Anatomical location of macrophage migration inhibitory factor in urogenital tissues, peripheral ganglia and lumbosacral spinal cord of the rat.
Previous work suggested that macrophage migration inhibitory factor (MIF) may be involved in bladder inflammation. Therefore, the location of MIF was determined immunohistochemically in the bladder, prostate, major pelvic ganglia, sympathetic chain, the L6-S1 dorsal root ganglia (DRG) and the lumbosacral spinal cord of the rat. In the pelvic organs, MIF immunostaining was prominent in the epithelia. MIF was widely present in neurons in the MPG and the sympathetic chain. Some of those neurons also co-localized tyrosine hydroxylase (TH). In the DRGs, some of the neurons that stained for MIF also stained for Substance P. In the lumbosacral spinal cord, MIF immunostaining was observed in the white mater, the dorsal horn, the intermediolateral region and in the area around the central canal. Many cells were intensely stained for MIF and glial fibrillary acidic protein (GFAP) suggesting they were glial cells. However, some cells in the lumbosacral dorsal horn were MIF positive, GFAP negative cells suggestive of neurons. Therefore, MIF, a pro-inflammatory cytokine, is localized to pelvic organs and also in neurons of the peripheral and central nervous tissues that innervate those organs. Changes in MIF's expression at the end organ and at peripheral and central nervous system sites suggest that MIF is involved in pelvic viscera inflammation and may act at several levels to promote inflammatory changes.


A metabolomics cell-based approach for anticipating and investigating drug-induced liver injury.
In preclinical stages of drug development, anticipating potential adverse drug effects such as toxicity is an important issue for both saving resources and preventing public health risks. Current in vitro cytotoxicity tests are restricted by their predictive potential and their ability to provide mechanistic information. This study aimed to develop a metabolomic mass spectrometry-based approach for the detection and classification of drug-induced hepatotoxicity. To this end, the metabolite profiles of human derived hepatic cells (i.e., HepG2) exposed to different well-known hepatotoxic compounds acting through different mechanisms (i.e., oxidative stress, steatosis, phospholipidosis, and controls) were compared by multivariate data analysis, thus allowing us to decipher both common and mechanism-specific altered biochemical pathways. Briefly, oxidative stress damage markers were found in the three mechanisms, mainly showing altered levels of metabolites associated with glutathione and γ-glutamyl cycle. Phospholipidosis was characterized by a decreased lysophospholipids to phospholipids ratio, suggestive of phospholipid degradation inhibition. Whereas, steatosis led to impaired fatty acids β-oxidation and a subsequent increase in triacylglycerides synthesis. The characteristic metabolomic profiles were used to develop a predictive model aimed not only to discriminate between non-toxic and hepatotoxic drugs, but also to propose potential drug toxicity mechanism(s).


Biogenic platinum nanoparticles using black cumin seed and their potential usage as antimicrobial and anticancer agent.
Herein, the biogenic platinum nanoparticles (Pt NPs) were synthesized by using black cumin seed (Nigella sativa L.) extract as a reducing agent. The biogenic platinum nanoparticles synthesized by black cumin seed extract was characterized in detail by Transmission Electron Microscopy (TEM), UV-vis spectrophotometer, X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS). According to TEM analysis, Pt nanoparticles have spherical shapes and sizes between 1-6 nm. Moreover, the biogenic Pt NPs was assessed for its cytotoxicity effect on MDA-MB-231 breast and HeLa cervical cancer lines and their antibacterial effect against selected strains of gram-positive and negative bacteria. The cytotoxicity and bacterial tests showed the effectiveness of biogenic Pt nanoparticles. Dose-dependent toxicity effects were shown in the MDA-MB-231 breast and HeLa cervical cancer lines (IC50: 36.86 μg/mL and 19.83 μg/mL, respectively). In addition, Pt NPs showed high zone diameters against gram-positive and gram-negative bacteria at concentrations of 100 and 500 μg/ml. These results contribute to the development of the pharmaceutical industry as a potential antibacterial and anticancer agent.


Novel expression system for Corynebacterium acetoacidophilum and Escherichia coli based on the T7 RNA polymerase-dependent promoter.
The industrially important species of corynebacteria viz. Corynebacterium acetoacidophilum appear to be alternative hosts for recombinant protein production; despite many efforts, a strong promoter-based system in corynebacteria has not been established so far. Described here is a T7 promoter-based expression system which was functional in both gram-positive C. acetoacidophilum and gram-negative Escherichia coli in an external inducer independent manner. This is the very first report of a T7 expression system for Corynebacterium sp. Also, it is a useful addition in the existing T7 expression systems of E. coli.


Properties of twitch motor units in snake costocutaneous muscle.
1. Single motor units of twitch muscle fibres were studied in isolated nerve-muscle preparations of m. costocutanei inferiores from grass and garter snakes. Preparations were superfused with Ringer solution at a controlled temperature of 22 degrees C.2. The peak and time-to-peak tension (contraction time) were measured for isometric twitches of forty-seven whole muscles and 83 motor units. The sample of motor units was drawn from an estimated total population of 213-355 twitch units. Peak tetanic tensions were also measured. The measurements were made at muscle lengths at which the twitch tension was maximal, and this length was not always the same for whole muscle and unit twitches. In fifty-nine cases 1 and in twelve cases 2 motor units were isolated from each muscle.3. Whole muscle contraction times ranged from 22-61 msec (mean +/- S.D. = 40.3 +/- 9.8 msec) and those for units from 18-92 msec (mean +/- S.D. = 46.9 +/- 15.9 msec). The wide range for whole muscles is discussed.4. The percentage of the whole muscle tetanic tension contributed by each unit (unit size) was calculated. Contraction time was inversely related to unit size.5. Twitch-tetanus ratios were calculated and found not to be related to unit contraction time.6. The conduction velocities of axons innervating 23 motor units were calculated from latency measurements at two points along the length of the nerve. They ranged from 1.9 to 10.4 m/sec. Axon conduction velocity was inversely related to unit contraction time, and directly related to unit size.


Cefadroxil concentrations in human serum, gingiva, and mandibular bone following a single oral administration.
Cefadroxil concentrations in human serum, gingiva, and mandibular bone were measured by a paper disk method following a single 500-mg oral dose. The mean peak concentrations in serum, gingiva, and mandibular bone occurred at the identical time, 3 hours, and were 12.92 micrograms/mL, 6.50 micrograms/g, and 2.67 micrograms/g, respectively. Mean cefadroxil concentration ratios of gingiva/serum and mandibular bone/serum at the peak time were 0.54 and 0.21, respectively. Mean concentrations in gingiva and mandibular bone at the peak time exceeded the minimum inhibitory concentrations for 90% of clinically isolated strains of a alpha-hemolytic streptococci.


Aspects of HIV disease relevant to dentistry in the 21st century.
HIV disease remains a significant health concern in Europe and the rest of the world. The present article details the epidemiological shifts, changes in therapy and oral manifestations of HIV disease of relevance to all oral healthcare professionals. Knowledge regarding the oral and dental aspects of HIV infection remain of importance to all dental healthcare professionals.


Mechanisms underlying the diuretic effect of Gomphrena celosioides Mart. (Amaranthaceae).
Gomphrena celosioides (Amaranthaceae) is a native medicinal plant found in Mato Grosso do Sul State that is used for treating urinary tract and kidney stones. This study aimed to evaluate the diuretic effects of ethanolic extract from G. celosioides (EEGC) on acute and extended diuresis to provide a pharmacological basis for its use in traditional medicine. To evaluate the diuretic and natriuretic activity of EEGC and its mechanism of action in an animal model. EEGC (30, 100 and 300mg/kg) was orally administered in male Wistar rats, and urinary excretion was measured at intervals of up to 8h after administration. To evaluate participation of the nitric oxide (NO), prostaglandin and bradykinin pathways in its effect, respective inhibitors were also administered together with effectives doses of EEGC and compared with control groups. A 7-day model with daily administration and urine measurement was also carried out. Oral administration of doses of 100 and 300 significantly increased urine output after 8h compared to the control group. It was observed this effect is dependent on the NO, prostaglandin and bradykinin pathways because their inhibitors reduced the diuretic effects of EEGC. Moreover, after 7 days of treatment, the effect was sustained and a decrease in serum aldosterone was observed in the extract group. According to the results, G. celosioides extract showed diuretic and natriuretic effects associated with more than one mechanism of action. Considering that all diuretic drugs are currently available for the treatment of volume and electrolyte disturbances, especially hypertensive status, the present results may have clinical relevance and open new possibilities for the development of new natural diuretics from G. celosioides.


Multi-imaging evaluation and long-term outcome of a patient with chest pain and an anomalous right coronary artery arising from pulmonary artery: a case report.
Anomalous right coronary artery from pulmonary artery (ARCAPA) is a rare coronary anomaly. Adult patients usually present with few symptoms due to extensive collateral network from left coronary artery, with little/absent symptoms. Few data exist regarding surgical vs. conservative strategy for paucisymptomatic cases. Moreover, consensus is lacking. We describe the case of a 52-year-old male patient with undiagnosed ARCAPA, who acceded to our emergency department with suspected acute myocardial infarction and was discharged with medical therapy after demonstration of mild ischaemia at myocardial perfusion imaging with dipyridamole and bicycle exercise test. The patient completed 2-year event-free follow up. After complete imaging assessment and thorough clinical evaluation, medical management could be regarded as valid alternative to surgery for paucisymptomatic ARCAPA patients with evidence of limited ischaemia.


Benign blue nevus of the vagina.
Pigmented lesions of the vagina are very rare. A benign blue nevus of the vagina in a 73-year-old woman, diagnosed clinically as malignant melanoma, is presented. Although 15 cases of blue nevi of the uterine cervix have been reported, this is the first case of blue nevus located exclusively in the vagina.


Relaxation and quenching of the excited states of tryptophan in keratin.
The temperature dependence of the fluorescence and phosphorescence originating from tryptophan residues in the solid protein keratin was studied. The position of the tryptophan fluorescence spectral maximum was measured as a function of temperature and was found to be substantially Stokes shifted even at 77 K. The activation energies for non-radiative relaxation of the singlet and triplet states of tryptophan in wool keratin, derived from Arrhenius plots of the fluorescence and phosphorescence yields, are 580 cm-1 and 995 cm-1 respectively. One possible fluorescence quenching mechanism which is consistent with these observations is a very effective, thermally induced mixing of the 1La and 1Lb excited singlet states which results in enhanced internal conversion apparent as a low fluorescent yield even at low temperatures. The phosphorescence decay from keratin in the absence of oxygen following excitation at 265 nm is non-single exponential. At room temperature it is dominated by a short-lived component with more than 80% of the decay completed within 3 microseconds of the flash. Longer living components with first-order lifetimes as long as 2-3 s were also observed.


