In vitro expression of HPV16 E7 linked to HMGB1 immunoadjuvant in mammalian cells.
E7 is the major transforming protein of human papillomavirus (HPV) that plays important role in maintaining the proliferative state in HPV-infected cells. Furthermore, high mobility group 1 protein (HMGB1) is a highly conserved component of chromatin that can be secreted by macrophages and activated monocytes and thus functions as an inflammation mediator. In the current study, cloning of HMGB1 gene and also HPV16E7-HMGB1 was performed in pEGFP-N1 eukaryotic expression vector in order to evaluate their expression in mammalian cells. For this purpose, the HEK-293T cells were transfected by pEGFP-E7, pEGFP-HMGB1 and pEGFP-E7-HMGB1 using TurboFect delivery system. The levels of protein expression were assessed by flow cytometry and fluorescent microscopy at 48 hr after transfection, as well as by western blot analysis using anti-GFP polyclonal antibody. Our data showed a clear band of ~ 684 bp and ~ 981 bp related to HMGB1 and E7-HMGB1 genes in agarose gel, respectively. The expression of HMGB1-GFP and E7-HMGB1-GFP proteins was confirmed for the bands of ~ 53 kDa and ~ 64 kDa in the transfected cells using western blot analysis, respectively. The linkage of HMGB1 gene to E7 could likely neutralize the negative charges of E7, thus a clear band of 64 kDa was detected instead of 76 kDa in western blot analysis. Moreover, the percentage of expression for E7-GFP, HMGB1-GFP and E7-HMGB1-GFP was 76 %, 55 %, and 52 %, in comparison with pEGFP-N1 (~82 %) as a positive control. Indeed, HMGB1 linked to HPV16 E7 gene decreased transfection efficiency of E7 DNA in HEK-293T cells. Generally, the electrophoretic mobility of HPV16 E7 was changed due to the linkage of HMGB1 gene. Furthermore, the fusion protein could be efficiently expressed in mammalian cells for the next use in immunotherapy (Fig. 3, Ref. 51).


The lognormal and gamma distribution models for estimating molecular weight distributions of polymers using PGSE NMR.
We present comprehensive derivations for the statistical models and methods for the use of pulsed gradient spin echo (PGSE) NMR to characterize the molecular weight distribution of polymers via the well-known scaling law relating diffusion coefficients and molecular weights. We cover the lognormal and gamma distribution models and linear combinations of these distributions. Although the focus is on methodology, we illustrate the use experimentally with three polystyrene samples, comparing the NMR results to gel permeation chromatography (GPC) measurements, test the accuracy and noise-sensitivity on simulated data, and provide code for implementation.


Two sibs with brachyolmia type Hobaek: five year follow-up through puberty.
A brother and a sister affected with brachyolmia (short trunk) are reported. Their radiological findings are compatible with brachyolmia, Hobaek type, which is characterized by platyspondyly, horizontal acetabular roof, short femoral neck, and vertical "mixed lucent and dense" striation pattern in the metaphyses of large long bones. Despite normal birth weight and length, the platyspondyly is present at infancy, but clinically the condition may not be noticeable until late childhood or early puberty, when stunted growth becomes apparent. Beyond puberty, the patients are short in stature, mainly due to a short trunk with decrease upper and lower body segment ratio. Brachyolmia type Hobaek is a relatively benign condition. It may cause a mild and nonspecific backache that usually is not debilitating. The inheritance mode is apparently autosomal recessive.


Decreased efficacy of the ketamine and scopolamine-induced sustained antidepressant-like effects in rats receiving metformin.
Metformin is the most widely used drug for treating type 2 diabetes mellitus (DM), which frequently co-occurs with depressive disorders. Thus, patients with depression are likely to receive metformin. Metformin activates AMP-activated kinase (AMPK), which inhibits mechanistic target of rapamycin complex 1 (mTORC1) signaling. mTORC1 activation is essential for the antidepressant effects of ketamine and scopolamine. Thus, we hypothesized that metformin may attenuate ketamine- or scopolamine-induced antidepressant efficacies by blocking their mTORC1 activation. We assessed the acute and sustained antidepressant-like actions of ketamine and scopolamine in male Sprague-Dawley rats subjected to the forced swim test with or without metformin pretreatment. The expressions of AMPK, mTORC1, and brain-derived neurotrophic factor (BDNF) in their prefrontal cortex were assessed. Metformin (50 mg/kg) attenuated the sustained, but not acute, antidepressant-like effects of ketamine (10 mg/kg) and scopolamine (25 μg/kg). Although metformin reduced mTORC1 downstream activated P70S6K, it did not significantly alter mTORser2448 activation and even increased BDNF expression. Notably, ketamine, scopolamine, and metformin all exerted significant antidepressant-like actions, as evidenced by increased AMPK phosphorylation and BDNF expression. Metformin-induced attenuation of sustained antidepressant-like effects are not directly dependent on AMPK-deactivated mTORC1. Our results indicate the complexity of interactions between AMPK, BDNF, and mTORC1. Further research, including mechanistic studies, is warranted to comprehensively evaluate the application of metformin in patients receiving mTORC1-based antidepressants.


Naltrexone maintenance for heroin dependence: uptake, attrition and retention.
With naltrexone registered only recently in Australia in 1999, it is important to examine the rate of uptake of naltrexone treatment, early attrition and retention rates during treatment, in order to inform the way naltrexone is used in Australian practice. Of 317 people screened for the study, 97 participants were recruited post-withdrawal from opiates and were inducted to naltrexone after a period of at least 5 days of abstinence. While in treatment, participants received a 50-mg dose of naltrexone daily, with daily dispensing for the first 7 days, and weekly dispensing for the following 11 weeks. For the naltrexone-treated sample as a whole, the rate of uptake of naltrexone treatment was 30%, with 30% retained in treatment for the entire 12-week program. Attrition from treatment was found to be steady throughout the 12 weeks. The authors conclude that further research is required to improve withdrawal and naltrexone induction techniques and to improve medication compliance and treatment retention.


Effects of coronary occlusion duration on reactive hyperemia in conscious dogs and ponies.
Coronary reactive hyperemia duration (RHD) and coronary blood flow debt repayment (BFDR) were compared in conscious dogs and ponies instrumented with coronary artery Doppler flow probes and pneumatic occluders. Additional ponies were instrumented with pacing electrodes. With the use of a Latin square design, eight animals of each species were subjected to a randomized series of nine coronary occlusions ranging from 5 s to 2 min in duration. In both species, postocclusion blood flow velocity rose rapidly and plateaued at similar peak levels relative to control, but in ponies this plateau lasted significantly longer. The interspecies difference in plateau duration increased as a function of coronary occlusion duration (COD). RHD ranged from 19.5 +/- 5.9 to 139.7 +/- 5.9 s in dogs and from 26.6 +/- 9.0 to 395.0 +/- 9.0 s in ponies. The slope of the RHD vs. COD curve was steeper in ponies. BFDR was similar in dogs and ponies at the shortest COD (418.1 +/- 26 vs. 451.4 +/- 58%) but declined in dogs as a function of COD to 232.3 +/- 26%. In ponies, BFDR increased as a function of COD to a maximum of 945.4 +/- 58% with a 60-s occlusion and then declined to 614.3 +/- 58%. RHD was not significantly altered in ponies when heart rate was changed to match that in dogs. Although the underlying basis for these interspecies differences in RHD and BFDR was not determined, the differences were considered to be too large to be explained by animal model differences in coronary conductance, collateral blood flow, or myocardial oxygen consumption.(ABSTRACT TRUNCATED AT 250 WORDS)


Simulations of cochlear-implant speech perception in modulated and unmodulated noise.
Experiment 1 replicated the finding that normal-hearing listeners identify speech better in modulated than in unmodulated noise. This modulated-unmodulated difference ("MUD") has been previously shown to be reduced or absent for cochlear-implant listeners and for normal-hearing listeners presented with noise-vocoded speech. Experiments 2-3 presented normal-hearing listeners with noise-vocoded speech in unmodulated or 16-Hz-square-wave modulated noise, and investigated whether the introduction of simple binaural differences between target and masker could restore the masking release. Stimuli were presented over headphones. When the target and masker were presented to one ear, adding a copy of the masker to the other ear ("diotic configuration") aided performance but did so to a similar degree for modulated and unmodulated maskers, thereby failing to improve the modulation masking release. Presenting an uncorrelated noise to the opposite ear ("dichotic configuration") had no effect, either for modulated or unmodulated maskers, consistent with the improved performance in the diotic configuration being due to interaural decorrelation processing. For noise-vocoded speech, the provision of simple spatial differences did not allow listeners to take greater advantage of the dips present in a modulated masker.


Manipulation of Chain Entanglement and Crystal Networks of Biodegradable Poly(butylene adipate-co-butylene terephthalate) During Film Blowing through the Addition of a Chain Extender: An In Situ Synchrotron Radiation X-ray Scattering Study.
One prerequisite for the large-scale application of biodegradable polymers is the manipulation of macroscopic performances of commercially available biopolymers during processing according to different real service requirements. Herein, the microstructural evolution of poly(butylene adipate-co-butylene terephthalate) (PBAT) modified by chain extender during film blowing was investigated by in situ synchrotron radiation X-ray scattering to unveil the origin of different performances. The chain dynamics difference induced by the chain extender was first characterized by the rheological measurement and 1H Multiple Quantum (MQ) NMR. It shows that the terminal relaxation is significantly slowed down, while the locally segmental dynamics is not apparently changed. With the assistance of the custom-built film blowing apparatus, the microstructure right above the die exit (D = 13-165 mm) was in situ, simultaneously captured by small- and wide-angle scattering (SAXS/WAXS), where four distinct regimes can be defined. Only the PBAT melt signals are found in regime I, whereas the formation of the mesomorphic domains as shown by the SAXS streaks appearing in regime II. The crystal shows up in regime III, where the WAXS signal appears. A dramatic increment of the crystallinity is found in regime III, which contributes to the continuous increasing bubble modulus with the formation of the crystal-based network. Such a crystal-based network is filled with crystals in regime IV, where the diameter of the PBAT bubble remains constant. The addition of the chain extender is found to significantly influence the structural evolution within different regimes. These dynamics and structure information could supply general guidance for bubble stability improvement and modification of macroscopic performances of biodegradable polymer products.


