical tool for the prediction of bone strength. However, quantitative computed tomography-based finite element models were created from image datasets with different image voxel sizes. The aim of this study was to investigate whether there is an influence of image voxel size on the finite element models. In all 12 thoracolumbar vertebrae were scanned prior to autopsy (in situ) using two different quantitative computed tomography scan protocols, which resulted in image datasets with two different voxel sizes (0.29 × 0.29 × 1.3 mm(3) vs 0.18 × 0.18 × 0.6 mm(3)). Eight of them were scanned after autopsy (in vitro) and the datasets were reconstructed with two voxel sizes (0.32 × 0.32 × 0.6 mm(3) vs. 0.18 × 0.18 × 0.3 mm(3)). Finite element models with cuboid volume of interest extracted from the vertebral cancellous part were created and inhomogeneous bilinear bone properties were defined. Axial compression was simulated. No effect of voxel size was detected on the apparent bone mineral density for both the in situ and in vitro cases. However, the apparent modulus and yield strength showed significant differences in the two voxel size group pairs (in situ and in vitro). In conclusion, the image voxel size may have to be considered when the finite element voxel modeling technique is used in clinical applications.


Acute surgical unit safely reduces unnecessary after-hours cholecystectomy.
The acute surgical model has been trialled in several institutions with mixed results. The aim of this study was to determine whether the acute surgical model provides better outcomes for patients with acute biliary presentation, compared with the traditional emergency surgery model of care. A retrospective review was carried out of patients who were admitted for management of acute biliary presentation, before and after the establishment of an acute surgical unit (ASU). Outcomes measured were time to operation, operating time, after-hours operation (6pm - 8am), length of stay and surgical complications. A total of 342 patients presented with acute biliary symptoms and were managed operatively. The median time to operation was significantly reduced in the ASU group (32.4 vs 25.4 hours, p=0.047), as were the proportion of operations performed after hours (19.5% vs 2.5%, p<0.001) and the median length of stay (4 vs 3 days, p<0.001). The median operating time, rate of conversion to open cholecystectomy and wound infection rates remained similar. Implementation of an ASU can lead to objective differences in outcomes for patients who present with acute cholecystitis. In our study, the ASU significantly reduced time to operation, the number of operations performed after hours and length of stay.


Reproducibility of left ventricular mass by echocardiogram in the ELSA-Brasil.
Echocardiography, though non-invasive and having relatively low-cost, presents issues of variability which can limit its use in epidemiological studies. To evaluate left ventricular mass reproducibility when assessed at acquisition (online) compared to when assessed at a reading center after electronic transmission (offline) and also when assessed by different readers at the reading center. Echocardiographers from the 6 ELSA-Brasil study investigation centers measured the left ventricular mass online during the acquisition from 124 studies before transmitting to the reading center, where studies were read according to the study protocol. Half of these studies were blindly read by a second reader in the reading center. From the 124 echocardiograms, 5 (4%) were considered not measurable. Among the remaining 119, 72 (61%) were women, mean age was 50.2 ± 7.0 years and 2 had structural myocardial abnormalities. Images were considered to be optimal/ good by the reading center for 110 (92.4%) cases. No significant difference existed between online and offline measurements (1,29 g, CI 95% -3.60-6.19), and the intraclass correlation coefficient between them was 0.79 (CI 95% 0.71-0.85). For images read by two readers, the intraclass correlation coefficient was 0.86 (CI 95% 0.78-0.91). There were no significant drifts between online and offline left ventricular mass measurements, and reproducibility was similar to that described in previous studies. Central quantitative assessment of echocardiographic studies in reading centers, as performed in the ELSA-Brasil study, is feasible and useful in clinical and epidemiological studies performed in our setting.


[Implications of receptors for the Fc portion of IgG (FcgammaRs) in mechanism of action of therapeutic antibodies].
From several years ago, recombinant monoclonal antibodies have allowed a revolution in therapeutic approach of cancer patients. Whereas the clinical efficacy of many antibodies is now demonstrated, their mechanism of action in patients remains elusive. For antibodies targeting membrane antigens, they particularly resort to cytotoxic effectors, which expressed receptors for Fc portion of IgG (FcgammaRs). This review analyses different functions depending of FcgammaR and their potential role in mechanism of action of therapeutic antibodies. A better knowledge of these functions should allow in the next future the optimisation of these treatments.