Changes in intracellular water volume after leg lymphedema onset and lymphaticovenular anastomosis as its surgical intervention.
To clarify the changes in the intracellular water (ICW) volume in lymphedema-affected legs after lymphedema onset and its surgical intervention (ie, lymphaticovenular anastomosis [LVA]), we investigated the changes in body water composition using bioelectrical impedance analysis. This retrospective case series included 41 women with unilateral secondary leg lymphedema. The volume changes in the ICW and extracellular water (ECW) of the affected leg were measured using an InBody S10 (InBody Co, Ltd) multifrequency bioelectrical impedance analyzer, at both lymphedema onset and 1 year after LVA. The volume increase with leg lymphedema onset was comparable between the ECW and ICW (0.59 L vs 0.56 L; 95% confidence interval [CI], -0.02 to 0.06; P = .27), and the increase rate was higher for ECW (35.3% vs 22.1%; 95% CI, 9.3%-17.2%; P < .001). The volume reduction at 1 year after LVA was comparable between ECW and ICW (0.23 L vs 0.27 L; 95% CI, -0.08 to 0.02; P = .20), and the reduction rate was higher for ECW (8.7% vs 7.0%, 95% CI, 0.04%-3.2%; P = .044). The volume difference between ICW and ECW remained constant throughout the six measurements before and after LVA (F[3.01, 120.20] = 1.85; P < .14). Leg LVA reduced ICW in the lymphedematous leg. The onset of leg lymphedema increased ECW and ICW in the affected limb, and LVA decreased both ECW and ICW. The volume change in the affected leg was comparable between ECW and ICW at both lymphedema onset and after LVA. However, the rate of change was higher for ECW. The volume difference between ICW and ECW remained constant. Using bioelectrical impedance analysis, alterations in ICW volume were detected in the legs affected by lymphedema, both after the onset of lymphedema and after LVA intervention.


Urolithiasis in childhood.
The management of 131 children with urinary calculi is described. Boys out-numbered girls 2:1. Five per cent of the patients had identifiable metabolic causes, while 78 per cent had infected renal lithiasis. With appropriate therapy, stone disease became inactive in 79 per cent of the children. The remaining 21 per cent continued with active disease. Stone formation may be regarded as a solitary complication or one of several manifestations of a large number of underlying disorders. Along with a thorough search for etiologic factors there must be an equally aggressive therapeutic effort. Becuase the disease is often sporadic, careful long-term follow-up of the patients with active as well as those with inactive stone disease is mandatory.


Determinants of Caregiver Burden in Early-Onset Dementia.
Caregivers of patients with early-onset dementia (EOD) experience high levels of burden, which is known to be affected by caregivers' psychological features as well as by patients' and caregivers' demographical and social variables. Although potential clinical, demographical, and social determinants have been separately examined, it is not known how they reciprocally interact. Ninety-two consecutive patient-caregiver dyads were recruited from the Cognitive Neurology Clinics of Modena, Northern Italy. Caregivers were asked to fill in questionnaires regarding their burden, psychological distress, and family economic status. Data were analyzed with multivariable regression models and then entered in a mediation model. Caregiver burden was positively related to female caregiver sex, spousal relationship to the patient, severity of patient's behavioral symptoms, diagnostic delay, and financial distress of the family. It was negatively related to disease duration, patient's education, region of birth, caregiver age, number of caregiver's days off work, number of offspring, and caregiver perception of patient's quality of life. While the effect of caregiver age, diagnostic delay, and of proxies of family or social network directly impacted on caregiver's burden, the effect of patient's disease duration, being a wife caregiver, financial distress, and number of caregiver's days off work was entirely mediated by the level of caregiver psychological distress. Both direct actions (such as increasing social networks and shortening diagnostic delay) and indirect actions aimed at reducing psychological distress (such as increasing the number of caregiver's days off work and financial support) should be planned to reduce caregiver's burden.


Erratum: Treatment of a multiple sclerosis animal model by a novel nanodrop formulation of a natural antioxidant [Corrigendum].
[This corrects the article on p. 7165 in vol. 10, PMID: 26648720.].


The feasibility and effectiveness of emergency department based hypertension screening: a systematic review.
Hypertension is a highly prevalent risk factor for cardiovascular disease, and its early identification and management results in reductions in morbidity and mortality. Our objectives were to: (1) determine the extent to which the emergency department (ED) has been used to screen patients for undiagnosed hypertension; (2) estimate the incidence of undiagnosed hypertension in the ED population; (3) identify and describe the programs for ED hypertension screening; and (4) determine the feasibility of ED-based hypertension screening programs and the requirements for further study. An online search of databases (i.e., OVID Search, CINAHL, Scopus, Web of Science), unpublished sources (i.e., ProQuest Dissertation & Theses and Papers First), and grey literature (i.e., OpenSIGLE and the New York Academy of Grey Literature) was conducted. A manual search of the reference lists of relevant studies was also completed. Hypertension screening in the ED is feasible. Individuals with elevated blood pressure (BP) in the ED should be referred for follow-up. Further study is needed to develop an ED screening tool that is predictive of persistently elevated BP in undiagnosed individuals. Nurse practitioners in the ED should identify patients with elevated BP, provide hypertension education, and ensure appropriate intervention and referral.


Twenty-four-hour endocrine and metabolic profiles following consumption of high-fructose corn syrup-, sucrose-, fructose-, and glucose-sweetened beverages with meals.
We have reported that, compared with glucose-sweetened beverages, consuming fructose-sweetened beverages with meals results in lower 24-h circulating glucose, insulin, and leptin concentrations and elevated triacylglycerol (TG). However, pure fructose and glucose are not commonly used as sweeteners. High-fructose corn syrup (HFCS) has replaced sucrose as the predominant sweetener in beverages in the United States. We compared the metabolic/endocrine effects of HFCS with sucrose and, in a subset of subjects, with pure fructose and glucose. Thirty-four men and women consumed 3 isocaloric meals with either sucrose- or HFCS-sweetened beverages, and blood samples were collected over 24 h. Eight of the male subjects were also studied when fructose- or glucose-sweetened beverages were consumed. In 34 subjects, 24-h glucose, insulin, leptin, ghrelin, and TG profiles were similar between days that sucrose or HFCS was consumed. Postprandial TG excursions after HFCS or sucrose were larger in men than in women. In the men in whom the effects of 4 sweeteners were compared, the 24-h glucose and insulin responses induced by HFCS and sucrose were intermediate between the lower responses during consumption of fructose and the higher responses during glucose. Unexpectedly, postprandial TG profiles after HFCS or sucrose were not intermediate but comparably high as after pure fructose. Sucrose and HFCS do not have substantially different short-term endocrine/metabolic effects. In male subjects, short-term consumption of sucrose and HFCS resulted in postprandial TG responses comparable to those induced by fructose.


Tumor microvasculature observed using different contrast agents: a comparison between Gd-DTPA-Albumin and B-22956/1 in an experimental model of mammary carcinoma.
The aim of this study was to compare a pure macromolecular contrast agent (Gd-DTPA-albumin) with a new protein-binding blood pool contrast agent (B22956/1) in terms of their capacity to investigate the microvasculature in an experimental model of mammary carcinoma. Tumors were induced by subcutaneous injection of 5 x 10(5) BB1 cells into the backs of 5-7 week-old female FVB/neuNT233 mice. The animals were observed using DCE-MRI when the longest diameter of the tumor was 10.2+/-2.0 mm. DCE-MRI experiments were carried out using B22956/1 and (24 h later) Gd-DTPA-albumin. DCE-MRI data showed that vasculature in the tumor rim was characterized by greater fractional plasma volume and transendothelial permeability than vasculature in the tumor core as measured by both contrast agents. Permeability to Gd-DTPA-albumin in the tumor core was hardly measurable while permeability to B22956/1 was substantial. Histologically the tumor core showed areas of well vascularized, viable tissue surrounded by necrotic regions. DCE-MRI experiments performed with B22956/1 are useful in the investigation of vasculature in those tumor regions that are characterized by low permeability to macromolecules.


Bat3 facilitates H3K79 dimethylation by DOT1L and promotes DNA damage-induced 53BP1 foci at G1/G2 cell-cycle phases.
The methyltransferase DOT1L methylates histone H3 at K79 to facilitate specific biological events. H3K79 dimethylation (H3K79-2Me) by DOT1L influences the DNA damage response by promoting 53BP1 recruitment to DNA damage sites; however, it is unclear if this methylation is required as 53BP1 interacts with dimethylated H4 (H4K20-2Me) with a much higher affinity. We demonstrate that H3K79-2Me, while negligible during S-phase, is required for ionizing radiation (IR)-induced 53BP1 foci formation during G1/G2-phases when H4K20-2Me levels are low. Further, we describe an essential role for HLA-B-associated transcript 3 (Bat3) in regulating this process in U2OS cells. Bat3 co-localizes with DOT1L at histone H3, and Bat3 knockdown results in decreased DOT1L-H3 interaction and H3K79-2Me, leading to a reduction in IR-induced 53BP1 foci formation, defects in DNA repair and increased sensitivity to IR. We demonstrate that a conserved Bat3 ubiquitin-like motif and a conserved DOT1L ubiquitin-interacting motif promote DOT1L-Bat3 interaction to facilitate efficient H3K79-2Me and IR-induced 53BP1 foci formation during G1/G2-phases. Taken together, our findings identify a novel role for Bat3 in regulating DOT1L function, which plays a critical role in DNA damage response.


[Practical Application of Body Mechanics Principles in the Process of Health Workers Doffing Personal Protective Equipment].
To examine the application effect of body mechanics principles in the process of health workers doffing personal protective equipment (PPE). A total of 360 health workers from a Fangcang shelter hospital, also known as alternate care site, in Shanghai were involved in a centralized 1-day training concerning essential skills for taking off PPE. The training was focused on integrating body mechanics principles, including expanding the support surface, lowering the center of gravity, reducing the shift in the the center of gravity, using the principle of leverage, and creating the appropriate operating space, in the PPE doffing process. Through remote video monitoring and recording, observations were made of the physical stability, pollution risks, and operational smoothness of the health workers when they applied body mechanics principles in their actions. The results of binary logistic regression showed that, compared with the actions taken without applying body mechanics principles, performing the operation of the body leaning forward and then slightly leaning backward was positively correlated with stability in the doffing process (odds ratio [O R]=3.291, 95% confidence interval [ CI]: 1.627-6.656), negatively correlated with pollution risks ( OR=0.203, 95% CI: 0.100-0.412), and positively correlated with operational smoothness ( OR=20.847, 95% CI: 8.061-53.916); performing the operation of taking off the boot sleeve in a horse-riding stance, with one foot standing ahead of the other, was positively correlated with stability ( OR=5.299, 95% CI: 1.041-26.957), negatively correlated with pollution risks ( OR=0.079, 95% CI: 0.009-0.692), and positive correlated with operational smoothness ( OR=16.729, 95% CI: 1.238-226.077); performing the operation of taking off the boot sleeve by lifting the heel and then the toes was positively correlated with stability ( OR=19.361, 95% CI: 8.391-44.671), negatively correlated with pollution risks ( OR=0.181, 95% CI: 0.084-0.393), and positively correlated with operational smoothness ( OR=10.977, 95% CI: 3.764-32.008); performing the operation of the leaning forward and keeping the face looking forward when taking off the mask was positively correlated with stability ( OR=2.935, 95% CI: 1.412-6.101), negatively correlated with pollution risks ( OR=0.123, 95% CI: 0.059-0.258), and positively correlated with operational smoothness ( OR=18.126, 95% CI: 6.665-49.297). In the process of medical staffs doffing PPE, correct and proper mechanical postures and actions can effectively assist medical staffs to maintain balance and stability and reduce the risks of infection, which has major significance and should be widely incorporated in personal protection skills training and applied in clinical practice.