A novel treatment strategy for ovarian cancer based on immunization against zona pellucida protein (ZP) 3.
We tested the principle of treating malignant ovarian tumors by vaccination against their ectopically expressed protein, zona pellucida glycoprotein (ZP) 3, using as the experimental model the granulosa cell tumors that develop in transgenic mice expressing the simian virus 40 T-antigen under the inhibin-α promoter (inhα/Tag). We found high ZP3 expression in granulosa cell tumors of the transgenic mice, in human surface ovarian cancer and granulosa cell lines, and in human granulosa cell tumors and their metastases. Early preventive immunization (between 2 and 5.5 mo of age) of transgenic mice with recombinant human (rh) ZP3 prevented ovarian tumorigenesis, and delayed therapeutic immunization (between 4.5 and 7 mo) reduced weights of existing tumors by 86 and 75%, respectively (P<0.001), compared to vehicle-treated control mice. No objective side effects of the immunizations were observed. Liver metastases were found in nontreated/vehicle-treated controls (n=7/39), but none following active rhZP3 immunizations (n=0/36; P<0.05). Immunization with rhZP3 was highly effective, as demonstrated by the induction of anti-ZP3 antibodies, as well as proliferative responses to the ZP3 antigen. These results signal rhZP3 immunization as a novel strategy to be developed for the immunotherapy of ovarian granulosa cell tumors, as well as for that of other malignancies that may express ZP3.


Computation of NMR shieldings at the CASSCF level using gauge-including atomic orbitals and Cholesky decomposition.
We present an implementation of coupled-perturbed complete active space self-consistent field (CP-CASSCF) theory for the computation of nuclear magnetic resonance chemical shifts using gauge-including atomic orbitals and Cholesky decomposed two-electron integrals. The CP-CASSCF equations are solved using a direct algorithm where the magnetic Hessian matrix-vector product is expressed in terms of one-index transformed quantities. Numerical tests on systems with up to about 1300 basis functions provide information regarding both the computational efficiency and limitations of our implementation.


Polar Indole-3-acetic Acid Diffusion in Nonliving and Model Systems.
Polar indole-3-acetic acid movement was observed in killed plant segments and in artificial model systems. The polar diffusion of indole-3-acetic acid was observed in tissue killed by chemical or physical means in an agar-plant system and in a multicelled Plexiglas dialysis chamber containing hypocotyl tissue gradients or gradients of anion exchange material.It was suggested that polar indole-3-acetic acid movement in excised segments may be a reflection of the diffusion of indole-3-acetic acid through asymmetric gradients of materials with binding characteristics somewhat similar to ion exchange.


The yeast hnRNP-Like proteins Yra1p and Yra2p participate in mRNA export through interaction with Mex67p.
Yra1p is an essential nuclear protein which belongs to the evolutionarily conserved REF (RNA and export factor binding proteins) family of hnRNP-like proteins. Yra1p contributes to mRNA export in vivo and directly interacts with RNA and the shuttling mRNP export receptor Mex67p in vitro. Here we describe a second nonessential Saccharomyces cerevisiae family member, called Yra2p, which is able to complement a YRA1 deletion when overexpressed. Like other REF proteins, Yra1p and Yra2p consist of two highly conserved N- and C-terminal boxes and a central RNP-like RNA-binding domain (RBD). These conserved regions are separated by two more variable regions, N-vr and C-vr. Surprisingly, the deletion of a single conserved box or the deletion of the RBD in Yra1p does not affect viability. Consistently, neither the conserved N and C boxes nor the RBD is required for Mex67p and RNA binding in vitro. Instead, the N-vr and C-vr regions both interact with Mex67p and RNA. We further show that Yra1 deletion mutants which poorly interact with Mex67p in vitro affect the association of Mex67p with mRNP complexes in vivo and are paralleled by poly(A)(+) RNA export defects. These observations support the idea that Yra1p promotes mRNA export by facilitating the recruitment of Mex67p to the mRNP.


Treatment of advanced soft tissue sarcoma with chlorozotocin: a phase II trial of the EORTC soft tissue and bone sarcoma group.
Chlorozotocin, 120 mg/m2 every 4 weeks, was administered to 22 patients with advanced soft tissue sarcoma. All patients had received extensive prior chemotherapy and had measurable progressive disease at the time of entry in the study. No objective responses were observed. The best individual results were in three patients with disease stabilization lasting 2--4 months. Toxic effects included nausea in one half of the patients and sweating episodes in one. One patient developed temporary leukopenia and three had thrombocytopenia that lasted for 3 weeks, 4 weeks, and 4 months. Blood sugar levels were unaffected by the treatment. No renal or hepatic toxicity was recorded.


[Toward a projection of families according to their principal characteristics].
"This article describes the main ingredients of a methodology currently under development for projecting families [in Canada]--these groups of individuals linked by conjugal ties or by blood--according to their principal characteristics: family type and number/ages of children. The crux of this methodology is a multidimensional model which can be viewed as an extension of the traditional cohort-components model that incorporates the conjugal and parity statuses of women. With an appropriate generalization of the conjugal status variable and the addition of an appendage for dealing with the special case of step families, this model eventually allows one to shift from the number of women according to demographic status (stemming from cross-classifying conjugal status and numbers of children present) to those families according to their main characteristics." (SUMMARY IN ENG AND SPA)


Pin sensation as a predictor of extensor carpi radialis recovery in spinal cord injury.
The purpose of this prospective study was to determine if initial preservation of C5 pin sensation could predict extensor carpi radialis (ECR) motor recovery in the zone of partial preservation after spinal cord injury (SCI). The study compared initial C5 pin sensation and initial ECR strength as predictors of ECR motor recovery after C4 and C5 SCI. The initial motor and sensory evaluation was done less than seven days after injury. Motor power was graded from absent (0/5) to normal strength (5/5). Pin sensation was graded as absent (0/2) decreased (1/2) or normal (2/2). The manual muscle test was performed weekly to four weeks and than at three, six, and 12 months after injury. An ECR muscle grade of > or = 3/5 was defined as recovery. C5 pin sensation at the lateral antecubital fossa significantly correlated with ECR recovery to > or = 3/5 (p < 0.001). Only two of nine subjects with absent C5 pin sensation recovered ECR to > or = 3/5, whereas 14 of 15 subjects with 1/2 or 2/2 C5 pin sensation had ECR motor recovery to > or = 3/5. All ten subjects with 1/5 or 2/5 initial ECR strength had ECR motor recovery. Five of six subjects with 0/5 initial ECR strength and subsequent ECR recovery to > or = 3/5 were found to have C5 pin preservation. In conclusion the presence of 1/5 to 2/5 initial ECR strength or 1/2 or 2/2 C5 pin sensation were highly significant predictors of ECR motor recovery to > or = 3/5 in C4 and C5 motor complete quadriplegic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)


Linking empirical estimates of body burden of environmental chemicals and wellness using NHANES data.
Biomonitoring of industrial chemicals in human tissues and fluids has shown that all people carry a "body burden" of synthetic chemicals. Although measurement of an environmental chemical in a person's tissues/fluids is an indication of exposure, it does not necessarily mean the exposure concentration is sufficient to cause an adverse effect. Since humans are exposed to multiple chemicals, there may be a combination effect (e.g., additive, synergistic) associated with low-level exposures to multiple classes of contaminants, which may impact a variety of organ systems. The objective of this research is to link measures of body burden of environmental chemicals and a "holistic" measure of wellness. The approach is demonstrated using biomonitoring data from the National Health and Nutrition Examination Surveys (NHANES). Forty-two chemicals were selected for analysis based on their detection levels. Six biological pathway-specific indices were evaluated using groups of chemicals associated with each pathway. Five of the six pathways were negatively associated with wellness. Three non-zero interaction terms were detected which may provide empirical evidence of crosstalk across pathways. The approach identified five of the 42 chemicals from a variety of classes (metals, pesticides, furans, polycyclic aromatic hydrocarbons) as accounting for 71% of the weight linking body burden to wellness. Significant interactions were detected indicating the effect of smoking is exacerbated by body burden of environmental chemicals. Use of a holistic index on both sides of the exposure-health equation is a novel and promising empirical "systems biology" approach to risk evaluation of complex environmental exposures.


Big picture.
Emma Cowen discusses the excitement of transitioning from healthcare assistant to A&E nurse. She hopes that during her first placement at an emergency department with different responsibilities and a different role, people will start to view her as a nurse.


A New Polar Transfer Alignment Algorithm with the Aid of a Star Sensor and Based on an Adaptive Unscented Kalman Filter.
Because of the harsh polar environment, the master strapdown inertial navigation system (SINS) has low accuracy and the system model information becomes abnormal. In this case, existing polar transfer alignment (TA) algorithms which use the measurement information provided by master SINS would lose their effectiveness. In this paper, a new polar TA algorithm with the aid of a star sensor and based on an adaptive unscented Kalman filter (AUKF) is proposed to deal with the problems. Since the measurement information provided by master SINS is inaccurate, the accurate information provided by the star sensor is chosen as the measurement. With the compensation of lever-arm effect and the model of star sensor, the nonlinear navigation equations are derived. Combined with the attitude matching method, the filter models for polar TA are designed. An AUKF is introduced to solve the abnormal information of system model. Then, the AUKF is used to estimate the states of TA. Results have demonstrated that the performance of the new polar TA algorithm is better than the state-of-the-art polar TA algorithms. Therefore, the new polar TA algorithm proposed in this paper is effectively to ensure and improve the accuracy of TA in the harsh polar environment.


Inhibition of photosynthetic electron transport in isolated spinach chloroplasts by two 1,3,4-thiadiazolyl derivatives.
Buthidazole (3-[5-(1,1-dimethylethyl)-1,3,4-thiadiazol-2-yl]-4-hydroxy-1-methyl-2-imidazolidinone) and tebuthiuron (N-[5-(1,1-dimethylethyl)-1,3,4-thiadiazol-2-yl]-N,N'-dimethylurea) are two new promising herbicides for selective weed control in corn (Zea mays L.) and sugarcane (Saccharum officinarum L.), respectively. The effects of these two compounds on various photochemical reactions of isolated spinach (Spinacia oleracea L.) chloroplasts were studied at concentrations of 0, 0.05, 0.5, 5, and 500 micromolar. Buthidazole and tebuthiuron at concentrations higher than 0.5 micromolar inhibited uncoupled electron transport from water to ferricyanide or to methyl viologen very strongly. Photosystem II-mediated transfer of electrons from water to oxidized diamonodurene, with 2,5-dibromo-3-methyl-6-isopropyl-p-benzoquinone (DBMIB) blocking photosystem I, was inhibited 34 and 37% by buthidazole and tebuthiuron, respectively, at 0.05 micromolar. Inhibition of photosystem I-mediated transfer of electrons from diaminodurene to methyl viologen with 3,4-dichlorophenyl-1,1-dimethylurea (DCMU) blocking photosystem II was insignificant with either herbicide at all concentrations tested. Transfer of electrons from catechol to methyl viologen in hydroxylamine-washed chloroplasts was inhibited 50 and 47% by buthidazole and tebuthiuron, respectively, at 0.5 micromolar. The data indicate that the inhibition of electron transport by both herbicides is primarily at the reducing side of photosystem II. However, since catechol is an electron donor at the oxidizing side of photosystem II, between water and chlorophyll a(680), and lower inhibition levels were observed in the last study (catechol to methyl viologen), it may be that there is also a small inhibition of the mechanism of water oxidation by both herbicides.


