Reproductive factors affecting survivorship in captive Callitrichidae.
Efforts to breed Callitrichidae in captivity have resulted in high fertility accompanied by high infant mortality. This paper investigates the relationship between reproductive characteristics and survivorship in the Oak Ridge and Associated Universities (ORAU) callitrichid colony. Records of 2,834 individuals were analyzed using Cox Proportional Hazards regression to investigate factors affecting infant survivorship. Species and birth cohort were found to have a significant (P less than 0.05) effect on survivorship. Litter size also was an important factor in determining survivorship. Individuals born into singlet and twin litters had significantly (P less than 0.001) higher survivorship than triplets. Factors which affect survivorship perinatally (0-1 months of age), prior to breeding age and subsequent to the first month of life were then investigated. Litter size was a significant (P less than 0.05) factor in determining survivorship perinatally, with twins having significantly higher survivorship than both singlets and triplets. After the first month of life, litter size no longer showed a significant effect on survivorship. Records of 145 dams were analyzed using the same procedures to investigate reproductive characteristics associated with survivorship. Age at first litter showed a significant (P less than 0.01) positive relationship with dam survivorship. These results suggest various factors affect survivorship at specific temporal points during development, and also suggest selection for survivorship perinatally to be strongly associated with litter size, possibly through sibling competition and maternal effects.


Lymphatic absorption of retinol in young, mature, and old rats: influence of dietary restriction.
Earlier studies have shown that hepatic vitamin A stores increase with age and that rats subjected to life-long dietary restriction (DR) have greater hepatic retinoid concentrations than ad libitum-fed rats. It was suggested that these changes may be attributed to altered intestinal absorption, and so we measured retinol absorption in 3, 12, and 22 month-old female Sprague-Dawley rats fed ad libitum (AL) or a restricted diet (40%) enriched (DR+) or not (DR) with vitamins and minerals. An in vivo model was used and lymph collected from the mesenteric duct while rats were infused a micellar solution containing [3H]retinol into the proximal duodenum. Aging significantly decreased lymph flow, and at all ages DR and DR+ rats exhibited a higher flow than age-matched AL rats. Absorption of retinol was not significantly modified by age in AL and DR+ rats. However, in the DR group, there was a marked decrease in absorption between 3 and 12 months of age. Retinol absorption was significantly higher in 12 and 22 month-old DR+ rats than in age-matched AL rats, a finding that may be explained by both higher lymph flow rate and higher long-term vitamin A intake per body weight. In conclusion, the increased content of vitamin A in the livers of older AL rats is not associated with changes in intestinal absorption. In DR rats, however, retinoid accumulation in the liver may be explained by increased intestinal absorption of the vitamin, though other mechanisms may be involved. A possible explanation may be a decreased output of retinol from the liver as a result of lower metabolic needs. The lower serum vitamin A concentrations observed in DR rats would tend to support this hypothesis.


Tetra-p-aminophenylporphyrin conjugated with Gd-DTPA: tumor-specific contrast agent for MR imaging.
Tetra-p-aminophenylporphyrin (TPP) was conjugated with gadolinium diethylenetriaminepentaacetic acid (DTPA) and used as a contrast agent in magnetic resonance (MR) imaging to achieve tumor selectivity in nude mice. A substantial decrease in T1 was measured in excised tissues (kidneys, tumor, and liver) from mice that received the porphyrin derivative Gd2(DTPA)4 TPP. Toxicity and phototoxicity were less than those obtained with hematoporphyrin derivative in both L1210 lymphoblastic leukemia cells and HT 29 human colonic cancer cells, as determined with in vitro assays. MR images showed an enhancement of contrast between the tumor and adjacent tissue after injection of this agent. The results indicate that Gd2(DTPA)4TPP could be a useful prototype paramagnetic porphyrin MR imaging contrast agent with an affinity for tumors.


Physiological and symptomatic responses to cycling and walking in intermittent claudication.
To shed light on the potential efficacy of cycling as a testing modality in the treatment of intermittent claudication (IC), this study compared physiological and symptomatic responses to graded walking and cycling tests in claudicants. Sixteen subjects with peripheral arterial disease (resting ankle: brachial index (ABI) < 0.9) and IC completed a maximal graded treadmill walking (T) and cycle (C) test after three familiarization tests on each mode. During each test, symptoms, oxygen uptake (VO2), minute ventilation (VE), respiratory exchange ratio (RER) and heart rate (HR) were measured, and for 10 min after each test the brachial and ankle systolic pressures were recorded. All but one subject experienced calf pain as the primary limiting symptom during T; whereas the symptoms were more varied during C and included thigh pain, calf pain and dyspnoea. Although maximal exercise time was significantly longer on C than T (690 +/- 67 vs. 495 +/- 57 s), peak VO2, peak VE and peak heart rate during C and T were not different; whereas peak RER was higher during C. These responses during C and T were also positively correlated (P < 0.05) with each other, with the exception of RER. The postexercise systolic pressures were also not different between C and T. However, the peak decline in ankle pressures from resting values after C and T were not correlated with each other. These data demonstrate that cycling and walking induce a similar level of metabolic and cardiovascular strain, but that the primary limiting symptoms and haemodynamic response in an individual's extremity, measured after exercise, can differ substantially between these two modes.


Septic hip dislocation in a child.
A 4-year-old girl presented with pain and disability of right side hip of about 1-week duration. High-grade fever and upper respiratory tract infection were also noted. A pelvic computed tomography scan showed a dislocated hip accompanied by a huge intrapelvic abscess. Culture of pus from the hip showed Streptococcus pneumonia. Emergency arthrotomy, drainage of abscess and reduction of hip, and immobilization with a hip spica cast were undertaken. Thereafter, intravenous antibiotics were given for 6 weeks. The infection was resolved. At a 2-year follow-up, the clinical result was fair and the radiography showed persisting hip damage.


[Salivary LH as an ovulation indicator: comparison between salivary LH, serum LH and ultrasonic findings].
A radioimmunological method of salivary LH determination has been developed as a new non invasive approach to hormonal ovulation detection. In this study salivary LH patterns have been compared to serum LH peak and daily sonographic assessment of follicle maturation in 15 spontaneous cycles of 9 women experienced in self-observation of their cycles (NFP). The day where the mature follicle was no longer visible sonographically was labelled day 0. Serum LH peaks occurred in 11 out of 15 cycles on day -1, two times on days -2 and 0 and preceded salivary LH peaks in 8 out of 15 cycles. The latter coincided in 7 cycles with day 0 in two cycles each with days -1 and +1 and in 4 cycles with day -2. Thus 13/15 serum- and 11/15 salivary-LH peaks occurred within +/- one day of the disappearance of the mature follicle. A time lag of up to six hours between the sampling of saliva and serum might explain the difference in the respective peak days, however, more studies into the kinetics of LH transport and its circadian rhythmicity seem necessary. Nevertheless, in principle also the salivary LH peak is considered a suitable indicator of ovulation.


Neurological disorders in Gulf War veterans.
We present a review of neurological function in Gulf War veterans (GWV). Twenty-two studies were reviewed, including large hospitalization and registry studies, large population-based epidemiological studies, investigations of a single military unit, small uncontrolled studies of ill veterans and small controlled studies of veterans. In nearly all studies, neurological function was normal in most GWVs, except for a small proportion who were diagnosed with compression neuropathies (carpal tunnel syndrome or ulnar neuropathy). In the great majority of controlled studies, there were no differences in the rates of neurological abnormalities in GWVs and controls. In a national US study, the incidence of amyotrophic lateral sclerosis (ALS) seems to be significantly increased in GWVs, compared to the rate in controls. However, it is possible that military service, in general, might be associated with an increased risk of ALS, rather than Gulf War service in particular. Taken together, the conclusion is that if a neurological examination in a GWV is within normal limits, then extensive neurological testing is unlikely to diagnose occult neurological disorders.


Safety of proton pump inhibitor exposure.
Proton pump (H(+)/K(+)-adenosine triphosphatase) inhibitors (PPIs) are widely used to treat patients with acid-related disorders because they are generally perceived to be safe and effective. However, as with any pharmacologic agent, they have the potential for side effects. Many studies have examined the side effects of long-term or short-term PPI exposure. We review the mechanism of action of PPIs, focusing on recently released products that might have greater risks of adverse effects than older products because of increased potency and/or duration of action. We summarize the data available on the putative adverse effects of PPI therapy and propose guidelines for clinicians who prescribe these agents to limit the potential for adverse outcomes in users of these effective therapeutic agents.