Expression levels of SIX1, ME2, and AP2M1 in adenoid cystic carcinoma and mucoepidermoid carcinoma.
Adenoid cystic carcinoma (AdCC) and mucoepidermoid carcinoma (MEC) are the most frequent malignancies in the salivary glands. The purpose of this study was to explore the roles of sine oculis homeobox homolog 1 (SIX1), malic enzyme 2 (ME2), and AP-2 complex subunit mu (AP2M1) in AdCC and MEC, as well as the potential relationship between SIX1, ME2, AP2M1, and proliferation marker cyclin D1. Immunohistochemistry was performed on human salivary gland tissue microarrays that contained 76 normal salivary glands (NSGs), 14 pleomorphic adenomas (PMAs), 81 AdCCs, and 52 MECs. We observed that the expression levels of SIX1 and ME2 were significantly elevated in AdCC and MEC when compared with NSG and PMA. In addition, we detected that AP2M1 was overexpressed in AdCC and MEC when compared with NSG. We also found that SIX1 and AP2M1 were positively associated with cyclin D1. These results may prove that SIX1 and AP2M1 are involved in the proliferation of AdCC and MEC to cause tumor growth.


Photodegradation of lambda-cyhalothrin and cypermethrin in aqueous solution as affected by humic acid and/or copper: intermediates and degradation pathways.
The influence of coexisting humic acids (HA) or Cu²⁺ on the photodegradation of pesticides lambda-cyhalothrin (λ-CHT) and cypermethrin (CPM) in aqueous solution was studied under xenon lamp irradiation. The removal efficiency of pesticides λ-CHT and CPM were enhanced in the presence of either Cu²⁺ or HA but restrained in the presence of both Cu²⁺ and HA. The photodegradation of λ-CHT and CPM followed first-order reaction kinetics. The photodegradation intermediates of λ-CHT and CPM were determined using gas chromatography/mass spectrometry. Possible photodegradation pathways included decarboxylation, ester bond cleavage, dechlorination, and phenyl group removal.


[Successful surgical case of DeBakey III b dissecting aortic aneurysm associated with right-sided aortic arch].
A 66-year-old man was admitted to our institute for surgical treatment of chronic dissecting aortic arch aneurysm with right-sided aortic arch which occurred 2 months previously. The size of the aortic arch aneurysm was larger than 6 cm. Total arch replacement using open stent grafting was performed through median sternotomy. The postoperative condition was well, and the patient was discharged without any complications.


Frequency and intensity of alcohol consumption: new evidence from Sweden.
There is an increasing body of evidence that the intensity in which alcohol is drunk is of greater concern than the frequency or overall quantity consumed. This paper provides an extensive analysis of the demand for alcohol as measured by total quantity, frequency, and intensity. A unique large sample of cross-sectional data from Sweden 2004-2011 allows reduced-form alcohol demand equations to be estimated for beer, wine, and spirits, split by alcohol drinking pattern (average vs. binge drinkers) and gender. Results find a negative beer excise rate effect for participation and frequency, and positive effect for intensity. The effect was stronger for binge drinkers. Generally, the results also show a positive socioeconomic (income and education) gradient in frequency demand and a negative gradient in the intensity demand. Female wine drinkers show a positive socioeconomic gradient in both frequency and intensity. The findings highlight the complexity of this policy space. Tax increases appear to reduce frequency but raise intensity consumed. The more educated and higher earners drink more in total, but less intensely when they do and this is likely to explain in part why poor health is concentrated amongst lower socioeconomic status individuals.


Contextual factors associated with organizational learning in hospitals: An instrument development study.
Develop a valid, reliable research instrument to measure contextual factors associated with organizational learning in hospitals. A valid, reliable instrument for measuring contextual factors associated with organizational learning is needed so nurse leaders and researchers can improve healthcare by facilitating and studying organizational learning. The Organizational Learning in Hospitals model guided development of the Organizational Learning Instrument-Context. Content validity was refined and evaluated through cognitive interviews and expert reviews. The instrument was distributed to direct care nurses in Magnet® hospitals in the United States. Intraclass correlation coefficients validated the use of multilevel analyses. Construct validity was assessed using multilevel confirmatory factor analysis, and coefficient omega was used to assess internal reliability. Participants were 1063 nurses in 120 inpatient units in 11 Magnet® hospitals. Results were as follows: item-level content validity = 0.86-1.0, scale-level content validity = 0.95, intraclass correlation coefficients = 0.171-0.270, coefficient omega = 0.945-0.982 and standardized factors loadings = 0.672-0.964. Model fit statistics were CFI = 0.963, TLI = 0.961 and RMSEA = 0.059. [Correction added on 31 May 2022, after first online publication: In the first line of the 'Results' section, "163 nurses" has been corrected to "1063 nurses" in this version.] CONCLUSIONS: Initial testing indicates the Organizational Learning Instrument-Context has adequate levels of reliability, content validity and construct validity. Hospital leaders and researchers may begin using this instrument to improve and study contextual factors associated with organizational learning in hospital units.


The effect of preload and Ca++-ions on the time-course of the isometric force and on the force-velocity relation: is Vmax dependent on the number of activated cross-bridges?
The maximum shortening velocity of the isolated, externally unloaded papillary muscle of cats, as can be obtained by quick-releases in the initial phase of isometric contractions, is clearly dependent on the Ca++-concentration of the bath solution as well as on the preload: In the range of 0.55 m-mole/1 to 4.4 m-mole/1 a doubling of the Ca++-concentration induces a mean increase of 23% in Vmax; in a range of muscle length assumed to be of physiological relevance, a rise in the extension of 10% of Lmax results in a mean augmentation of 20% in Vmax. In order to reveal possible differences in the effect of calcium and various degrees of filament overlap, firstly, isometric mechanograms were measured under low Ca++-concentration at the muscle length of Lmax. By correspondingly lowering the muscle extension under increased Ca++-concentration the reproduction of almost the entire rising phase of these isometric mechanograms was obtained. Both these experimental conditions result in congruent force-velocity relations and consequently in identical values for Vmax. It must therefore be concluded that there exists an inner relationship between the initial time-course of the isometric force and the force-velocity relations measured during this period. The interpretation of this fact involves weighing the hypothesis of an inner frictional force dependent on velocity against that of a maximum shortening velocity dependent on the number of activated cross-bridges. The resultant consequences for the estimation of the contractile qualities of the myocardium are discussed.


Blue light transurethral resection and biopsy of bladder cancer with hexaminolevulinate: Histopathological characteristics and recurrence rates in a single UK centre study.
Blue light cystoscopy with hexaminolevulinate (HAL) during transurethral resection of bladder cancer (TURBT) has been shown to improve detection, thereby reducing bladder cancer recurrence compared with white light cystoscopy. Single-centred UK (United Kingdom) study on 101 patients who underwent blue light cystoscopy between July 2017 and November 2020, performed by a single surgeon. Our study was divided into two arms; the primary arm had no prior diagnosis of bladder malignancy (N = 41), whereas secondary re-resection arm had (N = 57). Three patients with non-urothelial bladder cancer were excluded. Patients were followed up for 24 months. Data were collected on biopsy quality, histopathological characteristics and recurrence. The end points of the study were recurrence rate at 24 months in both arms and detection of CIS in patients who undergo TURBT or biopsy after initial white light study in the secondary, re-resection arm. This was analysed with Fisher's exact test. Of 98 patients, 39 had malignancy in their first blue light TURBT/biopsy: primary arm (10/41, 24.4%) and secondary arm (29/57, 50.9%), with detrusor present in 80.5% and 80.7%, respectively. In the secondary arm, blue light re-resection TURBT detected significantly more CIS (20.7% vs 51.7%, p = 0.0277) compared with white light with 3.4% upstaged to muscle invasive bladder cancer (G3pT2). Median time to re-resection was 3.06 months. Recurrence rate was 33.3% in the primary arm and 37.5% in the secondary arm after 24 months of follow-up. Our data confirm that blue light TURBT with HAL provides superior detection and diagnosis of CIS in patients with previous white light cystoscopy.


Safety aspects and cholesterol-lowering efficacy of chitosan tablets.
The purpose of this study was to determine the effect of two different doses of chitosan on serum fat-soluble vitamin concentrations, cholesterol concentrations, and other safety parameters. A total of 65 men and women consumed 0, 4.5, 6.75 g per day of chitosan or 6.75 g per day glucomannan for eight weeks in a parallel, placebo-controlled, single-blind study. Altogether, 56 participants completed the study. No differences were detected among the treatments in serum vitamins (vitamin A, vitamin E, 25-hydroxyvitamin D), carotenes (alpha- and beta-carotene), clinical chemistry or hematology measurements. The changes in the total and LDL-cholesterol concentrations among the study groups were not statistically significant. In the present study, the consumption of chitosan tablets was found to be safe, but there was no significant effect on cholesterol concentration.


Selenium and copper status - potential signposts for neurological remission after traumatic spinal cord injury.
Traumatic Spinal Cord Injury (TSCI) is a severe incident resulting in loss of motor and sensory function caused by complex pathological mechanisms including massive oxidative stress and extensive inflammatory processes. The essential trace elements selenium (Se) and copper (Cu) play crucial roles as part of the antioxidant defense. Remission after TSCI is associated with characteristic dynamics of early changes in serum Cu and Se status. Single-center prospective observational study. Serum samples from TSCI patients were analyzed (n = 52); 21 recovered and showed a positive abbreviated injury score (AIS) conversion within 3 months (G1), whereas 21 had no remission (G0). Ten subjects with vertebral fractures without neurological impairment served as control (C). Different time points (at admission, and after 4, 9, 12, and 24 h) were analyzed for total serum Se and Cu concentrations by total reflection X-ray fluorescence, and for Selenoprotein P (SELENOP) and Ceruloplasmin (CP) by sandwich ELISA. At admission, CP and SELENOP concentrations were higher in the remission group (G1) than in the non-remission group (G0). Within 24 h, there were marginal changes in Se, SELENOP, Cu and CP concentrations in the groups of controls (C) and G0. In contrast, these parameters decreased significantly in G1. Binary logistic regression analysis including Cu and Se levels at admission in combination with Se and CP levels after 24 h allowed a prediction for potential remission, with an area under the curve (AUC) of 87.7% (CI: 75.1%-100.0%). These data indicate a strong association between temporal changes of the Se and Cu status and the clinical outcome after TSCI. The dynamics observed may reflect an ongoing redistribution of the trace elements in favor of a better anti-inflammatory response and a more successful neurological regeneration.