Probability of an Obese Person Attaining Normal Body Weight: Cohort Study Using Electronic Health Records.
We examined the probability of an obese person attaining normal body weight. We drew a sample of individuals aged 20 years and older from the United Kingdom's Clinical Practice Research Datalink from 2004 to 2014. We analyzed data for 76,704 obese men and 99,791 obese women. We excluded participants who received bariatric surgery. We estimated the probability of attaining normal weight or 5% reduction in body weight. During a maximum of 9 years' follow-up, 1283 men and 2245 women attained normal body weight. In simple obesity (body mass index = 30.0-34.9 kg/m(2)), the annual probability of attaining normal weight was 1 in 210 for men and 1 in 124 for women, increasing to 1 in 1290 for men and 1 in 677 for women with morbid obesity (body mass index = 40.0-44.9 kg/m(2)). The annual probability of achieving a 5% weight reduction was 1 in 8 for men and 1 in 7 for women with morbid obesity. The probability of attaining normal weight or maintaining weight loss is low. Obesity treatment frameworks grounded in community-based weight management programs may be ineffective.


Living and Leaving Life on One's Own Terms: Certain Legal Rights of Older Adults and Persons with Disabilities.
While attention has been focused on granting equal rights based on race, religion, and gender, the rights of older and disabled persons have been overlooked for many years. Existing laws were of limited scope or were not enforced. However, with the adoption of the Americans with Disabilities Act of 1990, and the recognition and adoption by various states of living wills and related protections, the legal rights of older and disabled persons in attempting to live as normal a life as possible and to deal with serious or terminal illnesses have been greatly expanded. This article provides an overview of existing law in these areas.


Ictal functional TCD for the lateralization of the seizure onset zone--a report of two cases.
Ictal functional transcranial Doppler sonography (I-fTCD) was used to lateralize the ictal onset zone in the presurgical evaluation of two patients with temporal lobe epilepsy. In one patient, I-fTCD and ictal SPECT were performed simultaneously during EEG-monitoring. In both patients, results were concordant with the ictal SPECT findings, PET and semiology. I-fTCD seems to be an interesting new method to non-invasively lateralize the seizure onset zone with high temporal resolution. I-fTCD and SPECT may give complementary information to lateralize the seizure onset zone.


Pharmacoeconomic evaluation of treatments for refractory schizophrenia: clozapine-related studies.
Cost-effectiveness analyses determine whether a new therapy will find a place in clinical practice, based on the cost of its use and the health outcomes it produces, compared with other available therapies. Clozapine, indicated for treatment-resistant schizophrenia, has been evaluated in uncontrolled, mirror-image studies; clinical decision analysis models; and prospective, randomized clinical trials. Results from randomized trials demonstrate that clozapine controls symptoms of psychopathology and improves quality of life slightly more effectively than traditional neuroleptic medications. It has a lower incidence of extrapyramidal side effects than traditional medications, resulting in a lower drop-out rate. Beginning in the second year of treatment, clozapine may produce cost savings for the health care system, when its higher acquisition cost begins to be offset by reduced hospitalization. Mirror-image studies and clinical decision analysis models provide further support for these findings.


Impact of multiple risk factor clustering on the elevation of blood pressure.
A family history of hypertension, obesity, diabetes mellitus, hypercholesterolemia, and hypertriglyceridemia have all been associated with risk of hypertension. We retrospectively conducted a longitudinal study in a large screened cohort to explore the effect of the clustering of these five risk factors on the elevation of blood pressure (BP) in normotensive subjects at baseline. The study group comprised 4,857 normotensive subjects not treated with antihypertensive drugs (systolic BP < 140 mmHg, diastolic BP < 90 mmHg, 3,111 men and 1,746 women) who were followed up from 1997 to 1999. By 1999, 360 subjects had BP at the hypertensive level (systolic BP > or = 140 mmHg or diastolic BP > or = 90 mmHg). The incidence of subjects whose BP became hypertensive was 37 per 1,000 person-years. After adjusting for age, sex, systolic BP and other clinical factors, multiple logistic analysis showed that the relative risk of BP elevation was 1.49 (95% Cl: 1.09 to 2.05) in subjects with one risk factor; 1.65 (95% Cl: 1.15 to 2.27) in those with two risk factors; 1.42 (95% Cl: 0.91 to 2.32) in those with three; and 4.86 (95% Cl: 2.58 to 9.16) in those with four or more when compared with subjects with no risk factors. Multiple regression analysis showed that the number of risk factors was positively correlated with an increase in BP from 1997 to 1999; the regression coefficient was 0.51 (p = 0.001) for increase in systolic BP, and 0.31 (p = 0.008) for increase in diastolic BP after adjusting for age and sex. In conclusion, clustering of risk factors significantly predicted the development of hypertension.


Cutting Edge: A Natural Antisense Transcript, AS-IL1α, Controls Inducible Transcription of the Proinflammatory Cytokine IL-1α.
Natural antisense transcripts (NATs) are a class of long noncoding RNAs (lncRNAs) that are complementary to other protein-coding genes. Although thousands of NATs are encoded by mammalian genomes, their functions in innate immunity are unknown. In this study, we identified and characterized a novel NAT, AS-IL1α, which is partially complementary to IL-1α. Similar to IL-1α, AS-IL1α is expressed at low levels in resting macrophages and is induced following infection with Listeria monocytogenes or stimulation with TLR ligands (Pam3CSK4, LPS, polyinosinic-polycytidylic acid). Inducible expression of IL-1α mRNA and protein were significantly reduced in macrophages expressing shRNA that target AS-IL1α. AS-IL1α is located in the nucleus and did not alter the stability of IL-1α mRNA. Instead, AS-IL1α was required for the recruitment of RNA polymerase II to the IL-1α promoter. In summary, our studies identify AS-IL1α as an important regulator of IL-1α transcription during the innate immune response.


Is rat an appropriate animal model to study the involvement of D-serine catabolism in schizophrenia? Insights from characterization of D-amino acid oxidase.
D-Amino acid oxidase (DAAO; EC18.104.22.168) has been proposed to play a main role in the degradation of D-serine, an allosteric activator of the N-methyl-D-aspartate-type glutamate receptor in the human brain, and to be associated with the onset of schizophrenia. To prevent excessive D-serine degradation, novel drugs for schizophrenia treatment based on DAAO inhibition were designed and tested on rats. However, the properties of rat DAAO are unknown and various in vivo trials have demonstrated the effects of DAAO inhibitors on d-serine concentration in rats. In the present study, rat DAAO was efficiently expressed in Escherichia coli. The recombinant enzyme was purified as an active, 40 kDa monomeric flavoenzyme showing the basic properties of the dehydrogenase-oxidase class of flavoproteins. Rat DAAO differs significantly from the human counterpart because: (a) it possesses a different substrate specificity; (b) it shows a lower kinetic efficiency, mainly as a result of a low substrate affinity; (c) it differs in affinity for the binding of classical inhibitors; (d) it is a stable monomer in the absence of an active site ligand; and (e) it interacts with the mammalian protein modulator pLG72 yielding a ~100 kDa complex in addition to the ~200 kDa one, as formed by the human DAAO. Furthermore, the concentration of endogenous D-serine in U87 glioblastoma cells was not affected by transfection with rat DAAO, whereas it was significantly decreased when expressing the human homologue. These results raise doubt on the use of the rat as a model system for testing new drugs against schizophrenia and indicate a different physiological function of DAAO in rodents and humans.


Self-Reported Antidepressant Drug Side Effects, Medication Adherence, and Its Associated Factors among Patients Diagnosed with Depression at the Psychiatric Hospital of Nepal.
The present study is aimed at evaluating the side effects of antidepressant drugs, medication adherence (MA), and associated factors among patients diagnosed with depression at a psychiatric hospital in western Nepal. A prospective cross-sectional study was conducted among 174 patients visiting the outpatient clinic of a psychiatric hospital. The antidepressant side effect checklist (ASEC) was used to classify the reported antidepressant drug side effects into mild, moderate, and severe types. The Naranjo adverse drug reaction (ADR) probability scale was employed to assess the ADRs, and the Morisky Green Levine Adherence (MGLA) score was employed to determine the rate of medication adherence. Descriptive statistics and bivariate analysis were used, and a P value < 0.05 was taken as statistically significant in the multivariate analysis. The patients were mostly female (55.74%), with a median (IQR) age of 32 (20) years. Approximately 74.13% of the patients experienced antidepressant side effects, where insomnia (17.05%) and anxiety (17.05%) were the most common. More than half of the patients (52.29%) had a low level of adherence. Females were 1.01 times more likely to be nonadherent to their antidepressant medications compared to males, adjusted odds ratio (AOR): 1.001 (0.31-1.63). Similarly, illiterate patients tended to be more nonadherent compared to literates, AOR: 1.342 (0. 93-2.82), and unemployed individuals were 1.5 times more likely to be nonadherent to their medications compared to employed individuals, AOR: 1.46 (1.16-4.13). Likewise, patients with severe side effects were more prone to develop nonadherence than those with moderate side effects, AOR: 1.173 (0.42-3.25). A significant association was found between the Naranjo score and medication adherence. This study suggests that antidepressant drug side effects were more prevalent and medication adherence was extremely poor among depressive patients in psychiatric hospitals. Factors such as gender, occupation, education, side effects, and ADRs attributed to poor medication adherence in patients.


Complex colon polypectomy.
By interrupting the adenoma-carcinoma sequence, endo-scopic polypectomy can prevent the development of colorectal cancer (CRC). Endoscopic polypectomy has, therefore, become an accepted screening and surveillance modality for CRC and has been widely adopted by clinicians, policymakers, and professional organizations as an effective screening tool. Most gastroenterologists are adequately trained to endoscopically excise the majority of polyps found in a routine colonoscopy. However, some polyps, due to their size, location, or configuration, are considered more technically challenging or are associated with an increased risk of complications (such as bleeding or perforation) and, hence, are not routinely resected. These so-called complex polypectomies are the focus of this paper.