Blind deblurring of spiral CT images-comparative studies on edge-to-noise ratios.
A recently developed blind deblurring algorithm based on the edge-to-noise ratio has been applied to improve the quality of spiral CT images. Since the discrepancy measure used to quantify the edge and noise effects is not symmetric, there are several ways to formulate the edge-to-noise ratio. This article is to investigate the performance of those ratios with phantom and patient data. In the phantom study, it is shown that all the ratios share similar properties, validating the blind deblurring algorithm. The image fidelity improvement varies from 29% to 33% for different ratios, according to the root mean square error (RMSE) criterion; the optimal iteration number determined for each ratio varies from 25 to 35. Those ratios that are associated with most satisfactory performance are singled out for the image fidelity improvement of about 33% in the numerical simulation. After automatic blind deblurring with the selected ratios, the spatial resolution of CT is substantially refined in all the cases tested.


Local regulation of collateral ventilation by oxygen and carbon dioxide.
The effects of changes in CO2 and O2 on the mechanics of collateral ventilation were studied in anesthetized paralyzed dogs. A doublelumen catheter was wedged into a peripheral airway obstructing a segment of lung distal to the catheter. Through one lumen of the catheter, air, 5% CO2 in air, 10% CO2 in air, 5% O2 in N2, or 5% CO2 in N2 was infused at a constant flow (V). Pressure (Ps) was monitored through the other lumen. At functional residual capacity the resistance to collateral flor Rcoll = Ps/V. When V was interrrupted , the time for Ps to fall 63% was defined as the time constant for collateral ventilation, Tcoll. The effective compliance (Cs') = Tcoll/Rcoll. When air was replaced by 5% CO2, Rcoll fell 46.3% (+/- SE 2.8) and Tcoll fell 41.5% (+/- SE 3.0). When the CO2 concentration was increased from 5% to 10%, Rcoll fell an additional 9.2% (+/- SE 2.2) and Tcoll fell an additional 5.1% (+/- SE 4.4). When air was replaced by 5% O2 in N2, Rcoll rose 36.6% (+/- SE 6.0) and Tcoll rose 13.6% (+/- SE 10.5). No significant changes in Cs' were noted. We conclude that varying concentrations of CO2 and O2 provide potent mechanisms for the control of collateral ventillation which may be of importance in the regulation of ventillation perfusion relationships at the local level.


Artificial Intelligence and Hypertension: Recent Advances and Future Outlook.
Prevention and treatment of hypertension (HTN) are a challenging public health problem. Recent evidence suggests that artificial intelligence (AI) has potential to be a promising tool for reducing the global burden of HTN, and furthering precision medicine related to cardiovascular (CV) diseases including HTN. Since AI can stimulate human thought processes and learning with complex algorithms and advanced computational power, AI can be applied to multimodal and big data, including genetics, epigenetics, proteomics, metabolomics, CV imaging, socioeconomic, behavioral, and environmental factors. AI demonstrates the ability to identify risk factors and phenotypes of HTN, predict the risk of incident HTN, diagnose HTN, estimate blood pressure (BP), develop novel cuffless methods for BP measurement, and comprehensively identify factors associated with treatment adherence and success. Moreover, AI has also been used to analyze data from major randomized controlled trials exploring different BP targets to uncover previously undescribed factors associated with CV outcomes. Therefore, AI-integrated HTN care has the potential to transform clinical practice by incorporating personalized prevention and treatment approaches, such as determining optimal and patient-specific BP goals, identifying the most effective antihypertensive medication regimen for an individual, and developing interventions targeting modifiable risk factors. Although the role of AI in HTN has been increasingly recognized over the past decade, it remains in its infancy, and future studies with big data analysis and N-of-1 study design are needed to further demonstrate the applicability of AI in HTN prevention and treatment.


The value of ventilation-perfusion imaging in pregnancy.
Pulmonary embolism (PE) is a major cause of maternal death during pregnancy. The aims of this retrospective study were to review 5 years experience of ventilation-perfusion (V/Q) imaging in pregnancy, to evaluate the effect of the V/Q scan report on the referring clinician's use of anticoagulants and to monitor the course and outcome of pregnancy. 82 patients (aged 17-44 years, gestation 6-40 weeks) underwent V/Q imaging for suspected PE, over a 5 year period. Modified PIOPED criteria were used to assess the probability of PE. 31 patients were shown to have normal scans (38%); 19 (23%) had low probability (LP) scans; 14 (17%) had intermediate probability (IP) scans and 18 (22%) had high probability (HP) scans for PE. Referring clinicians saw the reports and took action within 12 h. Anticoagulation was continued or started in 31 patients (all HP, 12 IP and 1 LP). Anticoagulation was considered unnecessary in 52 patients (all normal, 19 LP and 2 IP). None of the patients with normal or LP scans had documented PE during the follow-up period (median 25 months, range 3-60 months). No complications of anticoagulation were observed and no adverse outcome of pregnancy were reported. V/Q imaging is a valuable technique in the management of pregnant women suspected of having PE.