High-Sensitivity Cardiac Troponin I Improves Cardiovascular Risk Prediction in Older Men: HIMS (The Health in Men Study).
Background The Framingham Risk Score estimates the 10-year risk of cardiovascular events. However, it performs poorly in older adults. We evaluated the incremental benefit of adding high-sensitivity cardiac troponin I (hs-cTnI) to the Framingham Risk Score. Methods and Results The HIMS (Health in Men Study) is a cohort study of community-dwelling men aged 70 to 89 years in Western Australia. Participants were identified from the electoral roll, with a subset undergoing plasma analysis. Hs- cTnI (Abbott Architect i2000 SR ) was measured in 1151 men without prior cardiovascular disease. The Western Australia Data Linkage System was used to identify incident cardiovascular events. After 10 years of follow-up, 252 men (22%) had a cardiovascular event ( CVE +) and 899 did not (CVE-). The Framingham Risk Score placed 148 (59%) CVE + and 415 (46%) CVE- in the high-risk category. In CVE - men, adding hs- cTnI affected the risk categories of 244 (27.2%) men, with 64.8% appropriately reclassified to a lower and 35.2% to a higher category, which decreased the number of high-risk men in the CVE- to 39%. In CVE + men, adding hs- cTnI affected the risk categories of 61 (24.2%), with 50.8% appropriately reclassified to a higher and 49.2% to a lower category and 82.5% remaining above the 15% risk treatment threshold. The net reclassification index was 0.305 ( P<0.001). Adding hs- cTnI increased the C-statistic modestly from 0.588 (95% CI , 0.552-0.624) to 0.624 (95% CI , 0.589-0.659) and improved model fit (likelihood ratio test, P<0.001). Conclusions Adding hs- cTnI to the Framingham Risk Score provided incremental prognostic benefit in older men, especially aiding reclassification of individuals into a lower risk category.


Immunotherapy via PD-L1-presenting biomaterials leads to long-term islet graft survival.
Antibody-mediated immune checkpoint blockade is a transformative immunotherapy for cancer. These same mechanisms can be repurposed for the control of destructive alloreactive immune responses in the transplantation setting. Here, we implement a synthetic biomaterial platform for the local delivery of a chimeric streptavidin/programmed cell death-1 (SA-PD-L1) protein to direct "reprogramming" of local immune responses to transplanted pancreatic islets. Controlled presentation of SA-PD-L1 on the surface of poly(ethylene glycol) microgels improves local retention of the immunomodulatory agent over 3 weeks in vivo. Furthermore, local induction of allograft acceptance is achieved in a murine model of diabetes only when receiving the SA-PD-L1-presenting biomaterial in combination with a brief rapamycin treatment. Immune characterization revealed an increase in T regulatory and anergic cells after SA-PD-L1-microgel delivery, which was distinct from naïve and biomaterial alone microenvironments. Engineering the local microenvironment via biomaterial delivery of checkpoint proteins has the potential to advance cell-based therapies, avoiding the need for systemic chronic immunosuppression.


Tc-99m-HMPAO labelled human platelets: in vitro and in vivo results.
The lipophilic 99mTc-HMPAO complex can be used for labelling platelets as well as granulocytes. Platelets were isolated according to standard isolation procedures for the evaluation of the optimal labelling parameters. The labelling efficiency (%) depends on incubation temperature (22 degrees C: 40%: 37 degrees C: 50%), incubation time (3 min: 20%, 25 min: 55%) and the incubation medium (plasma: 40%; saline 50%). The 60 min 99mTc elution out of the platelets ranged around 8%. The platelet recovery used as a quality control parameter is around 25% +/- 4% and is stable for at least 240 min. The high elution rate out of the platelets leads to renal excretion of the label and hence to significant kidney and bladder activity. Intestinal excretion of the label can also be frequently demonstrated. Fresh thrombotic lesions can normally be detected 4 h after reinjection of the labelled platelets, and in some patients as early as 1 h after reinjection. In conclusion, 99mTc-HMPAO seems to be a promising platelet label for imaging thrombotic lesions but not for platelet survival studies, because of the short physical half life of 99mTc.


Preventing postnatal growth restriction in infants with birthweight less than 1300 g.
To examine nutritional and growth outcomes in very preterm infants with a birthweight (BW) of ≤1300 g before and after the introduction of enhanced enteral and parenteral nutrition protocols. A comparison of two historical cohorts. There were 153 infants in cohort 1 and 118 in cohort 2. A total of 19% were growth restricted at birth in both cohorts. Feeds advanced more quickly in cohort 2, with decreased duration of central lines and TPN; breastmilk fortification occurred sooner. Calorie and protein intakes were increased during all of the first 14 days of life. Adverse clinical outcomes were unchanged, including NEC. The proportion of infants discharged <10th percentile of expected weight, decreased from 23% to 9%. In cohort 2, the z-score for body weight decreased by 0.39, compared to an average 1.03 in cohort 1 (p < 0.001). Head circumference and body weight were also significantly improved at discharge (p < 0.01), but length was improved to a lesser degree. Early and enhanced postnatal intravenous and enteral feeding can provide good postnatal growth among very immature infants without adverse effects. Calorie and particularly protein intake in early life could probably be further optimised.


Protein and virus crystal growth on international microgravity laboratory-2.
Two T = 1 and one T = 3 plant viruses, along with a protein, were crystallized in microgravity during the International Microgravity Laboratory-2 (IML-2) mission in July of 1994. The method used was liquid-liquid diffusion in the European Space Agency's Advanced Protein Crystallization Facility (APCF). Distinctive alterations in the habits of Turnip Yellow Mosaic Virus (TYMV) crystals and hexagonal canavalin crystals were observed. Crystals of cubic Satellite Tobacco Mosaic Virus (STMV) more than 30 times the volume of crystals grown in the laboratory were produced in microgravity. X-ray diffraction analysis demonstrated that both crystal forms of canavalin and the cubic STMV crystals diffracted to significantly higher resolution and had superior diffraction properties as judged by relative Wilson plots. It is postulated that the establishment of quasi-stable depletion zones around crystals growing in microgravity are responsible for self-regulated and more ordered growth.


Urbanization reduces soil microbial network complexity and stability in the megacity of Shanghai.
Urbanization is altering the co-occurrence networks of ecological communities that are critical to maintaining ecosystem functions and services. Soil microbial communities play key roles in various ecosystem processes, but how soil microbial co-occurrence networks respond to urbanization is unclear. Here we analyzed co-occurrence networks in soil archaeal, bacterial, and fungal communities from 258 soil sampling sites across the megacity of Shanghai along large urbanization gradients. We found that topological features of microbial co-occurrence networks were strongly altered by urbanization. In particular, microbial communities in more urbanized land-use and highly impervious land cover had less connected and more isolated network structures. These structural variations were accompanied by the dominance of connectors and module hubs affiliated with the Ascomycota in fungi and Chloroflexi in bacteria, and there were greater losses in efficiency and connectivity in urbanized than in remnant land-use in simulated disturbances. Furthermore, even though soil properties (especially soil pH and organic carbon) were major factors shaping topological features of the microbial networks, urbanization still uniquely explained a proportion of the variability, particularly those describing network connections. These results demonstrate that urbanization has clear direct and indirect effects on microbial networks and provide novel insights into how urbanization alters soil microbial communities.


Isolation and characterization of a convulxin-like protein from Crotalus durissus collilineatus venom.
A convulxin (Cvx)-like protein was isolated from Crotalus durissus collilineatus venom by a combination of molecular exclusion and reversed-phase HPLC chromatographies. The molecular mass of the Cvx-like protein in the absence and presence of DTT was 78 kDa and 12-13 kDa, respectively. The Cvx-like protein consisted of two nonidentical polypeptide chains (alpha and beta). The N-terminal amino-acid sequences of the alpha and beta subunits were GLHCPSDWYAYDGHCYKIFNEEMNWED and GFCCPSHWSSYSRYCYKFFSQEMNWEDAEK, respectively, with both subunits having a high content of Glu, Ser, Cys, and Asp. The Cvx-like protein showed high homology with other venom C-type lectins, but had low hemagglutinating activity on intact and trypsinized erythrocytes. The Cvx-like protein stimulated insulin receptor phosphorylation and potentiated insulin secretion from isolated islets in the presence of sub- (2.8 mM) or supra-physiological (16.7 mM) glucose concentrations. These results suggest that the increase in insulin secretion induced by Cvx-like protein may be mediated by a protein tyrosine kinase-dependent pathway and may involve other membrane receptors, such as GP VI or Scr family proteins.


Comparison of binding of [3H]-methionine-enkephalin, [3H]-naltrexone and [3H]-dihydromorphine in the mouse vas deferens and the myenteric plexus and brain of the ginea pig.
[3H]-Methionine-enkephalin, [3H]-naltrexone and [3H]-dihydromorphine are specifically bound in homogenates of not only the brain and myenteric plexus of the guinea pig but also the vas deferens of the mouse. Brain has a ratio of methionine-enkephalin to dihydromorphine binding in favour of methionine-enkephalin binding and the myenteric plexus a ratio in favour of dihydromorphine binding, with the mouse vas deferens being intermediate.


Discriminative stimulus effects of cocaine in squirrel monkeys: lack of antagonism by the dopamine D2 partial agonists terguride, SDZ 208-911, and SDZ 208-912.
The effects of cocaine alone and after pretreatment with the dopamine D2 partial agonists terguride, SDZ 208-911, and SDZ 208-912 were determined in squirrel monkeys trained to discriminate cocaine from saline using a two-lever drug discrimination procedure. When tested alone, cocaine engendered dose-related increases in the percentage of responses on the cocaine-associated lever, reaching virtually exclusive cocaine-appropriate responding after a dose of 1.0 mg/kg. Pretreatment with terguride (0.003-0.03 mg/kg), SDZ 208-911 (0.001-0.01), and SDZ 208-912 (0.003-0.018 mg/kg) did not consistently alter the discriminative stimulus effects of cocaine. Although some doses of each D2 partial agonist either increased (notably SDZ 208-911) or decreased (notably SDZ 208-912) the level of cocaine-appropriate responding engendered by low to intermediate doses of cocaine, none of the drugs reduced the percentage of cocaine-appropriate responding engendered by low to intermediate doses of cocaine, none of the drugs reduced the percentage of cocaine-appropriate responses engendered by 1.0 mg/kg cocaine. The results do not support the view that terguride, SDZ 208-911, or SDZ 208-912 would serve as functional antagonists of the subjective effects of cocaine.