Transverse myelitis associated with primary biliary cirrhosis: clinical, laboratory, and neuroradiological features.
Only five patients diagnosed with transverse myelitis (TM) associated with primary biliary cirrhosis (PBC) have been reported in the literature to date. We report two additional patients with TM associated with PBC at our hospital and review all seven cases. An association between neuromyelitis optic spectrum disease (NMOSD) and PBC is reported for the first time in one of our patients. The second patient was diagnosed with TM associated with PBC without Sjögren's syndrome (SS). A literature review was performed using the PubMed database. All patients diagnosed with TM associated with PBC were female with a median age of 53 years. TM was associated with SS in 71.4% of the patients. Complete TM and incomplete TM were diagnosed in 71.4% and 28.6% of the patients. The erythrocyte sedimentation rate was increased in 83.3% of patients. All patients were positive for anti-mitochondrial antibodies. Other autoantibodies, including anti-nuclear antibodies, rheumatoid factor, anti-SSA antibody, were detected in some patients. Cerebrospinal fluid analysis was abnormal in 83.3% of patients. The spinal cord lesions involved more than three vertebral segments in 85.7% of patients. Glucocorticoids were administered in 85.7% of patients, and good responses were observed. The association between TM and PBC may be missed by neurologists. More attention should be paid to the association between NMOSD and PBC. Most patients show SS and may experience relapse, and there is a good rationale for early commencement of immunosuppressive therapy.


Prevalence and burden of COPD misclassification in the Canadian Longitudinal Study on Aging (CLSA).
To examine the prevalence of chronic obstructive pulmonary disease (COPD) misclassification and the associated burden of symptoms, healthcare utilisation and physical performance status in the Canadian general population. This information is presently lacking from large population-based studies with high-quality spirometry data that can be generalised to the general population. The prevalence of self-reported physician-diagnosed COPD and the concordance with spirometry airflow obstruction (AO) were assessed in a cross-sectional cohort of Canadian older adults. The associations between confirmed COPD, under-diagnosis and over-diagnosis with self-reported respiratory symptoms, healthcare utilisation and physical performance (timed up and go, handgrip strength and 4 metres walk test) were assessed, adjusting for baseline characteristics using multivariable linear and logistic models. A total of 21 242 participants (mean age 64 (SD 10) years; 42% men) with high quality spirometry were included. Physician-diagnosed COPD was reported in (n=973) 5% of the participants. Only (n=217) 1% of the entire cohort had confirmed COPD supported by spirometry AO. Discordance between self-reported COPD and spirometry findings was observed in (n=1565) 8%: with 4% representing under-diagnosis cases (no self-reported COPD but AO) and 4% representing over-diagnosis cases (self-reported COPD but no AO). Compared with normals (no self-reported COPD and normal spirometry), those with confirmed, under-diagnosed or over-diagnosed COPD showed higher risks for respiratory symptoms (adjusted OR (aOR) 2.1 (95% CI: 1.6 to 2.7); aOR 1.8 (95% CI: 1.6 to 2.1]; aOR 1.6 (95% CI: 1.4 to 1.9)); healthcare utilisation in the prior 12 months (β coefficient 0.8 (95% CI: 0.2 to 2.6); β 0.9 (95% CI: 0.5 to 1.5); β 1.6 (95% CI: 0.7 to 4.0)). Mood disorders were higher in confirmed and over-diagnosed COPD (aOR 1.7 (95% CI: 1.3 to 2.4); 1.7 (95% CI: 1.4 to 2.0), respectively). Physical performance was lower for COPD groups. The prevalence of COPD misclassification is high in the general population of older adults. These were associated with significantly high burden of respiratory symptoms, healthcare utilisation and low physical performance compared with the general population with normal spirometry and no self-reported COPD. These findings highlight the high burden of COPD misclassification, which may be substantially reduced with greater accessibility to spirometry measurements in the community.


Neoplasms of the retinal pigment epithelium: the 1998 Albert Ruedemann, Sr, memorial lecture, Part 2.
Neoplasms of the retinal pigment epithelium (RPE) are rare, and little is known about their clinical variations, clinical course, and prognosis. Although most are benign, they can simulate choroidal melanoma. To evaluate the clinical characteristics, management, pathological features, and prognosis of acquired neoplasms of the RPE (adenoma and adenocarcinoma) and to define clinical features that help differentiate them from uveal melanoma. The medical records of patients with acquired tumor of the RPE were reviewed retrospectively, and the clinical features, management, and histopathologic findings were studied. Of 13 affected patients, 10 were women and 3 were men. Ten were white and 3 were African American. The mean age at diagnosis was 53 years (range, 28-79 years). All patients were referred with the diagnosis of suspected choroidal melanoma. All tumors were solitary, unilateral, and ranged from a small, asymptomatic lesion measuring 2 x 2 x 1 mm to a massive neoplasm that measured 17 x 17 x 17 mm. There was no predilection for retinal location or laterality. The tumors were dark brown to black in 11 patients and only minimally pigmented in 2. Prominent retinal feeder vessels were visualized in 8 patients, 5 of whom had an exudative retinal detachment. Two patients had recurrent vitreous hemorrhage. Transillumination generally revealed blockage of light by the tumor. Fluorescein angiography showed early hypofluorescence and late minimal hyperfluorescence of the tumor, without visibility of choroidal vessels. Ultrasonography typically demonstrated the tumor to be abruptly elevated and to have medium to high internal reflectivity and acoustic solidity. Results of diagnostic fine needle aspiration biopsy, performed on 4 patients, disclosed cells compatible with a pigment epithelial origin. Treatment ultimately included observation in 4 patients, enucleation in 3, local tumor resection in 3, irradiation in 2, and laser therapy in 1. Microscopic verification of the diagnosis was available in 3 eyes after fine needle aspiration biopsy, 3 eyes after local resection, 3 eyes after enucleation, and 1 eye post mortem. The microscopic diagnosis was adenoma in 8 patients and adenocarcinoma in 2. Microscopically, the lesions were composed of a neoplastic proliferation of RPE cells. Tumors arising from the anterior portion of the RPE had a vacuolated pattern, and those in the posterior portion of the RPE had a glandular or tubular configuration. Neoplasms of the RPE show considerable clinical variation. In contrast to melanoma, they generally are darker, more abruptly elevated, and more likely to have retinal feeder vessels and exudative retinal detachment; show early hypofluorescence and mild late hyperfluorescence on angiographic findings; and have high internal reflectivity on ultrasonographic findings. Although most acquired tumors of the RPE are benign cytologically, they can exhibit aggressive clinical behavior.


Turning the Knobs: The Impact of Post-translational Modifications on Carbon Metabolism.
Plants rely on the carbon fixed by photosynthesis into sugars to grow and reproduce. However, plants often face non-ideal conditions caused by biotic and abiotic stresses. These constraints impose challenges to managing sugars, the most valuable plant asset. Hence, the precise management of sugars is crucial to avoid starvation under adverse conditions and sustain growth. This review explores the role of post-translational modifications (PTMs) in the modulation of carbon metabolism. PTMs consist of chemical modifications of proteins that change protein properties, including protein-protein interaction preferences, enzymatic activity, stability, and subcellular localization. We provide a holistic view of how PTMs tune resource distribution among different physiological processes to optimize plant fitness.


Florida cluster of five children with endodermal sinus tumors. Possible environmental risk.
An unusual case clustering of endodermal sinus tumors in Jacksonville, Fla., is described, together with a variety of local environmental risk factors. Proximity to high-tension electrical power lines was observed, but chance aggregation of familially disposed persons or coincidental environmental factors not identified could also be responsible. However, this cluster is too remarkable to go unreported and is presented here as a preliminary report for those interested in the epidemiology of rare tumors, in an attempt to probe this peculiar episode of cancer. Further investigation of cancer clusters is encouraged, with suggestions to maintain surveillance for these types of clusters in comparably affected areas.