STATE OBLIGATIONS IN PROVISION OF THE PRIMARY PHYSICIAN'S RIGHT TO MEDICAL PRACTICE AS ENTREPRENEURSHIP IN LIGHT OF TRANSFORMATION OF THE HEALTH CARE SYSTEM IN UKRAINE.
In the article issues of state obligations to ensure the right of a doctor- entrepreneur providing primary medical care to such a type of business activity in the healthcare sector as general medical practice are under study. The attention is focused on the fact that the relevance of the research of this issue is challenged by the lack of comprehensive theoretical investigations, as well as practical necessity in the light of the transformation of the healthcare system of Ukraine. Attention is drawn to the fact that in 2018 the National Health Service of Ukraine was established as the central executive body. The having existed model for paying for every single place in the hospital in Ukraine is being replaced by a new model for financing the health system. The National Health Service of Ukraine being the Budget distributor implements basic principle of the medical reform "money goes after the patient". The commanding-administrative model of relations has been replaced by a contractual one: The National Health Service of Ukraine pays for the provision of guaranteed package of primary medical care services along with medical institutions and doctors as individual-entrepreneurs having become partners of the Service. The purpose of the article is to identify the obligations of the state to ensure the right of a doctor being individual-entrepreneur providing primary medical care to carry out such a type of business activity in the healthcare sector as general medical practice in the light of the transformation of the Ukrainian healthcare system. The object of the study is social relations that arise when the state ensures the right of doctors-entrepreneurs providing primary medical care. The methodological basis of the study is the general and special methods of scientific knowledge (formal logical method, comparative legal, structural logical). The system of obligations of the state to ensure the right of doctors-entrepreneurs having become partners of the National Health Service of Ukraine carrying out such a type of business activity in the healthcare sector as general medical practice is determined. The legal and organizational mechanisms for ensuring this right are analyzed. The assessment of their effectiveness is given. Attention is paid on the practice of the European Court of Human Rights, which is the source of law for member-states of the European Council. The concepts of "legitimate anticipation" or "legitimate expectation" are analyzed, which often relate to government payments that depend on economic and social policies in each sphere. It is argued that the doctor-entrepreneur having become a partner of the Service, has a "legal anticipation" so that funds should be transferred to his bank account on the basis of declarations signed with patients to provide them with a package of primary medical care services guaranteed to these patients. The state is obliged to provide such payments. If payments fail to be provided, the county's economic, social, or health policy cannot be an excuse for the state.


Electronic medical records in diabetes consultations: participants' gaze as an interactional resource.
Two routine consultations in primary care diabetes clinics are compared using extracts from video recordings of interactions between nurses and patients. The consultations were chosen to present different styles of interaction, in which the nurse's gaze was either primarily toward the computer screen or directed more toward the patient. Using conversation analysis, the ways in which nurses shift both gaze and body orientation between the computer screen and patient to influence the style, pace, content, and structure of the consultation were investigated. By examining the effects of different levels of engagement between the electronic medical record and the embodied patient in the consultation room, we argue for the need to consider the contingent nature of the interface of technology and the person in the consultation. Policy initiatives designed to deliver what is considered best-evidenced practice are modified in the micro context of the interactions of the consultation.


Androgens and the development of the vagina.
Today it is generally held that the vagina develops from sinovaginal bulbs and that the lower third of the definitive vagina is derived from the urogenital sinus. Here we show that the entire vagina arises by downward growth of Wolffian and Müllerian ducts, that the sinovaginal bulbs are in fact the caudal ends of the Wolffian ducts, and that vaginal development is under negative control of androgens. We designed a genetic experiment in which the androgen receptor defect in the Tfm mouse was used to examine the effects of androgens. Vaginal development was studied by 3D reconstruction in androgen-treated female embryos and in complete androgen-insensitive littermates. In androgen-treated females, descent of the genital ducts was inhibited, and a vagina formed in androgen-insensitive Tfm embryos as it does in normal females. By immmunohistochemical localization of the androgen receptor in normal mouse embryos, we demonstrated that the androgen receptor was expressed in Wolffian duct and urogenital sinus-derived structures, and was entirely absent in the Müllerian duct derivatives. We conclude that the Wolffian ducts are instrumental in conveying the negative control by androgens on vaginal development. The results are discussed under evolutionary aspects at the transition from marsupial to eutherian mammals.


Aprepitant, an antiemetic agent, interferes with metal ion homeostasis of Candida auris and displays potent synergistic interactions with azole drugs.
With the rapid increase in the frequency of azole-resistant species, combination therapy appears to be a promising tool to augment the antifungal activity of azole drugs against resistant Candida species. Here, we report the effect of aprepitant, an antiemetic agent, on the antifungal activities of azole drugs against the multidrug-resistant Candida auris. Aprepitant reduced the minimum inhibitory concentration (MIC) of itraconazole in vitro, by up to eight-folds. Additionally, the aprepitant/itraconazole combination interfered significantly with the biofilm-forming ability of C. auris by 95 ± 0.13%, and significantly disrupted mature biofilms by 52 ± 0.83%, relative to the untreated control. In a Caenorhabditis elegans infection model, the aprepitant/itraconazole combination significantly prolonged the survival of infected nematodes by ~90% (five days post-infection) and reduced the fungal burden by ~92% relative to the untreated control. Further, this novel drug combination displayed broad-spectrum synergistic interactions against other medically important Candida species such as C. albicans, C. krusei, C. tropicalis, and C. parapsilosis (ƩFICI ranged from 0.08 to 0.31). Comparative transcriptomic profiling and mechanistic studies indicated aprepitant/itraconazole interferes significantly with metal ion homeostasis and compromises the ROS detoxification ability of C. auris. This study presents aprepitant as a novel, potent, and broad-spectrum azole chemosensitizing agent that warrants further investigation.


RadiO: a prototype application ontology for radiology reporting tasks.
We introduce RadiO, a prototype application ontology for the support of electronic radiology reporting. This application ontology is implemented in Protégé and comprises three layers: 1. a radiology report layer, capturing observations made on patient examinations through the use of a controlled vocabulary of the radiographic imaging domain (RadLex), 2. an imaging domain ontology, representing knowledge about image entities and their image features, and 3. a reference ontology for anatomy (Foundational Model of Anatomy), representing canonical anatomical knowledge. The aim of this prototype is to support the identification of image features of image entities and their use in diagnostic interpretations, as well as to provide a basis for structured reporting applications in the domain of medical imaging.


Dentists' perception of the role they play in early detection of oral cancer.
Dentists are typically the first professionals who are approached to treat ailments within the oral cavity. Therefore they should be well-equipped in detecting suspicious lesions during routine clinical practice. This study determined the levels of knowledge on early signs and risk factors associated with oral cancer and identified which factors influenced dentist participation in prevention and early detection of oral cancer. A survey on dentists' knowledge and their practices in prevention and early detection of oral cancer was conducted using a 26-item self-administered questionnaire. A response rate of 41.7% was achieved. The level of knowledge on early signs and risk habits associated with oral cancer was high and the majority reported to have conducted opportunistic screening and advised patients on risk habit cessation. Factors that influenced the dentist in practising prevention and early detection of oral cancer were continuous education on oral cancer, age, nature of practice and recent graduation. Notably, dentists were receptive to further training in the area of oral cancer detection and cessation of risk habits. Taken together, the study demonstrated that the dental clinic is a good avenue to conduct programs on opportunistic screening, and continuous education in these areas is necessary to adequately equip dentists in running these programs. Further, this study also highlighted knowledge deficits and practice shortcomings which will help in planning and developing programs that further encourage better participation of dentists in prevention and early detection of oral cancer.


Treatment of esophageal carcinoma.
Cancer of the esophagus and gastroesophageal junction remains a virulent malignancy with an overall poor prognosis. Especially in the Western hemisphere, the incidence of adenocarcinoma is sharply rising. Over the last two decades, surgery has become the mainstay of treatment. Decreased surgical mortality and standardization of oncologic principles focusing on the completeness of resection are believed to be responsible for the improved 5-year survival rates, which are reaching > or = 30%. Until now, there has been no proven benefit from combined neoadjuvant treatment modalities using chemotherapy or chemoradiotherapy except for the subset of patients showing a complete response at pathologic examination. Further research should focus on new chemotherapeutic agents and the development of molecular markers that allow better identification of candidates for multimodality regimens.


Effect of serum and growth factors on chondrogenic differentiation of synovium-derived stromal cells.
We used fetal bovine serum (FBS) and different growth factors to investigate their potential for inducing chondrogenic differentiation of synovium-derived stromal cells. Human synovium was harvested from patients suffering from osteoarthritis and expanded in monolayer. To evaluate the effect of serum and growth factors on chondrogenic differentiation, 10 ng/mL of transforming growth factor-beta1 (TGF-beta1), 100 ng/mL of bone morphogenic protein-2 (BMP-2), 100 ng/mL of insulin-like growth factor-1, 20 ng/mL of basic fibroblast growth factor (bFGF), and 10% FBS were added to the chemically defined chondrogenic medium singly or in combination during pellet culture for 21 days. The cell size and weight, glycosaminoglycan content, histology, and cartilage matrix-associated genes expression were analyzed. TGF-beta1 alone and TGF-beta1 + BMP-2 induced chondrogenic differentiation of synovium-derived stromal cells and synthesized cartilage-like matrix confirmed by histological analysis and immunohistochemistry. FBS, BMP-2, insulin-like growth factor-1, and bFGF as a single factor or other combinations except for TGF-beta1 + BMP-2 hardly induced chondrogenesis. Chondrogenic differentiation appeared to be inhibited when bFGF or the serum was added to the chondrogenic medium during pellet culture. The results of this study demonstrate the negative or positive role of serum and growth factors on chondrogenic differentiation of synovium-derived stromal cells.


Atypical fibroxanthoma with regional lymph node metastasis: report of a case and review of the literature.
Atypical fibroxanthoma (AFX) is a low-grade sarcoma usually occurring on sun-damaged skin of the head and neck in elderly patients. Metastatic disease has been reported very rarely. The potential aggressiveness of AFX is controversial. We describe herein a patient who developed metastatic disease in cervical lymph nodes. Our patient was an 87-year-old man with a 7-week history of a rapidly growing AFX presenting as a 1.5-cm sessile nodule on his right mandible. Two months following excision, the patient developed cervical lymphadenopathy. Histopathologic analysis of the cervical lymph nodes revealed spindle-cell tumors with histologic characteristics identical to those of the primary AFX, and the tumors were immunonegative for cytokeratin MNF-116 and S-100. In addition, we review and analyze cases from the literature and articles related to immunohistochemical stains used to diagnose AFX. Atypical fibroxanthoma is a diagnosis of exclusion, and only a small number of metastatic AFX cases have been reported. A review of the literature pertaining to immunohistochemical stains suggests the potential benefit of use of CD10, procollagen I, CD99, CD117, p63, and LN-2 in differentiating AFX from other spindle-cell tumors. The metastatic potential of AFX may not be fully appreciated, and clinicians should be reminded of its potential aggressive behavior.