Pharmacokinetics and absorption of paromomycin and gentamicin from topical creams used to treat cutaneous leishmaniasis.
This study evaluated the pharmacokinetics of topical creams containing 15% paromomycin ("paromomycin alone") and 15% paromomycin plus 0.5% gentamicin (WR 279,396) in patients with cutaneous leishmaniasis. The investigational creams were applied topically to all lesions once daily for 20 days. Plasma samples were analyzed for simultaneous quantitation of paromomycin and gentamicin isomers and total gentamicin. Pharmacokinetic parameters for gentamicin could not be calculated because detectable levels were rarely evident. After one application, the paromomycin area under the concentration-time curve from 0 to 24 h (AUC0-24) was 2,180 ± 2,621 ng · h/ml (mean ± standard deviation [SD]) for the paromomycin-alone group and 975.6 ± 1,078 ng · h/ml for the WR 279,396 group. After 20 days of application, the paromomycin AUC0-24 and maximum concentration of drug (Cmax) were 5 to 6 times greater than those on day 1 for both treatment groups. For the paromomycin-alone group, the AUC0-24 was 8,575 ± 7,268 ng · h/ml and the Cmax was 1,000 ± 750 ng/ml, compared with 6,037 ± 3,956 ng · h/ml and 660 ± 486 ng/ml for the WR 279,396 group, respectively. Possibly due to large intersubject variability, no differences (P ≥ 0.05) in the AUC0-24 or Cmax were noted between treatment or between sites on day 1 or 20. The percentage of dose absorbed on day 20 was 12.0% ± 6.26% and 9.68% ± 6.05% for paromomycin alone and WR 279,396, respectively. Paromomycin concentrations in plasma after 20 days of application were 5 to 9% of those after intramuscular administration of 15 mg/kg of body weight/day to adults for the systemic treatment of visceral leishmaniasis. Effective topical treatment of cutaneous leishmaniasis appears to be possible with limited paromomycin and gentamicin systemic absorption, thus avoiding drug accumulation and toxicity. (The work described here has been registered at ClinicalTrials.gov under registration no. NCT01032382 and NCT01083576.).


Role of new sirolimus self-apposing stent in coronary interventions.
Device technology in interventional cardiology is continuously evolving. Self-expandable (SE) coronary artery stents were the first device to be implanted within a human coronary artery. However, because of their initial limitations, balloon-expandable (BE) stents were predominantly developed and used in the last 30 years. Unfortunately, in challenging anatomical settings such as bifurcation lesions, large, ectatic or aneurysmal vessels, tapered vessels or vasoconstricted arteries, outcomes with BE stents are not always optimal. The Stentys (Stentys SA, Paris, France) SE nitinol stents were initially developed for the treatment of coronary bifurcation lesions. The understanding of the underlying mechanism involved in incomplete stent apposition and subsequent stent thrombosis led to the introduction of self-apposing stents in the treatment of acute coronary syndrome in order to overcome the limitations of drug-eluting stents in presence of high thrombus burden. In this regard, Stentys allows a progressive stent expansion which could reduce the rates of incomplete stent apposition by conforming to vascular remodeling. Enhancing the advantages of this technology by adding the release of an antiproliferative drug to prevent restenosis is even more attractive and potentially effective. Recently, the results of the new Stentys sirolimus-eluting stent have been reported. This article provides an overview of the pathobiological rational, device characteristics and results of the new Stentys self-expandable sirolimus-eluting stent.


Dabigatran: life-threatening bleeding.
Dabigatran is an oral anticoagulant that inhibits thrombin but not vitamin K. In mid-2012, there was no commercial test to monitor its anticoagulant effect, nor an antidote. In mid-November 2011, the European pharmacovigilance database contained 256 reports of haemorrhagic deaths attributed to dabigatran. Nearly 800 cases of severe haemorrhage have been reported in Australia, Canada, Japan, New Zealand and the United States. A randomised trial comparing dabigatran with warfarin, and 5 studies of several hundred serious bleeding events, identified factors that increased the risk of bleeding. They included even mild renal failure, age over 75 years, body weight less than 60 kg, switching between anticoagulants, opening the dabigatran capsules before ingestion, and concomitant use of drugs that interact with dabigatran. A dabigatran dose below 220 mg per day does not protect patients from the risk of haemorrhage. In practice, dabigatran should be reserved for patients with a high risk of thrombosis in whom the target INR cannot be maintained on antivitamin K therapy alone. The risk of bleeding must be taken into account, renal function must be closely monitored, and patients and their carers must be correctly informed about this risk.