Phosphorylated mammalian target of rapamycin is associated with an adverse outcome in oral squamous cell carcinoma.
To evaluate the expression of phosphorylated mammalian target of rapamycin (p-mTOR) and phosphatase and tensin homolog deleted on chromosome TEN (PTEN) in oral squamous cell carcinomas (OSCCs) and relate them with clinicopathologic characteristics and outcome. We analyzed p-mTOR and PTEN protein expression by immunohistochemistry in 72 OSCCs. Multivariate analysis was conducted to examine their role in survival. p-mTOR expression was observed in 46 (63.9%) cancers and PTEN expression was absent in 22 (30.6%). An adverse independent prognostic value for high p-mTOR expression was found (P = .043) as well as for advanced tumor stage (P = .010) in patients' overall survival (OS). For disease-free survival (DFS), only advanced tumor stage (P = .001) presented an adverse independent prognostic value. The effect of p-mTOR in OS of OSCC suggests that this marker may serve as a reliable biological marker to identify high-risk subgroups and as a guide to therapy. Furthermore, the high expression of p-mTOR suggests that this protein may be a promising therapeutic target in OSCC.


Hydranencephaly in association with Roberts syndrome.
A clinicopathological study in a case of Roberts syndrome (tetraphocomelia, cleft lip and palate, and phallic hypertrophy) is reported. This patient had hydranencephaly and impeperforate anus, two additional congenital abnormalities so far not reported in this syndrome.


Congenital malformations of newborn infants after clomiphene-induced ovulation.
The effect of clomiphene citrate (CC) on the incidence of congenital malformations in newborn infants was assessed from the outcome of 1034 pregnancies after CC-induced ovulation recorded at nine university hospitals in a 5-year period. Of these pregnancies, 14.2% ended in abortion, 0.5% in ectopic pregnancy, 0.1% in molar pregnancy, and 1.6% in stillbirth. In all, 935 infants were born, and 21 (2.3%) showed visible malformations. This incidence of malformations was not significantly different from that in 30,033 infants (1.7%) after spontaneous ovulation (spontaneous ovulation group), and the types of malformations after CC treatment were similar to e those in the spontaneous ovulation group. These data indicate that CC has no teratogenic effect.


Nickel-Catalyzed N-Alkylation of Acylhydrazines and Arylamines Using Alcohols and Enantioselective Examples.
A borrowing-hydrogen reaction between amines and alcohols is an atom-economic way to prepare alkylamines, ideally with water as the sole byproduct. Herein, nickel catalysts are used for direct N-alkylation of hydrazides and arylamines using racemic alcohols. Moreover, a nickel catalyst of (S)-binapine was used for an asymmetric N-alkylation of benzohydrazide with racemic benzylic alcohols.


Vago-sympathoadrenal reflex in thermogenesis induced by osmotic stimulation of the intestines in the rat.
Duodenal infusion of hypertonic solutions elicits osmolality-dependent thermogenesis in urethane-anaesthetized rats. Here we investigated the involvement of the autonomic nervous system, adrenal medulla and brain in the mechanism of this thermogenesis. Bilateral subdiaphragmatic vagotomy greatly attenuated the first hour, but not the later phase, of the thermogenesis induced by 3.6 % NaCl (10 ml kg(-1)). Neither atropine pretreatment (10 mg kg(-1), I.P.) nor capsaicin desensitization had any effect on the osmotically induced thermogenesis, suggesting the involvement of non-nociceptive vagal afferents. Bilateral splanchnic denervation caudal to the suprarenal ganglia also had no effect, suggesting a lack of involvement of spinal afferents and sympathetic efferents to the major upper abdominal organs. Adrenal demedullation greatly attenuated the initial phase, but not the later phase, of thermogenesis. Pretreatment with the beta-blocker propranolol (20 mg kg(-1), I.P.) attenuated the thermogenesis throughout the 3 h observation period. The plasma adrenaline concentration increased significantly 20 min after osmotic stimulation but returned to the basal level after 60 min. The plasma noradrenaline concentration increased 20 min after osmotic stimulation and remained significantly elevated for 120 min. Therefore, adrenaline largely mediated the initial phase of thermogenesis, and noradrenaline was involved in the entire thermogenic response. Moreover, neither decerebration nor pretreatment with the antipyretic indomethacin (10 mg kg(-1), S.C.) had any effect. Accordingly, this thermogenesis did not require the forebrain and was different from that associated with fever. These results show the critical involvement of the vagal afferents, hindbrain and sympathoadrenal system in the thermogenesis induced by osmotic stimulation of the intestines.


Sinking heart: a Punjabi communication of distress.
Within transcultural psychiatry there is a continuing debate between universalist and relativist positions. This debate focuses on the translation of Western psychiatric categories to non-Western languages and cultural contexts, and on the cross-cultural applicability of a Western model of human nature. This debate is of concern to medical practitioners and other primary carers who work with ethnic minority patients. The paper describes a syndrome of heart distress referred to as "sinking heart' by Punjabis living in Bedford, and it discusses how far this condition correlates with Western psychiatric categories. "Sinking heart' is an illness in which physical sensations in the heart or in the chest are experienced and these symptoms are thought to be caused by excessive heat, exhaustion, worry and/or social failure. The Punjabi model of "sinking heart' offers a culture-bound explanation of somatic symptoms. It is based on culturally specific ideas about the person, the self and the heart and on the assumption that physical, emotional and social symptoms of pathology accompany each other. This model is compared with Western notions of depression and with medical models of heart distress, type A behaviour pattern and stress. The paper concludes that the Punjabi model of sinking heart does not exactly correspond to any of these. The sinking heart model bears closest resemblance to a Western model of stress. The similarity between these two models is in the form rather than in the content.


Soluble Triggering Receptor Expressed on Myeloid Cells-1: Diagnosis or Prognosis?
The diagnosis of sepsis, and especially its differentiation from sterile inflammation, may be challenging. The triggering receptor expressed on myeloid cells-1 is an amplifier of the innate immune response. Its soluble form is detectable in various biological fluids and can be used as a surrogate marker of triggering receptor expressed on myeloid cells-1 activation. In this article, we review the abundant literature evaluating the usefulness of soluble triggering receptor expressed on myeloid cells-1 for the diagnosis and the prognosis evaluation of sepsis or localized infections.


Equilibria in systems of interacting structured populations.
The existence of a stable positive equilibrium density for a community of k interacting structured species is studied as a bifurcation problem. Under the assumption that a subcommunity of k-1 species has a positive equilibrium and under only very mild restrictions on the density dependent vital growth rates, it is shown that a global continuum of equilibria for the full community bifurcates from the subcommunity equilibrium at a unique critical value of a certain inherent birth modulus for the kth species. Local stability is shown to depend upon the direction of bifurcation. The direction of bifurcation is studied in more detail for the case when vital per unity birth and death rates depend on population density through positive linear functionals of density and for the important case of two interacting species. Some examples involving competition, predation and epidemics are given.


The utility of 18F-FDG PET and PET/CT in the diagnosis and staging of chondrosarcoma: a meta-analysis.
Chondrosarcoma is the second most common primary bone sarcoma; however, unlike other tumors, the biopsy cannot easily make a definite diagnosis or predict the histological grade. This meta-analysis was performed to evaluate the utility of 18F-FDG PET and PET/CT to differentiate chondrosarcoma from benign cartilaginous lesions and to predict the histopathological grade of chondrosarcoma. A comprehensive search was performed in three electronic databases including Medline/PubMed, the Cochrane Library and Embase to retrieve diagnostic studies evaluating the role of 18F-FDG PET or PET/CT for appraising the status of chondrosarcoma. Reference lists of related articles were also scrutinized manually. Useful data were extracted to calculate the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), the summary receiver operating characteristic curve (sROC), and the area under the curve (AUC) of 18F-FDG PET or PET/CT in diagnosing chondrosarcoma, and pooled weighted mean differences (WMD) of maximum standardized uptake value (SUVmax) between different entities of cartilaginous neoplasms by using Stata 19.0. A total of twelve studies provided sufficient data for the quantitative analysis. For the diagnosis of chondrosarcoma, the pooled sensitivity, specificity, and DOR of 18F-FDG PET were 0.84 (95% confidence interval [CI] 0.46 to 0.97), 0.82 (95% CI 0.55 to 0.94), and 24.244 (95% CI 1.985 to 96.148), respectively while those of 18F-FDG PET/CT were 0.94 (95% CI 0.86 to 0.97), 0.89 (95% CI 0.82 to 0.93), and 112.999 (95% CI 41.341 to 308.866), respectively. The pooled WMD of SUVmax were - 0.89 (95% CI -1.67 to -0.10) between benign cartilaginous lesions and grade 1 (G1) chondrosarcoma, -1.94 (95% CI -2.76 to -1.12) between G1 and grade 2 (G2) chondrosarcoma, and - 2.37 (95% CI -5.79 to 1.05) between G2 and grade 3 (G3) chondrosarcoma. In a word, 18F-FDG PET/CT revealed excellent accuracy in the diagnosis of chondrosarcoma and might assist in clinical decision-making. Meanwhile, although SUVmax alone showed restricted ability to differentiate benign cartilaginous lesions and G1 chondrosarcoma, as well as between G2 and G3 chondrosarcoma, it can identify intermediate/high-grade chondrosarcoma from low-grade ones. Level I evidence, a summary of meta-analysis.


High-resolution cardiac imaging using an interleaved 3D double slab technique.
A three-dimensional (3D) gradient-echo sequence with interleaved double-slab excitation was developed and optimized for the requirements in pediatric cardiac imaging. For this purpose high contrast between blood and myocardium signal should be obtained without the use of contrast agents. An acceptable measuring time for a large region examined with high spatial resolution should be achieved as well, especially with regard to the small structures of the heart and vessels of infants. The presented approach works with gradient moment nulling and a short echo time of 5.5 ms resulting in generally high signal intensity and only minor signal losses due to turbulent flow. The sequence allows simultaneous ECG-gated recording of two separately excited slabs with small thickness (10 mm) and with a distance of several centimeters between them. Thus, common effects of presaturation in 3D imaging can be avoided, although a relatively short measuring time is achievable. In order to get a 3D data set with good signal homogeneity of blood and of the other structures across a large volume of interest several double-slab measurements with suitable positions must be performed. The latter aspect is especially important for postprocessing techniques as multiple planar reconstruction and maximum intensity projection. Examples of applications of the new technique and appropriately postprocessed images are presented allowing demonstration even of subtle cardiac malformations.