Impact of elevated copper on the rate and gaseous products of denitrification in freshwater sediments.
Application of Cu-containing algicides to water reservoirs for algal control leads to sediment Cu enrichment, but the impact of Cu accumulation on the NO(3)(-)-attenuation capacity of these ecosystems is uncertain. With the knowledge that the reduction of N(2)O to N(2) is mediated by a Cu-dependent enzyme, it is hypothesized that an inverse variation exists between Cu availability and the mole fraction of N(2)O (F(N2O)) in denitrification products. A study was conducted to test this hypothesis and also to assess the impact of elevated Cu on nitrification and denitrification. Sediments were collected from areas untreated (NCT) and treated (CT) with the algicide cutrine (Cu ethanolamine) in three central Indiana reservoirs, and were assayed at both in situ Cu content and after amendment with CuSO(4). Results showed that Cu addition had a depressive, but short-lived effect on the processes investigated, with nitrification being most sensitive. Past cutrine treatments did not significantly affect either denitrification or F(N2O). However, a significant difference (P < 0.04) among reservoirs was found with respect to denitrification (Eagle Creek: 3.2; Geist: 1.6 and Morse: 4.2 mg N kg(-1) h(-1)) and F(N2O) (0.51, 0.24, and 0.31, respectively). Negative relationships (r(2): 0.30-0.64) between F(N2O) and water extractable Cu were found only when the analysis was conducted separately for each reservoir, suggesting that Cu solubility is controlled by sediment properties specific to each reservoir. Overall, results of this study indicate that neither the NO(3)(-)-removal capacity of sediments nor the composition of denitrification N gases is affected by past treatments with cutrine.


Vertical integration and contractual network in the cardiovascular sector: the experience of the Italian region Emilia Romagna.
We analysed the integrated planning model adopted by the Italian region Emilia Romagna in year 2000 to cover the entire range of treatment of cardiovascular disease. This model, called "hub and spoke", provides for the transfer of patient care and treatment from peripheral units (the spokes) to central units (the hubs) once a certain complexity threshold has been reached. We examined inter-temporal variations in patients flows for the selection/referral and follow-up phases between cardiac surgery and cardiology units during two periods characterised by different organisational set-ups, in order to reflect on the progress being made in the organisation of the network. The database consisted of regional records of hospital discharges during the 1997-2001 period. The investigation pointed to the achievement of a good degree of coordination between structures at different levels of specialisation in the case of cardiac surgery, for which six centres were selected already in 1996. On the other hand, the more recent introduction of a hierarchical system for interventional cardiology points to the prevalence of operations on patients previously treated within the same centre, to admissions by direct access, and to follow-up mainly conducted within the hub providing the initial service. Despite the progress made towards the more effective rationalisation of the health care network, there is still room for improvement in relations between different centres, in particular with regard to the clearer definition of the roles and interdependence of those intermediate-level centres located between the hub centres and basic healthcare facilities.


The decrease of rat postprandial plasma triacylglycerol concentration after multiple cycles of starvation-refeeding.
The effect of multiple cycles of starvation-refeeding on rat body weight and on plasma lipid concentration was studied. After 1 cycle of starvation-refeeding, the rat body weight did not change significantly; however the postprandial plasma triacylglycerol concentration decreased approximately 2-fold as compared to rats fed ad libitum. After 8 cycles of starvation-refeeding, both rat body weight and plasma triacylglycerols concentration decreased. In contrast, the plasma cholesterol (both total and HDL cholesterol) concentration did not change appreciably either after 1 or 8 cycles of starvation-refeeding as compared to control. Although the postprandial plasma triacylglycerol concentration decreased in both groups (i.e. after 1 and 8 cycles of starvation-refeeding), this phenomenon appears to last longer after 8 cycles of starvation-refeeding. The epididymal white adipose tissue weight decreased after both 1 and 8 cycles of starvation-refeeding. After 1 cycle of starvation-refeeding followed by 3, 6 and 9 days of ad libitum feeding, the epididymal white adipose tissue weight increased progressively, reaching the control value at day 9. In contrast, after 8 cycles of starvation-refeeding followed by 9 days of ad libitum feeding, the epididymal white adipose tissue weight did not reach the control value. These results suggest that dieting is associated with body and adipose tissue weight loss as well as with the decrease of plasma triacylglycerol concentration. Furthermore, our results suggest that better maintenance of low adipose tissue weight and low plasma triacylglycerol concentration may be achieved after multiple cycles of starvation-refeeding.


The role of TNF-α in inflammatory olfactory loss.
Despite the significant health impact of olfactory loss in chronic rhinosinusitis (CRS), the underlying pathophysiology is incompletely understood. A transgenic mouse model of olfactory inflammation induced by tumor necrosis factor-alpha (TNF-α) has provided new insights into the cellular and molecular basis of inflammatory olfactory loss. Here, we utilize systemic corticosteroids to suppress downstream cytokine expression, in order to study the direct role of TNF-α in CRS-associated olfactory dysfunction. Transgenic mice were induced to express TNF-α in the olfactory epithelium for 6 weeks. In a subset of mice, 1 mg/kg prednisolone was administered concurrently to inhibit downstream inflammatory responses. The olfactory epithelium (OE) was analyzed by histology and electro-olfactogram (EOG) recordings. Treatment with prednisolone successfully prevented inflammatory infiltration over significant regions of the OE. In areas where significant subepithelial inflammation was present, a corresponding loss of olfactory neurons was observed. In contrast, areas without major inflammatory changes had normal olfactory neuron layers, despite chronic local expression of TNF-α. Prednisolone partially reversed the complete loss of olfaction in the mouse model, preserving odorant responses that were significantly diminished compared to controls, but not absent. The addition of prednisolone to the transgenic model of olfactory inflammation isolates the direct effects of induced TNF-α expression on the OE. The finding that prednisolone treatment prevents neuronal loss in some regions of the OE suggests that TNF-α does not directly cause neuronal apoptosis--rather, that subepithelial inflammation or other downstream mediators may be responsible. At the same time, EOG results imply that TNF-α directly causes physiologic dysfunction of olfactory neurons, independent of the inflammatory state. An understanding of the role of TNF-α and other inflammatory cytokines may suggest novel therapeutic strategies for CRS-associated olfactory loss.


Discrete-Event Simulation Modeling in Healthcare: A Comprehensive Review.
Discrete-event simulation (DES) is a stochastic modeling approach widely used to address dynamic and complex systems, such as healthcare. In this review, academic databases were systematically searched to identify 231 papers focused on DES modeling in healthcare. These studies were sorted by year, approach, healthcare setting, outcome, provenance, and software use. Among the surveys, conceptual/theoretical studies, reviews, and case studies, it was found that almost two-thirds of the theoretical articles discuss models that include DES along with other analytical techniques, such as optimization and lean/six sigma, and one-third of the applications were carried out in more than one healthcare setting, with emergency departments being the most popular. Moreover, half of the applications seek to improve time- and efficiency-related metrics, and one-third of all papers use hybrid models. Finally, the most popular DES software is Arena and Simul8. Overall, there is an increasing trend towards using DES in healthcare to address issues at an operational level, yet less than 10% of DES applications present actual implementations following the modeling stage. Thus, future research should focus on the implementation of the models to assess their impact on healthcare processes, patients, and, possibly, their clinical value. Other areas are DES studies that emphasize their methodological formulation, as well as the development of frameworks for hybrid models.


VP-16 (etoposide) and calphostin C trigger different nuclear but akin cytoplasmic patterns of changes in the distribution and activity of protein kinase C-betaI in polyomavirus-transformed pyF111 rat fibroblasts.
Protein kinase C (PKC) isoforms regulate cell proliferation and apoptosis. Since the PKC isoenzyme complement varies considerably from cell type to cell type, a PKC's responsiveness to an apoptogenic challenge must be defined for both the type of apoptogen and the type of cell. We have already reported that the changes in the distribution and activity of PKC-delta in apoptosing polyomavirus-infected/transformed Fischer rat embryo pyF111 fibroblasts depend on the type of apoptogen. Here, we show that this is also true for PKC-betaI in pyF111 cells treated with the slow DNA-damaging VP-16 (etoposide) or the fast-acting (in the cytoplasm) calphostin C. These apoptogens caused quite different shifts of the PKC-betaI level and activity in the nuclear membrane (NM) and nucleoplasm (NP), but corresponding changes in the cytosol (CS) and cytoplasmic particulate (CP) fractions. The hefty translocation of PKC-betaI onto the CP fraction and its increased activity there suggest the possible triggering of a cytochrome c/caspase-mediated apoptosis-inducing mechanism common to both agents. The present results are a necessary lead-up to functional proteomic analyses aimed at identifying the molecules forming the local PKC-betaI signalling modules under different conditions.