Effect of probiotic CenBiot on the control of diarrhoea and feed efficiency in pigs.
The production and testing of a probiotic formulated with a strain of Bacillus cereus (Probiotic CenBiot) is reported. The strain was grown in fed batch fermenters, desiccated, and mixed with cornflour. To test the effect of the probiotic in controlling piglet diarrhoea, two groups of sows and their respective litters received feed supplemented with probiotic CenBiot or Furazolidone; the control group received the same basic feed but not supplemented. Probiotic CenBiot was as effective as Furazolidone, reducing the prevalence of diarrhoea to half that in the control group. It also significantly improved feed conversion, daily weight gain and total weight gain in pigs in the nursery phase. Feed conversion ratios of weaned pigs were 1.904, 2.146 and 2.099 for the groups that received Probiotic CenBiot, a commercial probiotic, and basic feed, respectively. In terms of food consumption, the Probiotic CenBiot group consumed 12.6% less than the commercial probiotic group, and 10% less than the control group, to achieve the same weight.


Magnetic resonance imaging of bacterial and tuberculous spondylodiscitis with associated complications and non-infectious spinal pathology mimicking infections: a pictorial review.
Magnetic resonance (MR) imaging plays an important role in the evaluation of bacterial and tuberculous spondylodiscitis and associated complications. Owing to its high sensitivity and specificity, it is a powerful diagnostic tool in the early diagnosis of ongoing infections, and thus provides help in prompt initiation of appropriate, therapy which may be medical or surgical, by defining the extent of involvement and detection of complications such as epidural and paraspinal abscesses. More specifically, MR imaging helps in differentiating bacterial from tuberculous infections and enables follow up of progression or resolution after appropriate treatment. However, other non-infectious pathology can demonstrate similar MR imaging appearances and one should be aware of these potential mimickers when interpreting MR images. Radiologists and other clinicians need to be aware of these potential mimics, which include such pathologies as Modic type I degenerative changes, trauma, metastatic disease and amyloidosis. In this pictorial review, we will describe and illustrate imaging findings of bacterial and tuberculous spondylodiscitis, their complications and non-infectious pathologies that mimic these spinal infections.


Plasma catecholamine metabolites and early response to haloperidol.
Plasma homovanillic acid (HVA) and methoxyhydroxyphenyl glycol (MHPG) as well as serum haloperidol and prolactin were measured in patients admitted to a general hospital psychiatric service for treatment of acute psychosis. At 10 days, good responders compared to poor responders had higher mean plasma HVA values before and during the first week of treatment with 0.2-0.4 mg/kg haloperidol per day. MHPG values showed a similar pattern, although no significant differences were obtained between or within the two groups. Females predominated among good responders; neither DSM-III diagnoses nor steady state haloperidol levels differed significantly between the two groups. Significant correlations within some patients were obtained between prolactin and haloperidol (positive), prolactin and MHPG (negative), and HVA and MHPG (positive). Plasma catecholamine metabolites deserve further study as possible markers of early response to the treatment of acute psychosis with modest doses of neuroleptic drugs.


Nanoliter high throughput quantitative PCR.
Understanding biological complexity arising from patterns of gene expression requires accurate and precise measurement of RNA levels across large numbers of genes simultaneously. Real time PCR (RT-PCR) in a microtiter plate is the preferred method for quantitative transcriptional analysis but scaling RT-PCR to higher throughputs in this fluidic format is intrinsically limited by cost and logistic considerations. Hybridization microarrays measure the transcription of many thousands of genes simultaneously yet are limited by low sensitivity, dynamic range, accuracy and sample throughput. The hybrid approach described here combines the superior accuracy, precision and dynamic range of RT-PCR with the parallelism of a microarray in an array of 3072 real time, 33 nl polymerase chain reactions (RT-PCRs) the size of a microscope slide. RT-PCR is demonstrated with an accuracy and precision equivalent to the same assay in a 384-well microplate but in a 64-fold smaller reaction volume, a 24-fold higher analytical throughput and a workflow compatible with standard microplate protocols.