Does long-term administration of tamoxifen affect bone mineral density?
A retrospective study was performed to determine whether the long-term (5 years or more) administration of tamoxifen is detrimental to bone mineral density (BMD). 19 patients taking adjuvant tamoxifen for breast cancer were paired with 19 controls comparable in age, time since menopause and performance status. BMD was measured at the femoral neck, lumbar spine and total body by dual energy X-ray absorptiometry (DEXA). There was no detrimental effect on BMD at any site. There was a trend towards an increase in BMD at the femoral neck. There were minor decreases in the serum calcium, phosphate and alkaline phosphatase.


An Evaluation Model for a Multidisciplinary Chronic Pelvic Pain Clinic: Application of the RE-AIM Framework.
Chronic pelvic pain (CPP) is a prevalent, debilitating, and costly condition. Although national guidelines and empiric evidence support the use of a multidisciplinary model of care for such patients, such clinics are uncommon in Canada. The BC Women's Centre for Pelvic Pain and Endometriosis was created to respond to this need, and there is interest in this model of care's impact on the burden of disease in British Columbia. We sought to create an approach to its evaluation using the RE-AIM (Reach, Efficacy, Adoption, Implementation, Maintenance) evaluation framework to assess the impact of the care model and to guide clinical decision-making and policy. The RE-AIM evaluation framework was applied to consider the different dimensions of impact of the BC Centre. The proposed measures, data sources, and data management strategies for this mixed-methods approach were identified. The five dimensions of impact were considered at individual and organizational levels, and corresponding indicators were proposed to enable integration into existing data infrastructure to facilitate collection and early program evaluation. The RE-AIM framework can be applied to the evaluation of a multidisciplinary chronic pelvic pain clinic. This will allow better assessment of the impact of innovative models of care for women with chronic pelvic pain.


Avelumab in patients with gestational trophoblastic tumors with resistance to polychemotherapy: Cohort B of the TROPHIMMUN phase 2 trial.
There is a need for innovative treatments in women with gestational trophoblastic tumors (GTT) resistant to chemotherapy. The TROPHIMMUN trial assessed the efficacy of avelumab in patients with resistance to single-agent chemotherapy (cohort A), or to polychemotherapy (cohort B). Cohort B outcomes are reported here. In the cohort B of this phase 2 multicenter trial (NCT03135769), women with GTT progressing after polychemotherapy received avelumab 10 mg/kg intravenously every 2 weeks until human chorionic gonadotropin (hCG) normalization, followed by 3 consolidation cycles. The primary endpoint was the rate of hCG normalization enabling treatment discontinuation (2-stage Simon design). Between February 2017 and August 2020, 7 patients were enrolled. Median age was 37 years (range: 29-47); disease stage was I or III in 42.9% and 57.1%; FIGO score was 9-10 in 28.6%, 11 in 28.6%, and 16 in 14.3%, respectively. Median follow-up was 18.2 months. One patient (14.3%) experienced hCG normalization enabling treatment discontinuation. However, resistance to avelumab was observed in the remaining 6 patients (85.7%). The cohort B was stopped for futility. Grade 1-2 treatment-related adverse events occurred in 57.1%, most commonly fatigue (42.9%), nausea, diarrhea, infusion-related reaction, muscle pains, dry eyes (each 14.3%). The median resistance-free survival was 1.4 months (95% CI 0.7-5.3). Although avelumab is active in patients with single-agent chemotherapy-resistant GTT (cohort A), it was associated with limited efficacy in patients with resistance to polychemotherapy (cohort B). The prognosis of patients with polychemotherapy resistance remains poor, and innovative immunotherapy-based therapeutic combinations are needed.


Induction of IL-6 in co-culture of bronchial epithelial cells and eosinophils is regulated by p38 MAPK and NF-kappaB.
Prominent infiltration of eosinophils into the airway mucosa and release of inflammatory mediators upon their adhesion onto airway epithelial cells are the immunopathogical mechanisms of allergic asthma. We investigated the effect of normal and paraformaldyhyde-fixed human eosinophils on BEAS-2B cells, a human bronchial epithelial cell line, for the release of inflammatory cytokine interleukin (IL)-6. Interleukin-6 in cell culture supernatant, protein amount of p38 mitogen-activated protein kinase (MAPK), and nuclear factor-kappaB (NF-kappaB) activity in BEAS-2B cells were analyzed by Western blot and enzyme-linked immunosorbent assay (ELISA). IL-6 gene expression was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR), and p38 MAPK activity and inhibitor (I)kappaB-alpha induction were evaluated by Western blot. Co-culture of BEAS-2B cells and eosinophils induced a significant elevation of IL-6 expression in BEAS-2B cells. Interaction of eosinophils and BEAS-2B cells led to a marked induction in phospho-p38 MAPK, phospho-IkappaB-alpha and activity of NF-kappaB in BEAS-2B cells. NF-kappaB inhibitor BAY 11-7082 and p38 MAPK inhibitor SB 203580 significantly decreased IL-6 release in a co-culture of BEAS-2B cells and eosinophils. Fixed human eosinophils were able to maintain their ability to induce IL-6 release in co-culture, activate p38 MAPK and NK-kappaB, and up-regulate IL-6 gene expression in BEAS-2B cells. These data indicate that the interaction of eosinophils and bronchial epithelial cells plays an important role in airway inflammation, at least partly, via IL-6 induction.


Generalising uncertainty improves accuracy and safety of deep learning analytics applied to oncology.
Uncertainty estimation is crucial for understanding the reliability of deep learning (DL) predictions, and critical for deploying DL in the clinic. Differences between training and production datasets can lead to incorrect predictions with underestimated uncertainty. To investigate this pitfall, we benchmarked one pointwise and three approximate Bayesian DL models for predicting cancer of unknown primary, using three RNA-seq datasets with 10,968 samples across 57 cancer types. Our results highlight that simple and scalable Bayesian DL significantly improves the generalisation of uncertainty estimation. Moreover, we designed a prototypical metric-the area between development and production curve (ADP), which evaluates the accuracy loss when deploying models from development to production. Using ADP, we demonstrate that Bayesian DL improves accuracy under data distributional shifts when utilising 'uncertainty thresholding'. In summary, Bayesian DL is a promising approach for generalising uncertainty, improving performance, transparency, and safety of DL models for deployment in the real world.


Utilization of Minimally Invasive Surgery and Its Association with Chemotherapy for Locally Advanced Gastric Cancer.
Minimally invasive surgery (MIS) is increasingly used to treat gastric cancer in the USA. A potential benefit of MIS is increased likelihood of receiving adjuvant chemotherapy. Our objectives were (1) to assess trends and predictors of MIS for gastric cancer, (2) to evaluate the association between MIS and postoperative chemotherapy, and (3) to investigate the relationship between MIS and survival. Patients with T3 or greater and/or N+ gastric adenocarcinoma were identified from the National Cancer Database from 2010 to 2015. Patients aged ≥ 85, with metastatic disease, treated with only preoperative chemotherapy, or with contraindications to chemotherapy were excluded. Hierarchical logistic regression and Cox proportional hazards were used to assess associations between MIS and postoperative chemotherapy and survival. Of 21,872 gastric resections, 6083 (27.8%) were MIS and 15,789 (72.2%) open. The majority were partial/subtotal (68.3%). Utilization of MIS increased from 18 to 37% from 2010 to 2015 (p < 0.01). Predictors of MIS were Asian race, any insurance coverage, and treatment at high-volume centers. Among 7540 patients with locally advanced disease, MIS was associated with receiving postoperative chemotherapy compared to open surgery (77.7% vs. 71.9%; OR 1.31, 95% CI 1.11-1.54). MIS was associated with improved survival before adjusting for postoperative chemotherapy (HR 0.83; 95% CI 0.72-0.97) but not after (HR 0.87, 95% CI 0.75-1.01). Utilization of MIS for locally advanced gastric cancer approximately doubled during the study period. Compared to open surgery patients, MIS patients were more likely to receive postoperative chemotherapy. The increased utilization of postoperative chemotherapy may explain the associated survival advantage observed with MIS.


Growth induced translocation effectively directs an amino acid analogue to developing zones in Agaricus bisporus.
The vegetative mycelium of Agaricus bisporus supplies developing white button mushrooms with water and nutrients. However, it is not yet known which part of the mycelium contributes to the feeding of the mushrooms and how this depends on growth conditions. Here we used photon counting scintillation imaging to track translocation of the 14C-radiolabeled metabolically inert amino acid analogue α-aminoisobutyric acid (14C-AIB). Translocation to the periphery of the mycelium was observed in actively growing vegetative mycelium with a velocity of up to 6.6 mm h-1, which was 30-fold higher than the growth rate. Furthermore, 14C-AIB translocated to neighboring colonies after fusion by anastomosis depending on the relative growth rate in these colonies. When mushrooms started to develop, translocation of 14C-AIB was redirected to the fruiting bodies via mycelium and hyphal cords. More abundant mycelial cord formation and a 5-fold higher rate of translocation was observed for cultures growing directionally from inoculum located at one side of the substrate, when compared to non-directional growth (inoculum mixed throughout the substrate). The maximum translocation distance was also greater (≥50 and 22 cm, respectively). In conclusion, 14C-AIB translocation switches between vegetative growth and towards developing mushrooms, especially via cords and when source-sink relationships change.


[A comparison of the effects of cyproheptadine and propranolol on the development of poststressor lesions of the gastric mucosa in inbred mice].
The effects of central cyproheptadine and propranolol were virtually the same but differed in their intensity. Differences between genotypes were shown to be able to determine the differences in effects of the blocking agents on different kinds of stress-induced stomach damage. The data obtained suggest that genotypic properties of the serotoninergic system can interfere considerably with the reactions of the stomach mucosa to emotional stress.


Construction of PANoptosis signature: Novel target discovery for prostate cancer immunotherapy.
PANoptosis pathway gene sets encompassing pyroptosis, apoptosis, and necroptosis were identified from the MSigDB database. We analyzed the perturbations and crosstalk in the PANoptosis pathway in prostate adenocarcinoma (PRAD), including gene mutation, transcription, methylation, and clinical features. By constructing a PANoptosis signature, we accurately predicted the prognosis and immunotherapeutic response of PRAD patients. We further explored the molecular features and immunological roles of the signature, dividing patients into high- and low-score groups. Notably, the high-score group correlated with better survival outcomes and immunotherapeutic responses, as well as a higher mutation frequency and enrichment score in the PANoptosis and HALLMARK pathways. The PANoptosis signature also enhanced overall antitumor immunity, promoted immune cell infiltration, upregulated immune checkpoint regulators, and revealed the cold tumor characteristics of PRAD. We also identified potential drug targets based on the PANoptosis signature. These findings lead the way in identifying novel prognostic markers and therapeutic targets for patients with PRAD.