Carbamazepine toxicity resulting from generic substitution.
Generic substitution is practiced widely in both hospital and community settings. There have been several reports of reduced serum concentrations and seizure exacerbation following generic substitution of Tegretol. We describe the first 2 cases of carbamazepine toxicity resulting from the substitution of Tegretol with Epitol. Two 6-year-old children experienced increases in the maximum serum carbamazepine concentration, one of 22% and one of 41%. Both became asymptomatic when their serum concentrations were lowered and had no residual effects.


Inner-sphere electron transfer at the ruthenium-azo interface.
Metal complexes exhibiting multiple reversible redox states have drawn continuing research interest due to their electron reservoir features. In this context, the present article describes ruthenium-acac complexes (acac = acetylacetonate) incorporating redox-active azo-derived abim (azobis(1-methylbenzimidazole)) in mononuclear [RuII(acac)2(abim)] (1) and dinuclear [{RuIII(acac)2}2(μ-abim2-)] (2)/[{RuIII(acac)2}2(μ-abim˙-)]ClO4 ([2]ClO4) frameworks. Structural, spectroscopic, electrochemical, and theoretical analysis of the complexes revealed the varying redox states of the azo functionality of abim, i.e., [-NN-]0, [-NN-]˙-, and [-N-N-]2- in 1, [2]ClO4, and 2, respectively. Comparison between the calculated azo bond distances of analogous {Ru(acac)2}-coordinated azoheteroaromatics, i.e., abim and previously reported abbt (azobis(benzothiazole)) and abpy (azobis(pyridine)) examples, revealed the impact of varying amounts of intramolecular metal-to-azo electron transfer (i.e., the case of back-bonding) on stabilising radical anionic ([-NN-]˙-) and hydrazido ([-N-N-]2-) bridging modes in the complexes. An evaluation of the electronic forms of the complexes in accessible redox states via combined experimental and theoretical studies suggested a preferred resonance configuration rather than a precise description, primarily due to the severe mixing of metal-abim frontier orbitals. Moreover, the newly developed corresponding Cu-abim complex [CuI2(μ-abim)3](BF4)2 ([3](BF4)2) demonstrated the unique scenario of varying bridging modes of abim within the same molecular unit, involving both coordinated and non-coordinated azo functionalities. This also reemphasised the concept of the coordination-induced lengthening of the azo bond of abim (∼1.30 Å), via dπ(CuI) → π*(azo, abim) back-bonding, with reference to its non-coordinating counterpart (1.265(6) Å).


Children's toxicology from bench to bed--Drug-induced renal injury (1): The toxic effects of ARB/ACEI on fetal kidney development.
Development of fetal kidney is a finely programmed sequence, and is regulated by many important molecules. The perturbation of normal kidney development leads to congenital anomalies of kidney and urinary tract (CAKUT). CAKUT includes hypoplastic/dysplastic kidney, obstructive nephropathy and several other anomalies. CAKUT is of clinically importance, since it could lead to end stage renal failure when its anomaly grade is severe. So far, several causative genes responsible for development of CAKUT have been identified, including genes encoding molecules related to the renin-angiotensin-aldosterone system, RAS system. In humans, maternal administration of agents with inhibitory effects on the RAS system, such as angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin type 1 receptor blockers (ARBs), have been reported to cause severe renal malformation, designated as ACEI/ARB fetopathy. In this paper, we overview the development of fetal kidney and address the effects of ACEIs/ARBs on fetal kidney.


The effect of five artificial sweeteners on Caco-2, HT-29 and HEK-293 cells.
Artificial sweeteners (AS) have been associated with tumor development (including colon cancer) in both animals and humans although evidence has been conflicting. Additional research was thus conducted by studying the effects of 5 AS on the morphology, cell proliferation and DNA in cells by utilizing Caco-2, HT-29 (colon) and HEK-293 (kidney) cell lines. Cells were exposed to sodium cyclamate, sodium saccharin, sucralose and acesulfame-K (0-50 mM) and aspartame (0-35 mM) over 24, 48 and 72 hours. Morphological changes were presented photographically and % cell viability was determined by using the MTT cell viability assay. Possible DNA damage (comet assay) induced by the AS (0.1, 1 and 10 mM, treated for 24, 48 and 72 hours) was studied. The appearance of "comets" was scored from no damage to severe damage (0-4). Cells became flatter and less well defined at higher AS concentrations (>10 mM). At concentrations >10 mM, decreased cell viability was noted with both increasing concentration and increasing incubation time for all cell lines tested. In general, HEK-293 cells seemed to be less affected then the colon cancer cells. Sucralose and sodium saccharin seemed to elicit the greatest degree of DNA fragmentation of all the sweeteners tested in all the cell lines used. Morphological cell alterations, cell viability and DNA fragmentation seemed to be more in the colon cancer cells. Further studies have to be performed to clarify mechanisms involved causing these alterations in mammalian cells.


New records of deep-water-Scleractinia off Argentina and the Falkland Islands.
The twenty species of Scleractinia (all azooxanthellate) known to occur off Argentina and the Falkland Islands (the At lantic component of the cold temperate Magellan Province) are discussed, 15 of which are documented by new records Five new species are described: Caryophyllia kellerae, C. coronula, Solenosmilia australis, Flabellum cinctutum, and Ja vania cristata. Five geographic and nine bathymetric range extensions are also documented. A brief history of species dis covery in this region is given, and a key to the species is provided.


Chitosan Combined with ZnO, TiO₂ and Ag Nanoparticles for Antimicrobial Wound Healing Applications: A Mini Review of the Research Trends.
Chitosan is a natural polymer that has been widely utilized for many purposes in the food, textile, agriculture, water treatment, cosmetic and pharmaceutical industries. Based on its characteristics, including biodegradability, non-toxicity and antimicrobial properties, it has been employed effectively in wound healing applications. Importantly, however, it is necessary to improve chitosan's capacities by combination with zinc oxide (ZnO), titanium dioxide (TiO₂) and silver (Ag) nanoparticles (NPs). In this review of many of the latest research papers, we take a closer look at the antibacterial effectiveness of chitosan combined with ZnO, TiO₂ and Ag NPs and also evaluate the specific wound healing application potentials.


Tips on how to write a paper.
Academics involve the search, education, and communication of knowledge. The credibility, advancement, and prestige of any specialty, program, or person involved in academics is enhanced by the quality of papers published. This occurs in the form of peer-reviewed research, along with observations and wisdom from institutional and private practice. Learning and mentoring medical manuscript writing skills is a process that improves with training and doing. The purpose of this manuscript is to serve as a guide with tips to aide the process of better writing, which may be particularly helpful to those in search of writing skills mentorship.


Act No. 18.703 setting forth rules on the adoption of minors and repealing Act 16.346, 26 April 1988.
This Act sets forth new rules on the adoption of minors in Chile. It provides for two kinds of adoption: simple and full adoption. A simple adoption has no effect on civil status and a child retains its rights and obligations with respect to its natural family. Persons adopting act as foster parents who take on obligations to give food, shelter, and education to the child until it reaches the age of majority or a judicial decision has declared an end to the adoption, or the child has become the subject of a full adoption. Persons who have reached the age of majority and have full civil capacity may adopt, although a married person may adopt only if his or her spouse consents. A full adoption is irrevocable; under a full adoption a child's ties to its original parents are severed and it obtains the status of a legitimate child of the persons adopting. A child may be adopted under a full adoption if it is an orphan, if its parents are unknown, if it has been abandoned, or if it is the child of one of the adopting parties. A child may be considered abandoned, even if under the care of its parents, if it has not received their personal attention for a year or if it has been left in the care of an institution. Persons adopting under a full adoption must in general be married to each other for at least four years, be over the age of 25 and under the age of 60, be at least 20 years older than the adopted child, and have cared for the child for at least a year. The Act also contains provisions on minors leaving Chile for adoption abroad.