Enantiomeric separation of ornithine in complex mixtures of amino acids by EKC with off-line derivatization with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate.
A new analytical methodology was developed by EKC enabling the fast enantiomeric separation of Ornithine in complex mixtures of amino acids. A previous derivatization step with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) was achieved to enable the sensitive UV detection of amino acids as well as to make possible their interaction with the CDs employed as chiral selectors. A dual CD system containing an anionic and a neutral CD in phosphate buffer at acid pH showed a high resolving power allowing the enantiomeric separation of 18 protein amino acids and Orn. The method was applied to the analysis of fermented foods to investigate the extent of the presence of Orn enantiomers.


[The role of ciprofloxacine metabolites in its biliary and urinary elimination in man].
The purpose of the present work was the investigation of the urinary and biliary eliminations of M1, M2, M3 and M4, the four metabolites of ciprofloxacin in twelve recently cholecystectomized patients provided with a T-drain. The four metabolites were measured by HPLC under isocratic conditions for M2 and M4, and by gradient elution for M1 and M3. After a single oral dose of 500 mg of ciprofloxacin, the 24th urinary elimination of the parent compound and its metabolites respectively amounted to 130.1 +/- 15.6; 13 +/- 11; 46.6 +/- 8.2; 13 +/- 3.7 and 0 mg, representing 26.02; 0.54; 1.32; 2.60 and 0% of the administered dose (total: 192.4 mg; 38.5%). During the same investigation period, the biliary elimination respectively reached 1,587 +/- 222; 241 +/- 38; 11,042 +/- 2,489; 144 +/- 51 and 19 +/- 13 micrograms (total: 13 mg) corresponding to 0.32; 0.05; 2.21; 0.03 and 0% (total: 2.61%) of the dose. The urinary and biliary elimination of ciprofloxacin as metabolites respectively represents 12.5 and 2.3% of the dose (total: 14.8%). The important amount of M2 recovered in bile (7 times more than ciprofloxacin itself) let suggest a hepatic biotransformation of ciprofloxacin.


Release of hepatic stimulatory substance from cultures of free and microencapsulated hepatocytes: preliminary report.
The galactosamine induced liver failure animal model was used to study the release of hepatic stimulatory substance (HSS) from free and microencapsulated hepatocytes in culture. Free hepatocyte cultures released HSS which significantly increased DNA synthesis in hepatocyte and the survival time of this animal model. The release HSS was not observed when hepatocytes were microencapsulated in an alginate matrix. The alginate matrix has a pore size which does not allow molecules larger than albumin (64,000 M.W.) to pass through the matrix. This suggests that of the two different ranges of molecular weights suggested for the hepatic stimulatory substance, those in the higher molecular range are important for liver regeneration.


Benchmarking study of industry practices during commercial long haul transport of cattle in Alberta, Canada.
The objective of the present study was to document current commercial practices during long haul transport (≥400 km) of cattle in Alberta through surveys delivered to truck drivers (6,152 journeys that transported 290,362 animals). The live beef export industry to the United States (89% of all journeys) had a large influence on long haul transport. This was particularly true for fat cattle going to slaughter (82%) and backgrounded feeders going to feed yards (15%). Most drivers had either limited (31% with < 2 yr) or extensive (35% > 10 yr) experience hauling cattle. The type of tractors and trailers used most frequently were those with more number of axles (quad-axle trailers pulled with push tractors) because they can accommodate extra weight. Mean (± SD) distance travelled was 1,081 ± 343 km (maximum of 2,560 km) whereas time animals spent on truck averaged 15.9 ± 6.3 h with a maximum of 45 h. However, only 5% of all journeys were greater than 30 h. The most frequent cause of delay was at the Canada-United States border crossing due to paperwork and veterinary inspections. Border delays occurred on 77% of all journeys which had a mean of 1.3 ± 1.9 h and up to 15-h long. Driver rest stops and waiting to unload cattle at destination were the second most frequent and longest cause of delay. Ambient temperature across all journeys ranged from -42 to 45°C with a mean value of 18 ± 11.8°C while temperature variation within a journey was from 0 to 46°C with mean value of 15 ± 6.6°C. The proportion of dead, non-ambulatory, and lame cattle for all journeys was 0.011, 0.022, and 0.011%, respectively. The cattle transport industry showed compliance with federal regulations and to a lesser extent with recommendations. Findings showed extreme values and very large variability in transport conditions however further research is needed to assess their impact on animal welfare outcomes. Delays within the journey as a result of border crossing, weather conditions, time on truck, shrink and space allowance may play an important role in improving cattle welfare during long haul transport.