Surgonomics of unruptured intracranial aneurysms.
A comparison of reimbursement for endovascular coil embolization and surgical clipping of unruptured aneurysms has not been previously reported. The aim of this study is to assess the reimbursement to physicians and hospitals for each of these two unruptured aneurysm treatments with long-term follow-up. Hospital and physician payents were determined for 14 patients treated with coil embolization or surgical clipping of a single unruptured aneurysm per patient from 2004 to 2005, retrospectively. For this analysis, each considered hospital and physician payment encompassed one clipping or coiling procedure plus all pre- and post-operative diagnostic angiograms performed through 2007 to evaluate the treated aneurysm. Reimbursements were analyzed in three categories: physician payments, hospital payments and total payments. Average physician payments were significantly lower for coil embolization ($3422) than surgical clipping ($5645). Average length of stay after coil embolization was 2.6 days (range: 1-7) and after surgical clipping was 4.7 days (range: 2-11). The length of hospital stay directly affected hospital and total payments only, but was not significantly altered by which procedure was performed. This study suggests that physician payment for an unruptured aneurysm coil embolization treatment was statistically lower than for a surgical clip treatment. Although physicians were compensated at a lower rate for performing a coil embolization, there was no significant difference in the hospital or total payments between coil or clip treatment modalities.


Cloning and Sequence Analysis of the Chitinase Gene of Spodoptera litura Nuclear Polyhedrosis Virus.
Using AcMNPV chiA-containing fragment as a probe, the chitinase gene of Spodoptera litura nuclear polyhedrosis virus (SpltNPV) was localized in two contiguous fragments, XbaI 5.1 kb and 2.1 kb, and the intact SpltNPV chiA gene was obtained by cloning and sequencing those two fragments. The complete open reading frame of the gene was 1 695 nucleotide long, encoding a putative protein of 564 amino acids with molecular weight of 62.9 kD. Sequence analysis further revealed that the 5' noncoding region had a baculovirus late promoter motif TAAG. A polyadenylation signal, AATAAA, was located dowmnstream of the translation stop codon. A putative signal peptide was present at the N-terminus of the protein. This gene shares 57% homology with AcMNPV chitinase gene.


Effect of MgO Underlying Layer on the Growth of GaOx Tunnel Barrier in Epitaxial Fe/GaOx/(MgO)/Fe Magnetic Tunnel Junction Structure.
We investigated the effect of a thin MgO underlying layer (~3 monoatomic layers) on the growth of GaOx tunnel barrier in Fe/GaOx/(MgO)/Fe(001) magnetic tunnel junctions. To obtain a single-crystalline barrier, an in situ annealing was conducted with the temperature being raised up to 500 °C under an O₂ atmosphere. This annealing was performed after the deposition of the GaOx on the Fe(001) bottom electrode with or without the MgO(001) underlying layer. Reflection high-energy electron diffraction patterns after the annealing indicated the formation of a single-crystalline layer regardless of with or without the MgO layer. Ex situ structural studies such as transmission electron microscopy revealed that the GaOx grown on the MgO underlying layer has a cubic MgAl₂O₄-type spinel structure with a (001) orientation. When without MgO layer, however, a Ga-Fe-O ternary compound having the same crystal structure and orientation as the crystalline GaOx was observed. The results indicate that the MgO underlying layer effectively prevents the Fe bottom electrode from oxidation during the annealing process. Tunneling magneto-resistance effect was observed only for the sample with the MgO underlying layer, suggesting that Ga-Fe-O layer is not an effective tunnel-barrier.


Surgical management of tibial plateau fractures.
From 1992 to 1996, 49 patients with 49 tibial plateau fractures underwent operative treatment at the First Orthopaedic Department of the General Hospital of Athens. There were 3 type I fractures, 12 type II, 5 type III, 9 type IV, 5 type V and 15 type VI according to Schatzker's classification. 7 of the type VI fractures were open (5 grade II and 2 grade IIIA). All fractures were managed with open reduction and internal fixation and were followed to complete healing which averaged 4 months. 28 patients had excellent results, 13 good, 6 fair and 2 poor results. The fair and poor results were in polytrauma patients and in patients with open (grade II and grade IIIA) type VI fractures. Open reduction and internal fixation, when not strongly contraindicated, was found to be the preferred treatment in displaced tibial plateau fractures.


Laparoscopic endoluminal gastric surgery.
Laparoscopic endogastric surgery is a novel surgical approach that introduces the viewing laparoscope and instruments into the gastric lumen. The excellent visualization, improved instrument handling and versatility afforded by this technique enable local resection of mucosal lesions that are beyond the scope of peroral endoscopy. The authors describe this particular approach for the excision of gastric villous adenoma and early gastric cancer.


Assessing the roles of endogenous retrovirus EAV-HP in avian leukosis virus subgroup J emergence and tolerance.
Avian leukosis virus (ALV) subgroup J is thought to have emerged through a recombination event between an unknown exogenous ALV and the endogenous retrovirus elements designated EAV-HP. All EAV-HP elements identified to date in the chicken genome show large deletions, including that of the entire pol gene. Here we report the identification of four segregating chicken EAV-HP proviruses with complete pol genes, one of which shows exceptionally high sequence identity and a close phylogenetic relationship with ALV-J with respect to the env gene. Embryonic expression of EAV-HP env has been suggested as a factor associated with immunological tolerance induction in a proportion of ALV-J-infected meat-type chickens. In support of this, env gene transcripts expressed from two of the four newly identified EAV-HP proviruses were demonstrated in chicken embryos. However, when ALV-J-infected outbred meat-type chickens were assessed, the presence of intact EAV-HP proviruses failed to directly correlate with ALV-J tolerance. This association was further examined using F(2) progeny of two inbred lines of layer chicken that differed in EAV-HP status and immunological responses to ALV-J. Immunological tolerance developed in a small proportion of F(2) progeny birds, reflecting the expected phenotypic ratio for inheritance of a double-recessive genotype; however, the status of tolerance did not show any direct correlation with the presence of the intact EAV-HP sequence. Nevertheless, identification of an intact chicken EAV-HP locus showing a uniquely close relationship to the ALV-J prototype clone HPRS-103 in the env region provides the strongest evidence of its contribution to the emergence of ALV-J by recombination.


Network regulation of the immune response: modulation of suppressor lymphocytes by alternative signals including contrasuppression.
In the preceding paper we demonstrated that comparison of alternative designs for the immune network can be used to examine the functional significance of specified interactions in normal immune responses. In this paper we examine mathematically the functional significance of three interactions affecting the production of suppressor lymphocytes involved in regulation of normal immune responses. The interactions examined in detail are 1) antigenic stimulation of the production of suppressor lymphocytes, 2) idiotypic stimulation of the production of suppressor lymphocytes, and 3) antigenic inhibition of the production of suppressor lymphocytes (i.e., contrasuppression). The results of our analysis suggest that an immune system with only antigenic stimulation of suppressor production is less effective than a system with both antigenic and idiotypic stimulation of suppressor production on the basis of all of the criteria examined in this study. In turn, the latter system is less effective than a system with only idiotypic stimulation of suppressor production. Furthermore, a system with both idiotypic stimulation and antigenic inhibition of suppressor production can be equal or superior to a system with only idiotypic stimulation of suppressor production on the basis of the same criteria. Similar conclusions hold for the comparison of systems in which regulation by the suppressor lymphocytes of interest is exerted upon production of effector molecules rather than upon production of effector lymphocytes, and also for the comparison of systems in which interactions affecting the production of suppressor factors are of interest.


The use of the zebrafish model in stress research.
The study of the causes and mechanisms underlying psychiatric disorders requires the use of non-human models for the test of scientific hypotheses as well as for use in pre-clinical drug screening and discovery. This review argues in favor of the use of zebrafish as a novel animal model to study the impact of early (stressful) experiences on the development of differential stress phenotypes in later life. This phenomenon is evolutionary conserved among several vertebrate species and has relevance to the etiology of psychiatric disorders. Why do we need novel animal models? Although significant progress has been achieved with the use of traditional mammalian models, there are major pitfalls associated with their use that impedes progress on two major fronts: 1) uncovering of the molecular mechanisms underlying aspects of compromised (stress-exposed) brain development relevant to the etiology of psychiatric disorders, and 2) ability to develop high-throughput technology for drug discovery in the field of psychiatry. The zebrafish model helps resolve these issues. Here we present a conceptual framework for the use of zebrafish in stress research and psychiatry by addressing three specific domains of application: 1) stress research, 2) human disease mechanisms, and 3) drug discovery. We also present novel methodologies associated with the development of the zebrafish stress model and discuss how such methodologies can contribute to remove the main bottleneck in the field of drug discovery.


[Immature stages of Caligo illioneus illioneus (Cramer) (Nymphalidae: Morphinae: Brassolini)].
The biology and external morphology of the immature stages of Caligo illioneus illioneus (Cramer) are described from ovipositions collected on leaves of Heliconia velloziana (Heliconiaceae) in the Atlantic Forest in Pernambuco state, Brazil.


Pseudomonas aeruginosa: study of antibiotic resistance and molecular typing in hospital infection cases in a neonatal intensive care unit from Rio de Janeiro City, Brazil.
This study had the objective of to analyze the demographic and bacteriologic data of 32 hospitalized newborns in an neonatal intensive care unit of a public maternity hospital in Rio de Janeiro city, Brazil, seized by Pseudomonas aeruginosa sepsis during a period ranged from July 1997 to July 1999, and to determine the antimicrobial resistance percentage, serotypes and pulsed field gel electrophoresis (PFGE) patterns of 32 strains isolated during this period. The study group presented mean age of 12.5 days, with higher prevalence of hospital infection in males (59.4%) and vaginal delivery (81.2%), than females (40.6%) and cesarean delivery (18.8%), respectively. In this group, 20 (62.5%) patients received antimicrobials before positive blood cultures presentation. A total of 87.5% of the patients were premature, 62.5% presented very low birth weight and 40.6% had asphyxia. We detected high antimicrobial resistance percentage to b-lactams, chloramphenicol, trimethoprim/sulfamethoxazole and tetracycline among the isolated strains. All isolated strains were classified as multi-drug resistant. Most strains presented serotype O11 while PFGE analysis revealed seven distinct clones with isolation predominance of a single clone (75%) isolated from July 1997 to June 1998.