Effectiveness of seasonal influenza vaccines in children -- a systematic review and meta-analysis.
To assess the efficacy and effectiveness of seasonal influenza vaccines in healthy children up to the age of 18 years. MedLine, EMBASE, CENTRAL, CINAHL, WHOLIS, LILACS, and Global Health were searched for randomized controlled trials and cohort and case-control studies investigating the efficacy or effectiveness of influenza vaccines in healthy children up to the age of 18 years. The studies were assessed for their quality and data on the outcomes of influenza-like illness, laboratory-confirmed influenza, and hospitalizations were extracted. Seven meta-analyses were performed for different vaccines and different study outcomes. Vaccine efficacy for live vaccines, using random effects model, was as follows: (i) for similar antigen, using per-protocol analysis: 83.4% (78.3%-88.8%); (ii) for similar antigen, using intention to treat analysis: 82.5 (76.7%-88.6%); (iii) for any antigen, using per protocol analysis: 76.4% (68.7%-85.0%); (iv) for any antigen, using intention to treat analysis: 76.7% (68.8%-85.6%). Vaccine efficacy for inactivated vaccines, for similar antigen, using random effects model, was 67.3% (58.2%-77.9%). Vaccine effectiveness against influenza-like illness for live vaccines, using random effects model, was 31.4% (24.8%-39.6%) and using fixed-effect model 44.3% (42.6%-45.9%). Vaccine effectiveness against influenza-like illness for inactivated vaccines, using random effects model, was 32.5% (20.0%-52.9%) and using fixed-effect model 42.6% (38.3%-47.5%). Influenza vaccines showed high efficacy in children, particularly live vaccines. Effectiveness was lower and the data on hospitalizations were very limited.


Gene expression profiling of human macrophages at late time of infection with Mycobacterium tuberculosis.
Macrophages play an essential role in the immune response to Mycobacterium tuberculosis (Mtb). Previous transcriptome surveys, by means of micro- and macroarrays, investigated the cellular gene expression profile during the early phases of infection (within 48 hr). However, Mtb remains within the host macrophages for a longer period, continuing to influence the macrophage gene expression and, consequently, the environment in which it persists. Therefore, we studied the transcription patterns of human macrophages for up to 7 days after infection with Mtb. We used a macroarray approach to study 858 human genes involved in immunoregulation, and we confirmed by quantitative real-time reverse transcriptase polymerase chain reaction (q-rt RT-PCR) and by enzyme-linked immunosorbent assay the most relevant modulations. We constantly observed the up-regulation in infected macrophages versus uninfected, of the following genes: interleukin-1 beta and interleukin-8, macrophage inflammatory protein-1 alpha, growth-related oncogene-beta, epithelial cell-derived neutrophil-activating peptide-78, macrophage-derived chemokine, and matrix metalloproteinase-7; whereas macrophage colony-stimulating factor-receptor and CD4 were down-regulated in infected macrophages. Mtb is able to withstand this intense cytokine microenvironment and to survive inside the human macrophage. Therefore we simultaneously investigated by q-rt RT-PCR the modulation of five mycobacterial genes: the alternative sigma factors sigA, sigE and sigG, the alpha-crystallin (acr) and the superoxide dismutase C (sodC) involved in survival mechanisms. The identified host and mycobacterial genes that were expressed until 7 days after infection, could have a role in the interplay between the host immune defences and the bacterial escape mechanisms.


Multifunctional regulators of cell growth are differentially expressed in anergic murine B cells.
Defective anergy is a major cause of failed tolerance and is amenable to therapeutic manipulation. To better define the molecular basis of anergy in B cells tolerized by matrix self-antigen, we used complementary approaches of representational difference analysis (RDA) and microarray to identify genes differentially transcribed in anergic as compared to non-tolerant B cells isolated from a well-characterized murine autoantibody transgenic model. Forty RDA clones representing 16 genes were isolated from receptor-stimulated B cells and independently confirmed as differentially expressed in tolerant cells using custom microarray, dot blotting and/or quantitative PCR. Differential expression was conserved in tolerant cells from two different transgenic founder lineages and from two genetically disparate backgrounds. Prominent among recovered gene fragments were genes encoding multifunctional proteins not previously implicated in B cell biology, but with roles in biologic processes fundamental to the tolerance phenotype, including cell growth, proliferation and differentiation. RDA also identified a novel transcript not previously reported in nucleic acid databases. To further explore dependence on receptor stimulation and to identify additional genes, commercial oligonucleotide arrays were probed with labeled B cell transcripts and analyzed for genes differentially expressed in resting as well as stimulated cells and in both B6 and MRL mouse strains. Arrays identified differential expression of a subset of RDA genes as well as 46 additional genes, including subsets engaged in signal transduction, transcriptional regulation, cell growth and apoptosis. Immunoblotting confirmed differential protein expression for galectin-3 and galectin-1, two interactive members of the galectin family, suggesting a novel role for galectins as regulators of immune tolerance.


Expression of AP-2 alpha in SV40 immortalized human lung fibroblasts is associated with a distinct pattern of cytosine methylation in the AP-2 alpha promoter.
Activator protein-2 alpha (AP-2 alpha) is a cell type-specific, developmentally regulated, transcription factor that has been implicated as a critical regulator of gene expression during vertebrate development and carcinogenesis. We found that AP-2 alpha was differentially expressed in the normal human lung fibroblast cell strains WI38, MRC-5 and their respective SV40-transformed cell counterparts WI38-VA, MRC-5VA. Since CpG methylation within genetic regulatory regions has been implicated as a mechanism of gene regulation, we investigated the CpG methylation status of the AP-2 alpha gene promoter in these cells. High resolution mapping of methylated cytosines revealed that differential expression of the AP-2 alpha gene in normal human lung fibroblasts and their SV40-transformed counterparts was associated with distinct patterns of cytosine methylation in the AP-2 alpha promoter just 5' to the transcription initiation site. Site-specific methylation was positively correlated with increased AP-2 alpha gene expression in both transformed cell lines investigated. Interestingly, one of the two major centers of hypermethylation in the transformed cells encompassed the cis-element for the AP-2 repressing transcription factor AP-2rep (KLF12). Finally, a sequence variation in human lung fibroblasts relative to the published sequence revealed a previously unidentified AP-2 binding site at position -528 with respect to the transcription initiation site that overlapped the AP-2rep site. Our results suggest that transcriptional activation of AP-2 alpha in the SV40-transformed cells is mediated, at least in part, by site-specific methylation of a negative regulatory cis-element in the AP-2 alpha promoter.


Effects of retinacular release and tibial tubercle elevation in patellofemoral degenerative joint disease.
Release of the patellar retinaculum and tibial tubercle elevation have both been advocated for the treatment of patellofemoral degeneration. Questions remain, however, regarding the magnitude and predictability of such effects in diseased joints. Using cadaver knee joints exhibiting a range of patellofemoral cartilage degeneration, we investigated the effects on joint contact pressures on release of the patellar retinaculum, followed by tibial tubercle elevations of 1.25 and 2.5 cm. Retinacular release failed to alter the joint-loading parameters significantly. Tibial tubercle elevation reduced the patello-femoral joint contact area and contact force, but failed to cause a consistent change in contact pressure. Tibial tubercle elevation also caused a migration of the joint contact area superolaterally on the retropatellar surface. This migration occurred in conjunction with ventral tilting of the inferior pole of the patella as the tubercle was elevated, suggesting that significant changes in joint kinematics may result from this procedure.


Unexpected Like-Charge Self-Assembly of a Biguanide-Based Antimicrobial Polyelectrolyte.
Polyelectrolyte chains dissolved in good solvent are expected to collapse in compact configurations in the presence of multivalent ions. Here, we show that a weakly charged, hydrophilic polyelectrolyte containing biguanide groups self-assembles in water also in the presence of monovalent counterions, even at low salt concentrations. The polymer assembles in a compact, ordered, hairpin-like shape that, with increasing the ionic strength of the solution, can collapse further in three- or five-folded structures. Neither water nor ions mediate the self-assembly which, instead, is driven by the like-charge pairing of the biguanide units. The thermodynamics of the self-assembly show that the self-association is enthalpically driven, is isodesmic (at least at low aggregation number), and is favored by increasing salt concentration. This unique self-assembly behavior may be linked to the well-known polymer's antimicrobial properties and could help in rationalizing its biological activity.