Cycloid psychoses predominate in severe postpartum psychiatric disorders.
The nosological status of postpartum psychoses has remained controversial because of their often 'atypical' symptomatology. A polydiagnostic approach may further clarify this issue. In a retrospective study, we applied the ICD-10 and Leonhard's classification to 39 patients with severe postpartum psychiatric disorders. The patients were personally reexamined on average 12.5 years (6-26 years) after the onset of the illness. An acute onset and a polymorphous psychotic symptomatology with rapid changes characterized the majority of our cases. Unipolar depressive disorders (28%) and acute polymorphous psychotic disorders (21%) represented the largest proportions within the ICD-10-classification. Applying Leonhard's classification, over half the patients (54%) suffered from a cycloid psychosis. Among cycloid psychoses, motility psychoses clearly predominated. Schizophrenias occurred rarely (10%) according to both classifications. Due to the unknown prevalence of the various diagnoses among women of child-bearing age, it is impossible to statistically infer a specific association between childbirth and a distinct diagnosis from our data. Our findings suggest that cycloid psychoses, in particular motility psychoses, account for the majority of postpartum psychoses, and do not support the hypothesis of a nosological independence of postpartum psychoses.


Surface plasmon resonance imaging-based protein arrays for high-throughput screening of protein-protein interaction inhibitors.
The E7 protein produced by high-risk human papillomavirus (HPV) induces a degradation of the retinoblastoma tumor suppressor RB through direct interaction, which suggests that an inhibitor for the interaction can be a potential anticancer drug. A surface plasmon resonance (SPR) imaging-based protein array chip was developed for the high-throughput screening of inhibitor molecules targeting RB-E7 interaction. The glutathione S-transferase-fused E7 protein (GST-E7) was first layered onto a glutathionylated gold chip surface that had been designed to specifically bind to GST-fused proteins. Subsequently, a microarrayer was used to spot the hexa-histidine-tagged RB proteins (His(6)-RB) onto the GST-E7-layered gold chip surface, and the resulting SPR image was analyzed. Upon increased His(6)-RB concentration in the spotting solution, the SPR signal intensity increased proportionally, indicating that His(6)-RB bound to GST-E7 in a concentration-dependent manner. The His(6)-RB/GST-E7 interaction was challenged by spotting the His(6)-RB solution in the presence of a RB binding peptide (PepC) derived from a motif on E7. The SPR imaging data showed that PepC inhibited the His(6)-RB/GST-E7 interaction in a concentration-dependent manner. Our results show that the SPR imaging-based protein array chip can be applied to screen small molecule inhibitors that target protein-protein interaction.


Predictive value of systemic inflammatory response-related indices for survival in tongue cancer.
We assessed the potential prognostic significance of the preoperative systemic inflammation index, platelet-to-lymphocyte ratio, and neutrophil-to-lymphocyte ratio in patients who underwent surgical resection. This retrospective study included 224 patients with clinicopathologically confirmed squamous carcinoma of the tongue who underwent surgery between August 2009 and December 2017. The optimal cut-off values for the indices were determined by receiver operating characteristic curves. Correlations between the indices and clinicopathological variables were determined by Pearson chi-square or Fisher exact tests. The Kaplan-Meier test was used to compare overall survival between groups (high and low values); the log-rank or Breslow test was used to assess differences in survival. Univariate and multivariate Cox regression models were used to analyze predictive values of the indices as independent indicators of overall survival. Bilateral p values of <0.05 were considered statistically significant. Significant association was found between the indices and sex, tissue grade, tumor location, and lymph nodes metastases (p < 0.05). On Kaplan-Meier analysis, patients with lower values of the indices had longer overall survival (p < 0.05). Univariate and multivariate Cox regression models identified age, lymph node metastases, and neutrophil-to-lymphocyte ratio as independent predictors of overall survival. The studied indices have potential prognostic significance in patients with squamous tongue cancer.


The distribution of lung damage in children with cystic fibrosis and its relationship to colonisation with Pseudomonas aeruginosa.
Ventilation-perfusion lung scans were performed with 81mKr inhalation and 99mTc-albumin injection in 33 children with cystic fibrosis. It was found that both ventilation and perfusion scans yielded more information than radiographs of the chest in assessing lung damage. Using a scoring system, it was demonstrated by statistical methods that in the worst affected patients the disease was worse in the upper zones of the lungs, which changes were not detectable on chest radiographs. Pseudomonas was present in the sputum of these patients.


Effect of colchicine on the ultrastructure of secretory-state smooth muscle cells from the rabbit artery wall.
Little is known about the possible role of microtubules and related structures with respect to the structural and functional heterogeneity of arterial smooth muscle cells (SMC). This study demonstrates that a short-term treatment with an antitubulin, colchicine, resulted in two major structural changes in arterial SMC in the aortic arch, the thoracic aorta and the pulmonary trunk of 20-d-old rabbits. The SMC of control rabbits showed well-developed rough endoplasmic reticulum and Golgi complexes, and numerous microtubules. Colchicine treatment affected (a) microtubules in a monotypic way (all SMC contained no microtubules after colchicine), and (b) Golgi complexes and rough endoplasmic reticulum in a pleiotypic way. In effect two major structural subpopulations of SMC were obtained; the first subpopulation displayed markedly altered Golgi complexes, whereas the rough endoplasmic reticulum was unaltered; the second subpopulation showed a vacuolar dilation of rough endoplasmic reticulum (or extensively-developed smooth sarcoplasmic reticulum), but a disappearance of Golgi complex. These data suggest that an organelle-specific sensitivity to colchicine (most likely to its antitubulin action) may contribute to the heterogeneity of SMC. They also suggest that within control SMC two subpopulations might exist which can only be detected under special conditions like colchicine treatment. The disassembly of microtubules detected in parallel may be one trigger, but not the main mechanism in the heterogeneous changes of SMC in reaction to colchicine.


High-grade Neuroendocrine Carcinoma With Focal Squamous Metaplasia of Renal Pelvis Associated With Renal Calculus: Study of a Case.
Mixed neuroendocrine and non-neuroendocrine type of tumor in renal pelvis is rare and presents a high-grade malignancy. We present a case report that a 57-year-old man had no history of small cell cancer but presented a high-grade neuroendocrine carcinoma with focal squamous metaplasia and multiple stones simultaneously in the right renal pelvis. The patient underwent nephroureterocystectomy 9 months before this presentation, with evidence of multiple metastatic tumors in various parts of the body. The case of mixed neuroendocrine tumor with stones in the renal pelvis carries a poor prognosis and poses a therapeutic challenge to urologists.


Neurilemmoma of deep branch of ulnar nerve presenting as ulnar tunnel syndrome.
A rare case of neurilemmoma of the deep branch of the ulnar nerve presented as ulnar nerve compression syndrome. This tumour was arising from the deep branch at the wrist just distal to the ulnar tunnel. By its proximity to the sensory division, it led to sensory symptoms in the ulnar two digits. Certain features of this case, which are uncommon are discussed.


A Cross-Sectional Study of Breast Cancer Surgery and the Cost Based on Data From 77 Chinese 3A Hospitals in 2015.
We aimed to clarify the real-world status of breast cancer surgery and the cost in China. This cross-sectional survey relied on data obtained from the hospitalization summary reports (HSRs) in 77 top-ranked (grade 3A) hospitals in China to analyze breast cancer patients who underwent surgery between January 2015 and December 2015. The surgery and cost were mainly evaluated. Overall, 31,900 breast cancer patients underwent surgeries in 77 hospitals. The mean age in our study was 51.5 years (SD, 11.7 years). The primary types of surgical procedures were mastectomy (n = 24,629, 77.2%) and breast-conserving surgery (6,210, 19.5%). The rate of mastectomy was the highest at age band 50-65 years (n = 10,861, 82.1%) and in non-first-tier cities (n = 7,651, 88.4%) as well as in Northeast China (n = 3,107, 93.2%). The rate of breast-conserving surgery was less than 10% in non-first-tier cities (9.8%), Southwest China (6.1%), and Northeast China (5.8%). The median cost was $3,352.4 (interquartile range (IQR), $2,492.6-4,588.0). Mastectomy cost was significantly higher than breast-conserving surgery cost in both different city tiers and regional distribution except Northeast China (p < 0.001). This study demonstrated that the main breast cancer surgery in Chinese 3A hospitals was mastectomy and that the cost varied both across and within geographic regions and city tiers. This information helps describe the real-world status of breast surgery and the cost in China.


Effects of once-daily and twice-daily dosing on adherence with prescribed glipizide oral therapy for type 2 diabetes.
We evaluated differences in adherence and persistence with prescribed therapy of once-daily (OD) dosing compared with twice-daily (BID) dosing of glipizide in patients with type 2 diabetes. The study cohort was derived from a pharmacy benefit manager claims database. Patients new to extended-release gastrointestinal therapeutic system (GITS) and immediate-release glipizide therapy were identified and followed for 1 year. Adherence indices (AIs) were calculated and persistence curves were constructed. Adherence indices rates were 60.5% in the GITS OD cohort and 52.0% in the BID cohort. Rates of persistence at 12 months were 44.4% in the GITS OD cohort vs 35.8% in the BID cohort. Initiation of OD pharmacotherapy results in better adherence and persistence compared with a BID regimen, despite a greater daily pill burden in the OD cohort. These data suggest that dosing frequency exerts a greater impact on patient adherence and persistence than number of tablets per dose.


Sinefungin, a potent inhibitor of virion mRNA(guanine-7-)-methyltransferase, mRNA(nucleoside-2'-)-methyltransferase, and viral multiplication.
Sinefungin (A9145) and a related metabolite, A9145C, were found to be potent inhibitors of Newcastle disease virion and vaccinia virion mRNA(guanine-7-)-methyltransferase and vaccinia virion mRNA(nucleoside-2'-)-methyltransferase. Both Sinefungin and A9145C were competitive inhibitors of these S-adenosyl-L-methionine-dependent enzymes having inhibition constants substantially less than S-adenosyl-L-homocysteine. These compounds also inhibited plaque formation by vaccinia virus in mouse L-cells.