BMP-6 in renal cell carcinoma promotes tumor proliferation through IL-10-dependent M2 polarization of tumor-associated macrophages.
Dysregulated bone morphogenetic proteins (BMP) may contribute to the development and progression of renal cell carcinoma (RCC). Herein, we report that BMP-6 promotes the growth of RCC by interleukin (IL)-10-mediated M2 polarization of tumor-associated macrophages (TAM). BMP-6-mediated IL-10 expression in macrophages required Smad5 and STAT3. In human RCC specimens, the three-marker signature BMP-6/IL-10/CD68 was associated with a poor prognosis. Furthermore, patients with elevated IL-10 serum levels had worse outcome after surgery. Together, our results suggest that BMP-6/macrophage/IL-10 regulates M2 polarization of TAMs in RCC.


The effect of intra-arterial endothelin on resting blood flow and sympathetically mediated vasoconstriction in the forearm of man.
1. The hypothesis that endothelin (ET) influences sympathetically mediated vasoconstriction was investigated in 13 healthy, male subjects. 2. ET (1 pmol min-1) was infused for 60 min into the left brachial arteries of seven healthy male subjects. Resting forearm blood flow, and sympathetic vasoconstriction produced by lower body negative pressure (LBNP; 15 mm Hg), was measured in both arms by strain gauge plethysmography. In a further six subjects, noradrenaline (NA) was infused intra-arterially at doses of 150-600 pmol min-1, with and without co-infusion of ET (1 pmol min-1), with blood flow measured in both forearms. 3. ET produced a small but significant reduction of blood flow in the infused forearm from 3.9 +/- 0.6 ml 100 ml-1 min-1 during infusion of saline, to 3.3 +/- 0.7 ml 100 ml-1 min-1 during infusion of ET at 60 min (P less than 0.05). Blood flow in the non-infused forearm was not altered by ET infusion. 4. NA produced a significant and dose-dependent reduction of blood flow in the infused forearm from 3.13 +/- 0.5 ml 100 ml-1 min-1 during saline infusion, to 1.49 +/- 0.2 ml 100 ml-1 min-1 with NA at 600 pmol min-1 (P less than 0.001). During co-infusion of ET, blood flow was reduced similarly in the infused arm from 3.15 +/- 0.7 ml 100 ml-1 min-1 during saline infusion to 1.55 +/- 0.2 ml 100 ml-1 min-1 with NA at 600 pmol min-1. Blood flow in the non-infused arm was not altered by ET and NA infusion.(ABSTRACT TRUNCATED AT 250 WORDS)


Evolution of clutch size in cavity-excavating birds: the nest site limitation hypothesis revisited.
There are two major competing hypotheses for variation in clutch size among cavity-nesting species. The nest site limitation hypothesis postulates that nesting opportunities are more limited for weak excavators, which consequently invest more in each breeding attempt by laying larger clutches. Alternatively, clutch size may be determined by diet; the clutch sizes of strong excavators may be smaller because they are able to specialize on a more seasonally stable prey. We built a conceptual model that integrated hypotheses for interspecific variation in clutch size and tested it with comparative data on life-history traits of woodpeckers (Picidae) and nuthatches (Sittidae). In most analyses, diet explained more variation in clutch size among species than did propensity to excavate. Migratory status was positively associated with clutch size but was difficult to distinguish from diet since resident species consumed more bark beetles (a prey available in winter) and had smaller clutches than migratory species. The literature suggests that cavities are not limited in natural, old-growth forests. Although our data do not rule out nest site limitation, we conclude that annual stability of food resources has a larger impact on the evolution of clutch sizes in excavators than does limitation of nest sites.


Transport of L-proline and alpha-methyl-D-glucoside by chicken proximal cecum during development.
We examined the characteristics of amino acid and sugar absorption by the proximal cecum (PC) of chickens during posthatch development. Rates of absorption of L-proline (Pro) and alpha-methyl-D-glucoside (MG) were measured at 2 days, 5 wk, and 13 wk after hatch with an in vitro everted-sleeve method. For each age, pieces of PC and midjejunum were incubated in solutions containing 0.1-50 mM Pro or MG, and the active and passive components of Pro and MG absorption were determined. Five conclusions may be stated. 1) There are two carrier-mediated transport systems for Pro in the PC: a higher capacity Na(+)-dependent system (Vmax between 1.6 and 3.2 nmol.mg-1.min-1), and a lower capacity Na(+)-independent system (Vmax 0.3-0.8 nmol.mg-1.min-1). 2) Whereas both Pro transport systems are present in the PC at 5 and 13 wk, only the Na(+)-dependent system was found at 2 days. Although rates of transport per milligram tissue by the Na(+)-dependent system fell during development, when rates were normalized to nominal surface area, Vmax was significantly higher in the 5-wk-old group than in the other groups. 3) MG transport is by a Na(+)-dependent system. Vmax values (nmol.mg-1.min-1) were 0.32 (2 days), less than 0.43 (5 wk), and = 0.55 (13 wk). These differences were not affected by normalization to surface area. 4) Because at physiological concentrations passive influx of Pro and MG would be negligible, absorption of amino acids and sugars by the PC would be dependent on the presence of carrier-mediated systems.(ABSTRACT TRUNCATED AT 250 WORDS)


Heat shock induced changes of plant cell ultrastructure and autoradiographic localization of heat shock proteins.
Treating tomato cell cultures and leaves by a physiological heat shock (hs) at 35 to 39 degrees C results in a progressive disintegration of the nucleolus and the assembly of cytoplasmic hs granules. Other ultrastructural changes are not observed. The alterations of the nucleoli coincide with an immediate stop of the processing and with a strongly decreased synthesis of pre-rRNA. Both hs effects are reversed after shift-down to normal temperature conditions (25 degrees C). Assembly of cytoplasmic hs granules depends on the accumulation of the newly forming hs proteins and on supraoptimal temperatures. It is not observed in preinduced cultures synthesizing hs proteins at 25 degrees C. Autoradiographic studies reveal the preferential accumulation of hsp in the nucleoli and hs granules. Furthermore uridine labeling points to the presence of RNA in electron dense particles of both subcellular components. A survey on the state of hsp synthesis and structural binding as well as on the ultrastructural changes is given for 12 selected hs regimes.


Microwave hyperthermia for choroidal melanoma in rabbits.
Radiation has provided excellent local control rates in choroidal melanoma, but significant impairment in visual acuity has occurred in 30-60% of patients due in part to the development of radiation vasculopathy in the fovea and optic disc. Hyperthermia has been shown to have a synergistic effect when added to radiation therapy in human malignancies. The use of hyperthermia in ocular melanoma may allow a reduction in the total radiation dose necessary to achieve local control. A 2450-MHz microwave plaque applicator with integral surface cooling was used to deliver hyperthermia treatments to rabbit eyes containing choroidal melanomas. Extensive thermal mapping was done in acute eyes. In 18 survival animals, a single 23-G needle thermocouple probe with three sensors was inserted into the tumor. Target temperatures of 41.0-46.0 degrees C were maintained for 1 hour. All tumor-bearing eyes were followed for 1 month after treatment, or until tumor growth was noted, with serial ultrasound measurements and visual examinations. A 92% response rate was obtained in tumors treated at temperatures greater than 43.0 degrees C for 1 hour with no significant toxicity. Heat alone has significant tumoricidal properties in this animal model.


Reinjection of autologous fat in moderately deep upper lid sulci of anophthalmic sockets.
The purpose of this paper is to present the author 's experience with the transplantation of autologous adipose tissue into the moderately deep upper lid sulci of anophthalmic sockets. Coleman's lipostructuring technique may help oculoplastic surgeons with patients requiring cosmetic improvements; however, reinjection of autologous fat can be done only if it is known that the intra-orbital implant is of a suitable size and that there are no orbital volume deficits. In this study, the patient's own adipose tissue is harvested by the technique of liposuction by syringe, without trauma, and then refined and reinjected in an intricate layering of fat tissue via microcannulae. The author describes the technique and results after one year of follow-up.


Definition of the lectin-like properties of the molecular chaperone, calreticulin, and demonstration of its copurification with endomannosidase from rat liver Golgi.
Calreticulin was identified by immunochemical and sequence analyses to be the higher molecular mass (60 kDa) component of the polypeptide doublet previously observed in a rat liver Golgi endomannosidase preparation obtained by chromatography on a Glc alpha 1 --> 3Man-containing matrix. The affinity for this saccharide ligand, which paralleled that of endomannosidase and was also observed with purified rat liver calreticulin, suggested that this chaperone has lectin-like binding properties. Studies carried out with immobilized calreticulin and a series of radiolabeled oligosaccharides derived from N-linked carbohydrate units revealed that interactions with this protein were limited to monoglucosylated polymannose components. Although optimal binding occurred with Glc1Man9GlcNAc, substantial interaction with calreticulin was retained after sequential trimming of the polymannose portion down to the Glc1Man5GlcNAc stage. The alpha 1 --> 6-mannose branch point of the oligosaccharide core, however, appeared to be essential for recognition as Glc1Man4GlcNAc did not interact with the calreticulin. The carbohydrate-peptide linkage region had no discernible influence on binding as monoglucosylated oligosaccharides in N-glycosidic linkage interacted with the chaperone to the same extent as in their unconjugated state. The immobilized calreticulin proved to be a highly effective tool for sorting out monoglucosylated polymannose oligosaccharides or glycopeptides from complex mixtures of processing intermediates. The copurification of calreticulin and endomannosidase from a Golgi fraction in comparable amounts and the strikingly similar saccharide specificities of the chaperone and the processing enzyme have suggested a tentative model for the dissociation through glucose removal of calreticulin-glycoprotein complexes in a post-endoplasmic reticulum locale; in this scheme, deglucosylation would be brought about by the action of endomannosidase rather than glucosidase II.