Heart rate variability in critical care medicine.
The autonomic nervous system plays an integral role in homeostasis. Autonomic modulation can frequently be altered in critically ill patients. Assessment of heart rate variability (HRV) is based on analysis of consecutive normal R-R intervals and may provide quantitative information on the modulation of cardiac vagal and sympathetic nerve input. The hypothesis that depressed HRV may occur over a broad range of critical illness and injury and may be inversely correlated with disease severity and outcome has been tested in the last decade. In this article, we review recent literature concerning assessment of HRV in patients with critical illness or injury, as well as the potential clinical implications and limitations of HRV assessment in this area.


Biotransformation of hyoscyamine into scopolamine in transgenic tobacco cell cultures.
Hyoscyamine-6beta-hydroxylase (H6H) catalyses the conversion of hyoscyamine into its epoxide scopolamine, a compound with a higher added value in the pharmaceutical market than hyoscyamine. We report the establishment of tobacco cell cultures carrying the Hyoscyamus muticus h6h gene under the control of the promoter CAMV 35S. The cell cultures were derived from hairy roots obtained via genetically modified Agrobacterium rhizogenes carrying the pRi and pLAL21 plasmids. The cultures were fed with hyoscyamine, and 4 weeks later the amount of scopolamine produced was quantified by HPLC. The transgenic cell suspension cultures showed a considerable capacity for the bioconversion of hyoscyamine into scopolamine, and released it to the culture medium. Although the scale-up from shake-flask to bioreactor culture usually results in reduced productivities, our transgenic cells grown in a 5-L turbine stirred tank reactor in a batch mode significantly increased the scopolamine accumulation.


T-cell immunoglobulin and mucin domain 2 (TIM-2) is a target of ADAM10-mediated ectodomain shedding.
T-cell immunoglobulin and mucin domain (TIM)-2 is expressed on activated B cells. Here, we provide evidence that murine TIM-2 is a target of ADAM10-mediated ectodomain shedding, resulting in the generation of a soluble form of TIM-2. We identified ADAM10 but not ADAM17 as the major sheddase of TIM-2, as shown by pharmacological ADAM10 inhibition and with ADAM10-deficient and ADAM17-deficient murine embryonic fibroblasts. Ionomycin-induced or 2'(3')-O-(4-benzoylbenzoyl) ATP triethylammonium salt-induced shedding of TIM-2 was abrogated by deletion of 10 juxtamembrane amino acids from the stalk region but not by deletion of two further N-terminally located blocks of 10 amino acids, indicating a membrane-proximal cleavage site. TIM-2 lacking the intracellular domain was cleaved after ionomycin or 2' (3')-O-(4-benzoylbenzoyl) ATP triethylammonium salt treatment, indicating that this domain was not involved in the regulation of ectodomain shedding. Moreover, TIM-2 shedding was negatively controlled by calmodulin. Shed and soluble TIM-2 interacted with H-ferritin. In summary, we describe TIM-2 as a novel target for ADAM10-mediated ectodomain shedding, and reveal the involvement of ADAM proteases in cellular iron homeostasis.


Specialization in interlimb transfer between dominant and non-dominant hand skills.
[Purpose] This study aimed to confirm the specialization of interlimb transfer in occupationally embedded tasks between dominant and non-dominant hands. [Subjects] Twelve neurologically intact participants were recruited. [Methods] The participants were divided into two training groups and performed training with their dominant or non-dominant hand. Three subtests of the Jebsen-Taylor Hand Function Test were used to practice interlimb transfer training in each group. All Jebsen-Taylor Hand Function Test subtests were evaluated using the untrained hand before and after 5 days of training. [Results] The dominant hand group showed significant differences after training when using the untrained hand in the simulated feeding and lifting large heavy objects subtests. Meanwhile, the non-dominant hand group showed significant differences after training when using the untrained hand in the turning cards, simulated feeding, stacking checkers, and lifting large heavy objects subtests. [Conclusion] When performing occupationally embedded tasks, the dominant hand has interlimb transfer advantages with respect to predictable dynamic movements, while the non-dominant hand has interlimb transfer advantages in stabilization.


Ex vivo construction of an artificial ocular surface by combination of corneal limbal epithelial cells and a compressed collagen scaffold containing keratocytes.
We have investigated the use of a laminin-coated compressed collagen gel containing corneal fibroblasts (keratocytes) as a novel scaffold to support the growth of corneal limbal epithelial stem cells. The growth of limbal epithelial cells was compared between compressed collagen gel and a clinically proven conventional substrate, denuded amniotic membrane (AM). Following compression of the collagen gel, encapsulated keratocytes remained viable and scanning electron microscopy showed that fibers within the compressed gel were dense, homogeneous, and similar in structure to those within denuded AM. Limbal epithelial cells were successfully expanded upon the compressed collagen, resulting in stratified layers of cells containing desmosome and hemidesmosome structures. The resulting corneal constructs of both the groups shared a high degree of transparency, cell morphology, and cell stratification. Similar protein expression profiles for cytokeratin 3 (CK3) and CK14 and no significant difference in CK12 mRNA expression levels by real-time polymerase chain reaction were also observed. This study provides the first line of evidence that a laminin-coated compressed collagen gel containing keratocytes can adequately support limbal epithelial cell expansion, stratification, and differentiation to a degree that is comparable to the leading conventional scaffold, denuded AM.


Vacuum Thermoforming Process: An Approach to Modeling and Optimization Using Artificial Neural Networks.
In the vacuum thermoforming process, the group effects of the processing parameters, when related to the minimizing of the product deviations set, have conflicting and non-linear values which make their mathematical modelling complex and multi-objective. Therefore, this work developed models of prediction and optimization using artificial neural networks (ANN), having the processing parameters set as the networks' inputs and the deviations group as the outputs and, furthermore, an objective function of deviation minimization. For the ANN data, samples were produced in experimental tests of a product standard in polystyrene, through a fractional factorial design (2k-p). Preliminary computational studies were carried out with various ANN structures and configurations with the test data until reaching satisfactory models and, afterwards, multi-criteria optimization models were developed. The validation tests were developed with the models' predictions and solutions showed that the estimates for them have prediction errors within the limit of values found in the samples produced. Thus, it was demonstrated that, within certain limits, the ANN models are valid to model the vacuum thermoforming process using multiple parameters for the input and objective, by means of reduced data quantity.


Cyanoacetohydrazide under Pressure: Chemical Changes in a Hydrogen-Bonded Material.
Cyanoacetohydrazide (CAH, C3H5N3O) has been studied under pressure using diamond anvil cell techniques. CAH was characterized using Raman spectroscopy to 30 GPa and synchrotron X-ray diffraction to 45 GPa. The Raman spectra of CAH show reasonable qualitative agreement with first-principle calculations. The X-ray data reveal that CAH maintains its monoclinic structure to approximately 22 GPa with a density change of 12% over this range. Near 22 GPa, the Raman modes and most of the X-ray diffraction peaks disappear. These pressure-induced changes are irreversible upon the release of pressure, and the transformed sample can be recovered to ambient pressure. The recovered sample is photosensitive and shows reaction even at low laser powers of 10 mW at 532 nm. The paper concludes with observations of the roles of hydrogen bonding, molecular configurations, and the behavior of the cyano group in the pressure-induced changes in CAH.


Is age a risk factor for cognitive changes following hematopoietic cell transplantation?
Cognitive deficits following hematopoietic cell transplantation (HCT) are common and affect post-HCT treatment regimen adherence and quality-of-life. Little is known about effects of age on cognition following HCT. The current study aimed to identify the effects of age on cognition one-year post-HCT, compared to pre-HCT baseline functioning. Participants were 78 autologous and allogeneic transplant recipients who underwent neuropsychological assessments at baseline and one-year post-HCT. Mixed model analyses indicated that no statistically significant main effect of age was observed for any cognitive variable. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Index Score and Trail Making Test (parts A and B) showed significant interaction effects between age and transplant type. These findings indicate that older autologous and allogeneic transplant recipients were predicted to perform similarly; however, young allogeneic HCT recipients were predicted to perform substantially below young autologous transplant recipients. Hierarchical regressions indicated that age failed to predict changes in neuropsychological test performance between baseline and one-year post-HCT. These findings indicate that advanced age may not be a risk factor for worse cognitive outcome post-HCT, though younger allogeneic transplant recipients may be at risk for worse cognitive outcomes, relative to younger autologous recipient counterparts. Clinical implications are discussed.