Teenage pregnancy and child health in the urban Sahel.
Longitudinal data for more than 20,000 live births in the cities of Bamako (Mali) and Bobo-Dioulasso (Burkina Faso) are used to study the effects of young maternal age (less than 18 years and 18-19) on birth weight, child health care and feeding behavior, and child mortality, after controlling for other socioeconomic and demographic factors. Teenage pregnancies are associated with significantly worse prenatal health care and vaccination behavior, lower birth weights, earlier weaning, and, especially during the second year of life, higher mortality. A proxy for mother's school enrollment at the time of pregnancy is strongly linked to worse prenatal health behavior and weakly associated with other poor behaviors and health outcomes. Overall, the results highlight the importance of behavioral factors relative to strictly biological factors for explaining child health differentials.


Isolation and characterization of cetirizine degradation product: mechanism of cetirizine oxidation.
The goal of the study was to isolate and analyze a cetirizine degradation product, formed within a PEG-containing formulation and to elucidate the mechanism of oxidation of cetirizine. Cetirizine, formulated in PEG-containing matrix, was subjected to forced degradation conditions in the pH range from 3 to 10, and the product was analyzed by HPLC and LC-MS/MS. Additionally, pure cetirizine was subjected to selective oxidization by hydrogen peroxide and sodium percarbonate. The reaction mixture was purified, and the isolated material was analyzed by (1)H NMR. Oxidation process was investigated in order to model the degradation of cetirizine in PEG-containing formulation. Site of oxidation is proposed based on correlation of the results of forced degradation with ionization scheme of cetirizine. The finding was verified by spiking of cetirizine degradation sample with cetirizine N-oxide reference standard. Degradation of cetirizine in polyethylene glycol arose from the reaction between the drug and the reactive peroxide intermediates such as peroxyl radicals formed through oxidation of PEG. Selective oxidation of cetirizine and isolation/characterization of the oxidation product allowed the identification of the oxidation product as cetirizine N-oxide. The mechanism of oxidation is proposed.


Enantioselective catalytic radical decarbonylative azidation and cyanation of aldehydes.
Empowered by the ubiquity of carbonyl functional groups in organic compounds, decarbonylative functionalization was prevalent in the construction of complex molecules. Under this context, asymmetric decarbonylative functionalization has emerged as an efficient pathway to accessing chiral motifs. However, ablation of enantiomeric control in a conventional 2e transition metal-catalyzed process was notable because of harsh conditions (high temperatures, etc.) that are usually required. To address this challenge and use readily accessible aldehyde directly, we report the asymmetric radical decarbonylative azidation and cyanation. Diverse aldehydes were directly used as alkyl radical precursor, engaging in the subsequent inner-sphere or outer-sphere ligand transfer where functional motifs (CN and N3) could be incorporated in excellent site- and enantioselectivity. Mild conditions, broad scope, excellent regioselectivity (driven by polarity-matching strategy), and enantioselectivity were shown for both transformations. This radical decarbonylative strategy using aldehydes as alkyl radical precursor has offered a powerful reaction manifold in asymmetric radical transformations to construct functional motifs regio- and stereoselectively.


Evidence for aceticlastic methanogenesis in the presence of sulfate in a gas condensate-contaminated aquifer.
The anaerobic metabolism of acetate was studied in sediments and groundwater from a gas condensate-contaminated aquifer in an aquifer where geochemical evidence implicated sulfate reduction and methanogenesis as the predominant terminal electron-accepting processes. Most-probable-number tubes containing acetate and microcosms containing either [2-(14)C]acetate or [U-(14)C]acetate produced higher quantities of CH(4) compared to CO(2) in the presence or absence of sulfate.(14)CH(4) accounted for 70 to 100% of the total labeled gas in the [(14)C]acetate microcosms regardless of whether sulfate was present or not. Denaturing gradient gel electrophoresis of the acetate enrichments both with and without sulfate using Archaea-specific primers showed identical predominant bands that had 99% sequence similarity to members of Methanosaetaceae. Clone libraries containing archaeal 16S rRNA gene sequences amplified from sediment from the contaminated portion of the aquifer showed that 180 of the 190 clones sequenced belonged to the Methanosaetaceae. The production of methane and the high frequency of sequences from the Methanosaetaceae in acetate enrichments with and without sulfate indicate that aceticlastic methanogenesis was the predominant fate of acetate at this site even though sulfate-reducing bacteria would be expected to consume acetate in the presence of sulfate.