Buffering hypercapnic acidosis worsens acute lung injury.
Hypoventilation, associated with hypercapnic acidosis (HCA), may improve outcome in acute lung injury (ALI). We have recently reported that HCA per se protects against ALI. The current study explored whether the mechanisms of protection with HCA were related to acidosis versus hypercapnia. Because CO(2) equilibrates rapidly across cell membranes, we hypothesized that (1) HCA would afford greater protection than metabolic acidosis. We further hypothesized that (2) buffering HCA would attenuate its protection. Forty isolated perfused rabbit lung preparations were randomized to: control (normal pH, PCO(2)); HCA; metabolic acidosis; or buffered hypercapnia. After ischemia-reperfusion (IR) injury wet:dry ratio was greatest with control and buffered hypercapnia, and rank order of capillary filtration coefficient was: control approximately buffered hypercapnia > metabolic acidosis > HCA. Isogravimetric pressure reduction was greatest with buffered hypercapnia. Despite comparable injury, pulmonary artery pressure elevation was less with buffered hypercapnia versus control. In vitro xanthine oxidase (XO) activity depended on pH, not PCO(2). We conclude that: (1) HCA and metabolic acidosis are protective, but HCA is the most protective; (2) buffering HCA attenuates its protection; (3) buffering HCA causes pulmonary vasodilation; (4) because metabolic acidosis and HCA similarly inhibit in vitro XO activity, the differential effects cannot be explained solely on the basis of extracellular XO activity.


HFE p.H63D polymorphism does not influence ALS phenotype and survival.
It has been recently reported that the p.His63Asp polymorphism of the HFE gene accelerates disease progression both in the SOD1 transgenic mouse and in amyotrophic lateral sclerosis (ALS) patients. We have evaluated the effect of HFE p.His63Asp polymorphism on the phenotype in 1351 Italian ALS patients (232 of Sardinian ancestry). Patients were genotyped for the HFE p.His63Asp polymorphism (CC, GC, and GG). All patients were also assessed for C9ORF72, TARDBP, SOD1, and FUS mutations. Of the 1351 ALS patients, 363 (29.2%) were heterozygous (GC) for the p.His63Asp polymorphism and 30 (2.2%) were homozygous for the minor allele (GG). Patients with CC, GC, and GG polymorphisms did not significantly differ by age at onset, site of onset of symptoms, and survival; however, in SOD1 patients with CG or GG polymorphism had a significantly longer survival than those with a CC polymorphism. Differently from what observed in the mouse model of ALS, the HFE p.His63Asp polymorphism has no effect on ALS phenotype in this large series of Italian ALS patients.


Structural basis for certain naturally occurring bioflavonoids to function as reducing co-substrates of cyclooxygenase I and II.
Recent studies showed that some of the dietary bioflavonoids can strongly stimulate the catalytic activity of cyclooxygenase (COX) I and II in vitro and in vivo, presumably by facilitating enzyme re-activation. In this study, we sought to understand the structural basis of COX activation by these dietary compounds. A combination of molecular modeling studies, biochemical analysis and site-directed mutagenesis assay was used as research tools. Three-dimensional quantitative structure-activity relationship analysis (QSAR/CoMFA) predicted that the ability of bioflavonoids to activate COX I and II depends heavily on their B-ring structure, a moiety known to be associated with strong antioxidant ability. Using the homology modeling and docking approaches, we identified the peroxidase active site of COX I and II as the binding site for bioflavonoids. Upon binding to this site, bioflavonoid can directly interact with hematin of the COX enzyme and facilitate the electron transfer from bioflavonoid to hematin. The docking results were verified by biochemical analysis, which reveals that when the cyclooxygenase activity of COXs is inhibited by covalent modification, myricetin can still stimulate the conversion of PGG(2) to PGE(2), a reaction selectively catalyzed by the peroxidase activity. Using the site-directed mutagenesis analysis, we confirmed that Q189 at the peroxidase site of COX II is essential for bioflavonoids to bind and re-activate its catalytic activity. These findings provide the structural basis for bioflavonoids to function as high-affinity reducing co-substrates of COXs through binding to the peroxidase active site, facilitating electron transfer and enzyme re-activation.


Carcinoma of the gall-bladder: an experience and review of the literature.
This paper summarizes the treatment results of 28 cases of gall-bladder carcinoma at Toowoomba Base Hospital, Toowoomba, Queensland, Australia. The literature is reviewed in order to determine whether more extensive resection is improving the outcome of a disease generally understood to have a deplorable prognosis. The complete records of 28 patients with this malignancy were obtained from the period 1978 to 1994 and analysed retrospectively. Twenty-three patients had cholecystectomy, but only one underwent formal lymph node dissection. Overall, the 5 year survival rate was 13%, and long-term survivors all had stage I or II disease. Those with stage III or IV disease had a median survival of 46 days. Recent literature confirms that simple cholecystectomy is not always curative for early lesions discovered incidentally and also that some patients with advanced disease can achieve long-term survival if treated with radical resection. Wedge resection of the liver and nodal clearance of the hepatoduodenal ligament at least has been recommended in patients with T2 lesions (subserosal/perimuscular), and in selected patients with stage III disease.


Correlation of Sarcopenia With Modified Frailty Index as a Predictor of Outcome in Critically Ill Elderly Patients: A Cross-Sectional Study.
Frailty phenotype represents weight loss, decreased functional and physical capacity and activity, falls, slow gait, and memory impairment. Sarcopenia is a generalized and progressive loss of skeletal muscle mass, strength, and function, which occurs due to primary effects of aging and secondary effects of other causes including diseases, malnutrition, and inactivity. This prospective cross-sectional study was performed on 70 critically ill geriatric patients (of age > 60 years) admitted in Medicine ICU (MICU) from December 2020 to May 2021 at a rural medical school at Wardha in central rural India. We assessed sarcopenia in all the patients by the European Working Group on Sarcopenia in Older People (EWGSOP) criteria and compared it with the modified frailty index. All the patients were divided in sarcopenic and non-sarcopenic groups; frailty index was applied, and outcomes were measured in terms of mortality, the need for ventilation, and length of ICU stay. In this study, the mean age of the patients was 68.61 ± 5.88 years in the sarcopenic group and 69.10 ± 6.31 years in the non-sarcopenic group. Eighteen (42.86%) patients in the sarcopenic group were severely frail, whereas eight (28.57%) patients in the non-sarcopenic group (p = 0.532) were not. In the sarcopenic severely frail group, mortality was six (14.29%), and eight (19.05%) required ventilation (p = 0.001), whereas in the non-sarcopenic severely frail group, mortality as well as the need for ventilation were four (14.29%) (p = 0.0001). Total duration of ICU stays was 4.30 ± 1.07 days in the sarcopenic group (n = 42), whereas it was 3.85 ± 1.23 days in the non-sarcopenic group (n = 28) (p = 0.10). Our study found that critically ill patients with sarcopenia had more tendency to become frail, thereby increased risk of mortality. A timely routine assessment for sarcopenia upon ICU admission may provide an important prognostic factor in patient outcomes.


Photoinhibition and P700 in the Marine Diatom Amphora sp.
The marine diatom Amphora sp. was grown at a light intensity of 7.0 x 10(15) quanta centimeter(-2) second(-1). Light saturation of photosynthesis for these cells was between 6.0 and 7.0 x 10(16) quanta centimeter(-2) second(-1). At light intensities greater than saturation, photosynthetic (14)CO(2) fixation was depressed, while P700 unit size (chlorophyll a concentration/P700 activity) increased and number of P700 units per cell decreased. After a 1-hour exposure of Amphora sp. to a photoinhibitory light intensity of 2.45 x 10(17) quanta centimeter(-2) second(-1), there was a 45 to 50% decrease in the rate of (14)CO(2) fixation relative to the rate at the culture light intensity. There also was a 25% increase in P700 unit size and a 30% reduction in the number of P700 units per cell but no change in total chlorophyll a concentration. Following this period of photoinhibition, the cells were returned to a light regime similar to that in the original culture conditions. Within 1 hour, both number of P700 units per cell and P700 unit size returned to levels similar to those of cells which were kept at the culture light intensity. The rates of photosynthesis did not recover as rapidly, requiring 2 to 3 hours to return to the rate for the nonphotoinhibited cells. Our results indicate that a decrease in P700 activity (with a resultant increase in P700 unit size) may be partially responsible for the photoinhibition of algal photosynthetic carbon dioxide fixation.


Gamified Web-Delivered Attentional Bias Modification Training for Adults With Chronic Pain: Protocol for a Randomized, Double-blind, Placebo-Controlled Trial.
To date, research has found variable success in using attentional bias modification training (ABMT) procedures in pain samples. Several factors could contribute to these mixed findings, including boredom and low motivation. Indeed, training paradigms are repetitive, which can lead to disengagement and high dropout rates. A potential approach to overcoming some of these barriers is to attempt to increase motivation and engagement through gamification (ie, the use of game elements) of this procedure. To date, research has yet to explore the gamified format of ABMT for chronic pain and its potential for the transfer of benefits. The aim of this study is to investigate the effects of a gamified web-delivered ABMT intervention in a sample of adults with chronic pain via a randomized, double-blind, placebo-controlled trial. A total of 120 adults with chronic musculoskeletal pain, recruited from clinical (hospital outpatient waiting list) and nonclinical (wider community) settings, will be included in this randomized, double-blind, placebo-controlled, 3-arm trial. Participants will be randomly assigned to complete 6 web-based sessions of dot-probe nongamified sham control ABMT, nongamified standard ABMT, or gamified ABMT across a period of 3 weeks. Active ABMT conditions will aim to train attention away from pain-relevant words. Participant outcomes will be assessed at pretraining, during training, immediately after training, and at the 1-month follow-up. Primary outcomes include pain intensity, pain interference, and behavioral and self-reported engagement. Secondary outcomes include attentional bias for pain, anxiety, depression, interpretation bias for pain, and perceived improvement. The ethical aspects of this research project have been approved by the human research ethics committees of the Royal Brisbane and Women's Hospital (HREC/2020/QRBW/61743) and Queensland University of Technology (2000000395). Study recruitment commenced in August 2021 and is ongoing. Data collection and analysis are expected to be concluded by October 2022 and January 2023, respectively. This trial will be the first to evaluate the effects of gamification techniques in a pain ABMT intervention. The findings will provide important information on the potential therapeutic benefits of gamified pain ABMT programs, shed light on the motivational influences of certain game elements in the context of pain, and advance our understanding of chronic pain. Australian New Zealand Clinical Trials Registry ACTRN12620000803998; https://anzctr.org.au/ACTRN12620000803998.aspx. PRR1-10.2196/32359.