[A case-control study of airway management for 68 patients with cervical spine injury: comparison of the direct laryngoscope with a Macintosh blade and the fiberoptic bronchoscope].
As for cervical spine injury, special consideration for airway management is required but the optimal strategy remains controversial. Direct laryngoscopy (DL) creates some degree of cervical extension leading to secondary neurologic deterioration. Fiberoptic bronchoscopy (FOB) may facilitate tracheal intubation with little cervical motion, but has several inherent limitations. A few objective data prompted us to compare the neurologic outcome relating to the orotracheal intubation using the different types of technique, the DL with a Macintosh blade or the FOB. To identify the effect of different methods on the intubation time, neurologic disability, and adverse effects, 68 cervical spine-injured patients with the use of DL (group L; 36 patients) or FOB (group F; 32 patients) were retrospectively reviewed using hospital records. Following the induction of general anesthesia, the trachea was intubated with no immobilizing forces in group L, while awake intubation was accomplished in group F after judicious application of local anesthesia to the larynx and trachea. No significant differences were observed between the groups in age, BMI, intubation time, postoperative neurologic outcome or incidence of aspiration pneumonia. Moreover, no neurologic deterioration was shown after DL and orotracheal intubation. We found no evidence to support the routine practice of the bronchoscope-assisted awake intubation in patients with cervical spine injury. The clinical value of this technique in offering some neurologic advantage remains limited.


Added value of radiomics analysis in MRI invisible early-stage cervical cancers.
To determine the diagnostic ability of cervical mucosa radiomics signature of sagittal T2WI and T1 contrast-enhanced (CE) imaging in detecting early-stage cervical cancers with negative MRI. Preoperative images of postoperative pathology confirmed early-stage cervical cancer patients and normal cervix patients admitted to our hospital between January 2013 and December 2020 were retrospectively reviewed. Patients with cancer signals on T2WI, T1CE and DWI were deleted. Regions of interests (ROIs) were delineated on cervical mucosa (from cervical canal to cervical dome) with 5 mm width on sagittal T2WI and T1CE. The maximum-relevance and minimumredundancy (mRMR) and least absolute shrinkage and selection operator (LASSO) methods were used for the calculation of radiomics signature scores. Diagnostic performance was assessed and compared between radiomics prediction models (model 1: T1CE; model 2: T2WI; model 3: model one combined with model 2). Differential diagnostic ability of radiomics signature in detecting lymphatic vascular space invasion (LVSI) was further explored. Diagnostic performance of model three was higher than model 1 and model 2 both in primary (model 3 0.874, model 1 0.857, model 2 0.816) and validation (model 3 0.853, model 1 0.847, model 2 0.634) cohorts. Model 3 showed statistical diagnostic difference compared with model 2 (primary p = 0.008, validation p = 0.000). However, the diagnostic improvement ability of model 3 showed no statistical difference compared with model 1 (primary p = 0.351, validation p = 0.739). Diagnostic efficiency of model 3 in detecting LVSI was not apparent (AUC 0.64). Radiomics analysis of cervical mucosa combining T1CE and T2WI is promising for predicting MRI invisible early-stage cervical cancers, however further ability in detecting LVSI was not apparent. Conventional MRI was originally defined as meaningless in very early-stage cervical cancers. However, whether MRI radiomics analysis of cervical mucosa can detecting tiny changes of invisible early stage cervical cancers has not been researched yet.


Imaging leukocyte adhesion to the vascular endothelium at high intraluminal pressure.
Worldwide, hypertension is reported to be in approximately a quarter of the population and is the leading biomedical risk factor for mortality worldwide. In the vasculature hypertension is associated with endothelial dysfunction and increased inflammation leading to atherosclerosis and various disease states such as chronic kidney disease(2), stroke(3) and heart failure(4). An initial step in vascular inflammation leading to atherogenesis is the adhesion cascade which involves the rolling, tethering, adherence and subsequent transmigration of leukocytes through the endothelium. Recruitment and accumulation of leukocytes to the endothelium is mediated by an upregulation of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intracellular cell adhesion molecule-1 (ICAM-1) and E-selectin as well as increases in cytokine and chemokine release and an upregulation of reactive oxygen species(5). In vitro methods such as static adhesion assays help to determine mechanisms involved in cell-to-cell adhesion as well as the analysis of cell adhesion molecules. Methods employed in previous in vitro studies have demonstrated that acute increases in pressure on the endothelium can lead to monocyte adhesion, an upregulation of adhesion molecules and inflammatory markers(6) however, similar to many in vitro assays, these findings have not been performed in real time under physiological flow conditions, nor with whole blood. Therefore, in vivo assays are increasingly utilised in animal models to demonstrate vascular inflammation and plaque development. Intravital microscopy is now widely used to assess leukocyte adhesion, rolling, migration and transmigration(7-9). When combining the effects of pressure on leukocyte to endothelial adhesion the in vivo studies are less extensive. One such study examines the real time effects of flow and shear on arterial growth and remodelling but inflammatory markers were only assessed via immunohistochemistry(10). Here we present a model for recording leukocyte adhesion in real time in intact pressurised blood vessels using whole blood perfusion. The methodology is a modification of an ex vivo vessel chamber perfusion model(9) which enables real-time analysis of leukocyte-endothelial adhesive interactions in intact vessels. Our modification enables the manipulation of the intraluminal pressure up to 200 mmHg allowing for study not only under physiological flow conditions but also pressure conditions. While pressure myography systems have been previously demonstrated to observe vessel wall and lumen diameter(11) as well as vessel contraction this is the first time demonstrating leukocyte-endothelial interactions in real time. Here we demonstrate the technique using carotid arteries harvested from rats and cannulated to a custom-made flow chamber coupled to a fluorescent microscope. The vessel chamber is equipped with a large bottom coverglass allowing a large diameter objective lens with short working distance to image the vessel. Furthermore, selected agonist and/or antagonists can be utilized to further investigate the mechanisms controlling cell adhesion. Advantages of this method over intravital microscopy include no involvement of invasive surgery and therefore a higher throughput can be obtained. This method also enables the use of localised inhibitor treatment to the desired vessel whereas intravital only enables systemic inhibitor treatment.


PDX: Moving Beyond Drug Screening to Versatile Models for Research Discovery.
Patient-derived xenografts (PDXs) are tools of the trade for many researchers from all disciplines and medical specialties. Most endocrinologists, and especially those working in oncology, commonly use PDXs for preclinical drug testing and development, and over the last decade large collections of PDXs have emerged across all tumor streams. In this review, we examine how the field has evolved to include PDXs as versatile resources for research discoveries, providing evidence for guidelines and changes in clinical practice.


Role of inducible nitric oxide synthase in skeletal adaptation to acute increases in mechanical loading.
To clarify the role of nitric oxide (NO) in regulation of bone metabolism in response to skeletal loading, we examined inducible NO synthase (iNOS) gene knockout mice in the tail-suspension model. Histomorphometric analyses of proximal tibias revealed that 7 days of tail suspension decreased the bone volume (BV/TV) and bone formation rate (BFR/BS) and increased the osteoclast surface (Oc.S/BS) in mice with all iNOS genotypes. Both iNOS+/+ and iNOS+/- mice responded to subsequent 14-day reloading, with increases in BV/TV and BFR/BS and a decrease in Oc.S/BS, whereas these responses were abolished in iNOS-/- mice. The osteoblasts flattened after tail suspension appeared cuboidal during subsequent reloading. Immunoreactivity for iNOS was detected in these osteoblasts and osteocytes by immunohistochemistry. These defective responses after reloading were rescued in iNOS-/- mice by treatment with an NO donor nitroglycerine (NG). Conversely, the responses in iNOS+/+ mice were inhibited by treatment with an NOS inhibitor aminoguanidine (AG). In bone marrow cell cultures, mineralized nodules derived from iNOS-/- mice after reloading were significantly reduced. Taken together, our results suggest that NO generated by iNOS in osteoblasts plays a critical role in adjusting bone turnover and increasing osteogenic activity in response to the acute increase in mechanical loading after tail suspension.