Nociception-specific blink reflex: pharmacology in healthy volunteers.
The physiology and pharmacology of activation or perception of activation of pain-coding trigeminovascular afferents in humans is fundamental to understanding the biology of headache and developing new treatments. The blink reflex was elicited using a concentric electrode and recorded in four separate sessions, at baseline and two minutes after administration of ramped doses of diazepam (final dose 0.07 mg/kg), fentanyl (final dose 1.11 μg/kg), ketamine (final dose 0.084 mg/kg) and 0.9 % saline solution. The AUC (area under the curve, μV*ms) and the latency (ms) of the ipsi- and contralateral R2 component of the blink reflex were calculated by PC-based offline analysis. Immediately after each block of blink reflex recordings certain psychometric parameters were assessed. There was an effect due to DRUG on the ipsilateral (F 3,60 = 7.3, P < 0.001) AUC as well as on the contralateral (F 3,60 = 6.02, P < 0.001) AUC across the study. A significant decrement in comparison to placebo was observed only for diazepam, affecting the ipsilateral AUC. The scores of alertness, calmness, contentedness, reaction time and precision were not affected by the DRUG across the sessions. Previous studies suggest central, rather than peripheral changes in nociceptive trigeminal transmission in migraine. This study demonstrates a robust effect of benzodiazepine receptor modulation of the nociception specific blink reflex (nBR) without any μ-opiate or glutamate NMDA receptor component. The nociception specific blink reflex offers a reproducible, quantifiable method of assessment of trigeminal nociceptive system in humans that can be used to dissect pharmacology relevant to primary headache disorders.


Controllable growth of wafer-scale monolayer transition metal dichalcogenides ternary alloys with tunable band gap.
The tuning of band gap is very important for the application of two-dimensional (2D) materials in optoelectronic devices. Alloying of 2D transition metal dichalcogenides (TMDCs) is an important way to tune the wide band gap. In this study, we report a multi-step vapor deposition method to grow monolayer TMDC ternary alloy films with wafer scale, including Mo1-xWxS2, Mo1-xWxSe2and MoS2xSe2(1-x), which are accurately controllable in the elemental proportion (xis from 0 to 1). The band gap of the three 2D ternary alloy materials are continuously tuned for the whole range of metal and chalcogen compositions. The metal compositions are controlled by the as-deposited thickness. Raman, photoluminescence, elemental maps and TEM show the high spatial homogeneity in the compositions and optical properties across the whole wafer. The band gap can be continuously tuned from 1.86 to 1.99 eV for Mo1-xWxS2, 1.56 to 1.65 eV for Mo1-xWxSe2, 1.56 to 1.86 eV for MoS2xSe2(1-x). Electrical transport measurements indicate that Mo1-xWxS2and MoS2xSe2(1-x)monolayers shown-type semiconductor behaviors, and the carrier types of Mo1-xWxSe2can be tuned asn-type, bipolar andp-type. Moreover, this control process can be easily generalized to other 2D alloy films, even to quaternary or multi-element alloy materials. Our study presents a promising route for the preparation of large-scale homogeneous monolayer TMDC alloys and the application for future functional devices.


Antihaemolytic and snake venom neutralizing effect of some Indian medicinal plants.
To validate traditional claims of usefulness of the Indian plants in management of poisonous snakebite and evaluate the antivenom properties displayed by the alcoholic extracts of Andrographis paniculata (A. paniculata), Crateva magna (C. magna), Gloriosa superba (G. superba) and Hydrocotyle javanica (H. javanica). These plants were collected, identified and the extracts were prepared by using conventional Soxhlet ethanol extraction technique. The venom neutralization activity was accessed in mice (20-25g) and number of mortalities was observed against clinically important snake (Naja nigricollis) venom. Present study also deals with in vitro membrane stabilizing activity of these plants against hyposaline induced human red blood corpuscles (HRBC). Extracts of H. javanica and G. superba gave 80 % and 90 % protection to mice treated with minimum lethal dose of venom (LD(99)). These two plants showed significant neutralization effect against the venoms of Naja nigricollis venom. H. javanica and G. superba (25-100 mg/mL) produced significant changes of membrane stabilization of human red blood cells (HRBC) exposed to hyposaline-induced haemolysis. We conclude that probably due to presence of various phytochemicals plays an important role in the anti-venom potential of these Indian medicinal plants against Naja nigricollis venom. The above observations confirmed that A. paniculata, C. magna, G. superba and H. javanica plant extracts possess potent snake venom neutralizing capacity and could potentially be used as an adjuvants for antivenin therapy in case of snakebite envenomation, especially against the local effects of cobra venoms.


Biochemical genetics of altered acetylcholinesterase resistance to insecticides in the house fly.
Resistance to the organophosphate insecticide tetrachlorvinphos was examined in a house fly (Musca domestica L.) strain with an altered acetylcholinesterase (AChE) of decreased sensitivity to inhibition by the insecticide. Genetic tests showed that both resistance and the altered AChE were controlled by semi-dominant gene(s) on chromosome II. The gene for resistance was five crossover units from the mutant marker stubby wing (stw). A house fly strain was prepared in which resistance was introduced in to a susceptible stw strain by recombination. Biochemical assays revealed that the altered AChE was introduced along with resistance. Assays of the AChE of resistant and susceptible stw strains by two independent methods showed that the enzyme from resistant flies was 30 times more slowly inhibited by tetrachlorvinphos than the enzyme from susceptible flies.


Lymphocyte activation and correlation with IMPDH activity under therapy with mycophenolate mofetil.
In an attempt to monitor the pharmacodynamics of mycophenolate mofetil (MMF) we investigated the association of inosine monophosphate dehydrogenase (IMPDH) activity in peripheral blood mononuclear cells with the expression of lymphocyte activation markers in stable cardiac transplant recipients treated with MMF. Twenty-four study patients were switched from azathioprine to MMF 7.2+/-4.1 years after heart transplantation. While the MPA trough level remained unchanged, the mean activity of IMPDH declined from 890 to 462 pmol/10(6)PBMC/h three months after onset of MMF therapy, was almost completely inhibited at six months and partially restored to 160 pmol/10(6)PBMC/h 12 months after switch to MMF (p< .0001). We detected also significant changes in a number of activated lymphocyte subsets: CD4+/25+, CD8+/38+, CD19+/69+, CD3+/16+/56+, natural killer (NK) cells, and monocytes. Moreover, the IMPDH activity profile correlated positively with the number of CD8+/38+ T cells (correlation coefficient (CC) +0.53), and inversely with NK cells (CC -0.52) and CD19+/69+ cells (CC -0.61). We revealed a close association of IMPDH baseline activity in mononuclear cells with the expression of lymphocyte activation markers in stable heart transplant patients after introduction of MMF therapy. This supports the assumption of a rather immunomodulatory than immunosuppressive effect of MMF.


Reference values for analytes of 24-h urine collections known to be complete.
One hundred and twenty two 24-h urine collections were obtained from a representative sample of men and women in the general population aged 25-44 years. The collections were verified for their completeness by urine recovery of oral doses of para-amino benzoic acid. Means (with 0.95 reference intervals) for both sexes for 24-h urinary output were determined for nitrogen, urea, creatinine, urate, ammonia, sodium, potassium, volume, and pH. Within person variation in nitrogen, urea, creatinine, ammonia, sodium and potassium was estimated for a consecutive 28-day series of 24-h urine collections for eight individuals. Within person variation was greatest for sodium and least for creatinine. These differences when compared with the between person variation in the analytes studied have implications for the precision with which a result from a single specimen can be used to place an individual within a distribution of values for epidemiological purposes. In clinical biochemistry, the population results reported here should be appropriate as a reference base for comparison with individual patient results.


Delay on the in vitro kinetic development of prepubertal ovine embryos.
In the present study we characterize the developmental potential of prepubertal and adult ovine oocytes, analyzing the developmental speed to two-cell and blastocyst stages and its relationship with hatching from the zona pellucida, development after vitrification and the number and allocation of inner mass and trophoblastic cells. Prepubertal and adult ovine oocytes were matured and fertilized in vitro and first cleavage rates at 22, 26 and 32 h were recorded. Cleaved oocytes were cultured and blastocyst production was assessed at 6-9 days post-fertilization (dpf). Blastocysts from the two sources obtained on different days were divided into two groups: the first was vitrified, warmed and cultured in vitro to evaluate re-expansion of the blastocoelic cavity; blastocysts of the second were cultured separately to allow for hatching and count of trophoblastic and inner mass cells of hatched blastocysts by differential staining. We observed a significantly lower rate (P < 0.01) of cleaved prepubertal oocytes at 22 and 26 h after fertilization while it was higher (P<0.01) at 32 h than in the adult ones. Adult blastocyst production was significantly lower (P < 0.01) in prepubertal than in adult groups and began on the seventh dpf, later (P < 0.01) than in the adult group, where they appeared on the sixth dpf. Prepubertal blastocysts hatched at a lower rate than the adult ones (P < 0.01) and in both experimental groups faster blastocysts showed a higher (P < 0.01) hatching rate. Similarly, prepubertal derived blastocysts showed lower viability after vitrification (P < 0.01) compared to the adult counterparts, and in particular slower embryos had reduced viability after vitrification compared to the fastest (P < 0.01). Cell number was not different between blastocysts of both groups obtained at 6 and 7 dpf, which were higher (P < 0.01) than those obtained at 8 and 9 dpf. The ICM/trophoblast cell ratio was similar in 6- and 7-day obtained blastocyst and increased (P < 0.01) in those obtained 1 or 2 days later. These findings show that differences in kinetic development between prepubertal and adult derived embryos reflect differences in developmental capacity of the oocytes from which they derive and could be indicative of embryo quality.


What influences availability of medicines for the community management of childhood illnesses in central Uganda? Implications for scaling up the integrated community case management programme.
The integrated Community Case Management (iCCM) of childhood illnesses strategy has been adopted world over to reduce child related ill health and mortality. Community Health workers (CHWs) who implement this strategy need a regular supply of drugs to effectively treat children under 5 years with malaria, pneumonia and diarrhea. In this paper, we report the prevalence and factors influencing availability of medicines for managing malaria, pneumonia and diarrhea in communities in central Uganda. A cross sectional study was conducted among 303 CHWs in Wakiso district in central Uganda. Eligible CHWs from two randomly selected Health Sub Districts (HSDs) were interviewed. Questionnaires, check lists, record reviews were used to collect information on CHW background characteristics, CHW's prescription behaviors, health system support factors and availability of iCCM drugs. Multivariable logistic regression analysis was done to assess factors associated with availability of iCCM drugs. Out of 300 CHWs, 239 (79.9%) were females and mean age was 42.1 (standard deviation =11.1 years). The prevalence of iCCM drug availability was 8.3% and 33 respondents (11%) had no drugs at all. Factors associated with iCCM drug availability were; being supervised within the last month (adjusted OR = 3.70, 95% CI 1.22-11.24), appropriate drug prescriptions (adjusted OR = 3.71, 95% CI 1.38-9.96), regular submission of drug reports (adjusted OR = 4.02, 95% CI 1.62-10.10) and having a respiratory timer as a diagnostic tool (adjusted OR =3.11, 95% CI 1.08-9.00). The low medicine stocks for the community management of childhood illnesses calls for strengthening of CHW supervision, medicine prescription and reporting, and increasing availability of functional diagnostic tools.


Identification of the novel HLA-C*07:446 allele in a volunteer bone marrow donor.
HLA-C*07:446 differs from HLA-C*07:02:01:01 by one nucleotide substitution at position 809 (C → T) in exon 4.