An economic evaluation of a school-based sexually transmitted disease screening program.
A school-based sexually transmitted disease (STD) screening program was implemented in eight New Orleans public high schools to detect chlamydia and gonorrhea. The goal was to assess the incremental cost-effectiveness of replacing non-school-based screening with the school-based screening program. A decision-analysis model was constructed to compare costs and cases of expected pelvic inflammatory disease (PID) in the school-based screening scenario versus a non-school-based screening scenario. Cost-effectiveness was quantified and measured as cost per case of PID prevented. Under base-case assumptions, at an intervention cost of $86,449, the school screening program prevented an estimated 38 cases of PID, as well as $119,866 in treatment costs for PID and its sequelae, resulting in savings of $1524 per case of PID prevented. Results remained cost-saving over a reasonable range of model parameter estimates. The New Orleans school-based chlamydia screening program was cost-effective and cost-saving and could be cost-effective in other settings. School-based screening programs of this type are likely to be a cost-effective use of public funds and can reduce the burden of STDs among adolescents.


Detection of Toxoplasma gondii in Cord Blood Samples from Neonates in Tehran, Iran.
Toxoplasmosis is an infectious disease caused by the coccidian protozoan parasite Toxoplasma gondii. The infection is life-threatening in congenital form because of transmission of the parasite from mother to fetus. In order to investigate the prevalence of congenital toxoplasmosis, the present study was performed for detection of IgG and IgM antibodies in cord blood samples of newborns by ELISA method in Tehran, Iran. This cross-sectional survey was carried out on 1000 cord blood samples collected from Shahid Mostafa Khomeini Hospital in Tehran, Iran in 2015. Sera were separated and evaluated for the presence of IgG and IgM antibodies against T. gondii by ELISA method. At the same time, whole cord blood samples were stored at -20 °C for complementary PCR test. From 1000 cord blood serum samples 198 cases (19.8%) were positive for anti T. gondii IgG antibody. IgG positive samples were examined for IgM antibody, among them 1 sample had borderline levels of IgM antibody. PCR was performed for this sample but no positive result was seen. Although congenital toxoplasmosis is of importance, no acute form of infection was seen in pregnant women in this study.


[Dry cough in the elderly patients treated with angiotensin converting enzyme inhibitor].
Since dry cough has recently been recognized as a side effect of angiotensin converting enzyme (ACE) inhibitors employed in the treatment of hypertension or congestive heart failure, the incidence of dry cough in elderly patients receiving ACE inhibitors was investigated. There were 237 out-patients on either captopril, enalapril, or delapril, in August and November 1989. Questionnaires concerning dry cough and smoking were completed by 184 patients. Patients either less than 50 years of age, or with chronic pulmonary disease were excluded. The remaining 168 patients, 63 males, 105 females, with a mean age of 73 years were analyzed for the incidence of a dry cough in relation to age, sex, smoking, and type of drugs. The overall incidence of a dry cough was 21/168 (12.5%), 7/63 (11.1%) for males and 14/105 (13.3%) for females, and was less frequent with advancing age; in the 51-60 age group 4/11 (36.4%), in the 61-70 age group 5/39 (12.8%), in the 71-80 age group 9/75 (12.0%), in the 81-90 age group 3/40 (7.5%), in the 91- age group 0/3 (0%). Enalapril showed significantly higher incidence of dry cough than captopril (16/93, 17.2% vs 7/88, 8.0%, p less than 0.05). Delapril showed an incidence 4/11, 36.4%, however, 9 out of the 11 patients who were given delapril had had a history of a dry cough with captopril or enalapril, and in 4 out of these 9 patients the dry cough disappeared by replacement of captopril or enalapril by delapril.(ABSTRACT TRUNCATED AT 250 WORDS)


Simultaneous administration of 111In-human immunoglobulin and 99mTc-HMPAO labelled leucocytes in inflammatory bowel disease.
Technetium-99m hexamethylpropylene amine oxime (HMPAO) labelled leucocytes and indium-111 polyclonal immunoglobulin (IgG) were simultaneously injected into a group of 27 patients routinely referred for the investigation of inflammatory bowel disease (IBD). Ten-minute anterior abdomen and tail on detector views were obtained at 30 min, 4 h and 24 h p.i. of both tracers. The diagnosis of IBD was obtained in all cases by endoscopy with biopsy and/or surgery. Images were blindly evaluated by two experienced observers who only knew of the clinical suspicion of IBD. IBD was confirmed in 20 patients (12 with Crohn's disease and eight with ulcerative colitis). Sensitivity, specificity and accuracy were 100%, 85% and 96% respectively for labelled leucocytes and 70%, 85% and 74% for IgG. Both IgG and leucocyte scans were normal in six out of seven patients in whom a diagnosis of IBD was excluded; the remaining patient, with ischaemic colitis, was falsely positive with both agents. As far as disease extension is concerned, the IgG study localized 27 diseased segments, whereas 49 were seen with the leucocyte study. Eighty-four segments were normal and 25 showed tracer uptake with both agents. Twenty-four were positive only with the leucocyte study and two were positive only with the IgG study. Agreement between the agents was 80.7%. These results confirm that 111In-human polyclonal scintigraphy is less sensitive than 99mTc-HMPAO scintigraphy both for the diagnosis of IBD and in the evaluation of disease extension. Nevertheless, if leucocyte labelling is not available, labelled IgG can be used only for diagnostic purposes.


Strangers in a strange land: a psychobiological study of infant monkeys before and after separation from real or inanimate mothers.
Some rhesus monkey (Macaca mulatta) infants have a "despair" or depression-like response to mother-infant separation, while others do not. The presumed interrelation between early rearing conditions and the neurobiological status of the infant that might lead to increased risk for despair is not understood. In this study, the characteristics of the "mother" were controlled by rearing infant rhesus monkeys with their biological mothers, or with inanimate mothers. Behavioral data were collected before and after separation at 6-7 months of age. The neurobiological status of the infants was evaluated by measuring the concentration of norepinephrine, its major metabolite, and the metabolites of dopamine and serotonin in cerebrospinal fluid. The results suggest that despair is not simply a behavioral response to separation. Instead, despair may reflect the inability to cope with the separation environment. Coping with the separation environment appears to depend on neurobiological and behavioral characteristics of the infant that are related to, if not determined by, characteristics of the mother.


Depot leuprolide acetate dosage for sexual precocity.
Twenty-one children with early puberty have been evaluated to determine adequate dosage of depot leuprolide acetate. The minimal dosage of depot leuprolide acetate required, using intervals of 1.5 mg or less when given every 28 days, was determined. This dosage, as determined by suppression of gonadotropin responses to GnRH stimulation, was 4.14 +/- 1.33 mg (mean +/- SD) and 0.15 +/- 0.07 mg/kg.28 days. The dosage correlates with bone age and pubertal stage and is larger among patients with more advanced puberty. Five patients required a larger dosage from 5-10 months after initial suppression. Therefore, to monitor suppression, GnRH testing should be repeated at least at 6-month intervals. Samples 20 and 40 min after GnRH stimulation are sufficient to indicate adequacy of treatment, so an abbreviated test could be used.


Clinical indicators to define etiology in patients with primary amenorrhea: Lessons from a decade of experience.
Primary Amenorrhea is worrisome for the adolescent as well as their guardian. It is essential to be able to identify the underlying pathology and initiate appropriate management strategies, well in time. To study the clinical features, with an aim to identify discriminatory clinical features to indicate a most probable diagnosis. A prospective, observational study. The Gynecologic Endocrinology Clinic of Department of Obstetrics and Gynecology and Endocrinology Outpatient Department of a tertiary centre in North India. In total 328 women with primary amenorrhea, registered during a duration of 10 years (January 2008 to December 2017), were enrolled for the study and a proforma was filled with their medical details. It was observed that patients with normal stature and underdeveloped breasts were likely to be hypogonadotropic hypogonadism, whereas those with short stature and underdeveloped breasts were more likely to be gonadal failure with underlying chromosomal abnormality. The three most common causes of primary amenorrhea in the index population were hypogonadotropic hypogonadism (117/328 = 35.1%), gonadal dysgenesis (99/328 = 30.2%) and mullerian agenesis (53/328 = 16.2%). Age, height, and Tanner staging at presentation can provide a clue toward diagnosis, even before confirmatory tests are available. One of the largest studies reported on primary amenorrhea, we found hypogonadotropic hypogonadism to be the commonest cause, in contrast to previous studies.


[Presence of hormonal polypeptides in the pure pancreatic secretion in man under stimulation by cerulein and secretin].
We have investigated in stimulated human pancreatic juice the presence of the following peptides: insulin, glucagon, gastrin, somatostatin, VIP and secretin. Collection of pancreatic juice (3 periods: 20 min each) was completed by endoscopic cannulation of the pancreatic duct during the infusion of secretin (0.5 U/kg/h) and cerulein (75 ng/kg/h) in 6 healthy volunteers. Pure pancreatic juice was recovered in the presence of kallikrein inhibitor (iniprol 8,000 U/ml) in refrigerated collection tubes (4 degrees C). The material was acidified, boiled for 5 min and centrifuged. Radioimmunoassays were performed on the supernatant solutions. The elution profiles on Sephadex G 25 gel filtration of the immunoreactivities were compared with standard samples of hormones, immuno-reactive insulin, glucagon and somatostatin were found in every sample: insulin was present at a constant level (50 microU/ml) during the three periods of collection; glucagon was encountered in large amounts in the first sample and decreased significantly during the subsequent periods; somatostatin which occurred at a low level during the first period was significantly increased in the following periods. Gastrin, VIP and secretin were undetectable or only inconstantly found in very small amounts. These results are in agreement with a two-directional secretion of the human pancreatic endocrine cells. The cellular origin and function of these exocrine secreted peptides need further studies.


Immunoglobulin administration to fetuses with anemia due to alloimmunization to D.
The purpose of this study was to examine fetal tolerance of high-dose intravenous immunoglobulin (IVIG), given directly at the time of intravascular transfusion, and its effects on fetal hemolysis and pregnancy outcome in the setting of alloimmunization to D. Thirteen consecutive D+ fetuses requiring transfusion for maternal alloimmunization received high-dose IVIG (1.0 g/kg) and red cell transfusions. Twenty-four previous, consecutive fetuses with maternal anti-D served as controls. The schedules for subsequent transfusions were the same in the two groups. High-dose IVIG was well tolerated by all fetuses. In the IVIG group, daily decreases in hematocrit were smaller than those in controls after the second administration of IVIG (mean hematocrit decrease, 0.72 percent/day vs. 1.45 percent/day; p = 0.007). No significant difference was found in the total number of fetal transfusions, the gestational age at delivery, the duration of neonatal intensive care, the number of neonates requiring postnatal transfusion therapy, and perinatal mortality. In this small pilot study, direct administration to fetuses of IVIG with red cell transfusions was well tolerated and appeared to have a beneficial effect on fetal hemolysis.