Scalable Neural Decoder for Topological Surface Codes.
With the advent of noisy intermediate-scale quantum (NISQ) devices, practical quantum computing has seemingly come into reach. However, to go beyond proof-of-principle calculations, the current processing architectures will need to scale up to larger quantum circuits which will require fast and scalable algorithms for quantum error correction. Here, we present a neural network based decoder that, for a family of stabilizer codes subject to depolarizing noise and syndrome measurement errors, is scalable to tens of thousands of qubits (in contrast to other recent machine learning inspired decoders) and exhibits faster decoding times than the state-of-the-art union find decoder for a wide range of error rates (down to 1%). The key innovation is to autodecode error syndromes on small scales by shifting a preprocessing window over the underlying code, akin to a convolutional neural network in pattern recognition approaches. We show that such a preprocessing step allows to effectively reduce the error rate by up to 2 orders of magnitude in practical applications and, by detecting correlation effects, shifts the actual error threshold up to fifteen percent higher than the threshold of conventional error correction algorithms such as union find or minimum weight perfect matching, even in the presence of measurement errors. An in situ implementation of such a machine learning-assisted quantum error correction will be a decisive step to push the entanglement frontier beyond the NISQ horizon.


Perceptual variation in categorizing individuals according to American College of Rheumatology classification criteria for hand, knee, and hip osteoarthritis (OA): observations based on an Australian Twin Registry study of OA.
The American College of Rheumatology (ACR) classification criteria for osteoarthritis (OA) permit the categorization of individuals for hand, knee, and hip OA and are of defined sensitivity and specificity. They depend on both clinical and radiographic aspects of OA. The clinical diagnosis of OA in the peripheral skeleton is dependent on the skilled examination of several clinical features characteristic of the condition, while the interpretation of radiographs is a perceptual skill based on appreciating specific structural features on plain radiographs. We investigated the interrater reliability of the ACR classification criteria for OA when applied in a community based sample. The study was part of a multifaceted diagnostics protocol, evaluating methodologic issues, in the conduct of genetic research in OA. From a cohort of 118 pairs of twins registered with the Australian Twins Registry (ATR), standard clinical examinations of hands, knees, and hips were performed on 74 complete and 11 incomplete pairs of twins over age 50 years. The pairs were selected to represent both twin pairs who had previously self-reported a diagnosis of OA, as well as those who had not. Rheumatologists who performed the assessments were blind to the original self-report. All subjects were examined independently by one of 2 pairs (NB/AK or NB/KM) of consultant rheumatologists, blind to one another's assessments. Each rheumatologist separately assessed the hands, knees, and hips, rating them clinically by ACR criteria for OA. The observations were made without reference to any radiographic or serologic information. Interrater agreement was different for the 3 different anatomic areas and was different for the 2 pairs of rheumatologists. The actual (observed) interrater agreements based on ACR clinical criteria were as follows: hand OA NB/AK = 0.92, NB/KM = 1.00; knee OA NB/AK = 0.94, NB/KM = 0.92; hip OA NB/AK = 0.98, NB/KM = 0.97. Interrater agreement based on ACR clinical criteria, as assessed by the adjusted kappa statistic, was as follows: hand OA NB/AK = 0.84, NB/KM = 1.00; knee OA NB/AK = 0.87, NB/KM = 0.84; hip OA NB/AK = 0.95, NB/KM = 0.93. Since clinical agreement was extremely high in all 3 anatomic sites, and for both pairs of assessors, we conclude that for genetic epidemiology purposes, subjects can be examined by a single experienced rheumatologist using the ACR classification criteria.


Synthetic peptide conjugates with horseradish peroxidase and beta-galactosidase for use in epitope-specific immunocytochemistry and ELISA.
Synthetic peptide-alkaline phosphatase conjugates can be used to detect the epitope specificity of (i) antibody-forming cells in vivo by immunocytochemistry; (ii) of antibody secreting cells in vitro by spot-ELISA; and (iii) antibodies in solution by capture ELISA. The availability of synthetic peptide-enzyme conjugates using detector enzymes other than alkaline phosphatase would offer several important advantages, for example in double staining approaches. This paper reports the production of synthetic peptide-horseradish peroxidase conjugates and synthetic peptide-beta-galactosidase conjugates. A peptide of 21 amino acids (SP 29) was coupled to peroxidase in seven differing molar ratios of peptide over peroxidase, ranging from 1:3.4 to 1:575, using periodate oxidation of the enzyme. SP 29 was coupled to beta-galactosidase in four molar ratios ranging from 1.25 to 10, using glutaraldehyde pre-activation of the enzyme. The enzyme activity of the different conjugates was determined, the conjugates were tested in direct capture-ELISA with peptide-specific monoclonal antibodies, and the conjugates were tested in immunocytochemistry to detect peptide-specific B cells. The results show that the conjugates perform best if the peptide is coupled to the enzyme at relatively low molar ratios (1-30). The availability of these new peptide-enzyme conjugates broadens the applicability of synthetic peptides for detection purposes in several assay systems.


Circadian rhythm of the autonomic nervous system in insulin resistant subjects with normoglycemia, impaired fasting glycemia, impaired glucose tolerance, type 2 diabetes mellitus.
In type 2 diabetes mellitus both insulin resistance and hyperglycemia are considered responsible for autonomic dysfunction. The relation between the autonomic activity, impaired fasting glycemia and impaired glucose tolerance is, however, unclear. The purpose of this study was to evaluate and compare the circadian autonomic activity expressed as heart rate variability (HRV) measured by 24-hours ECG recording in insulin resistant subjects (IR) with characteristics as follow: IR subjects with normal oral glucose tolerance test results, IR subjects with impaired fasting glucose, IR subjects with impaired glucose tolerance and subjects with type 2 diabetes mellitus. Eighty Caucasian insulin resistant subjects (IR) and twenty five control subjects were recruited for the study. IR subjects were divided into four groups according to the outcoming results of oral glucose tests (OGTTs): IR subjects with normal glucose regulation (NGR), IR subjects with impaired fasting glycemia (IFG), IR subjects with impaired glucose tolerance (IGT) and subjects with type 2 diabetes mellitus (DM). Autonomic nervous activity was studied by 24-hours ECG recording. Heart rate variability analysis was performed in time and frequency domains: SDNN, RMS-SD, low frequency (LF) and high frequency (HF) were calculated. The total SDNN showed statistically significant reduction in all four groups with insulin resistant subjects (IR) when compared to the control group (p <0,001). During night LF normalized units (n.u.) were found to be higher in all four groups including IR subjects than in the control group (all p < 0,001) and subjects with normal glucose regulation (NGR), with impaired fasting glycemia (IFG) and with impaired glucose tolerance (IGT) were found to have higher LF n.u. than those in the type 2 diabetes mellitus group. The linear regression model demonstrated direct association between LF values and the homeostasis model assessment-index (HOMA-I), in the insulin resistant group (r = 0,715, p <0,0001). The results of our study suggest that insulin resistance might cause global autonomic dysfunction which increases along with worsening glucose metabolic impairment. The analysis of sympathetic and parasympathetic components and the sympathovagal balance demonstrated an association between insulin resistance and sympathetic over-activity, especially during night. The results indicated that the sympathetic over-activity is directly correlated to the grade of insulin resistance calculated according to the HOMA-I. Since increased sympathetic activity is related to major cardiovascular accidents, early diagnosis of all insulin resistant patients should be contemplated.


Monoamine oxidase inhibitors: a new generation.
Monoamine oxidase inhibitors (MAOIs), which ushered in the modern era of psychopharmacology in the 1950s, have remained useful in the treatment of depression despite important safety concerns, such as acute hypertensive episodes brought on by ingestion of foods with high-tyramine content. Experience has shown that MAOIs are broadly effective in the treatment of depressive disorders, including atypical, chronic, and double depressions. Newer selective and reversible inhibitors of the two forms of mitochondrial monoamine oxidase (MAO) enzymes, MAO-A and MAO-B, have been developed in an effort to improve the safety and tolerability of MAOIs. Selegiline, a selective inhibitor of MAO-B has been shown to be effective in the treatment of depression at higher oral doses where selectivity for MAO-B is lost. Transdermal delivery of selegiline bypasses first-pass metabolism and avoids impairment of the gastrointestinal barrier provided by MAO-A of the gastrointestinal mucosa. Studies have shown that the selegiline transdermal system (STS) does not significantly affect sensitivity to ingested tyramine, unlike tranylcypromine, which markedly increases sensitivity. STS has been found to be efficacious in the treatment of patients with major depression in placebo-controlled trials, without the need for dietary precautions. The favorable safety profile of STS should allow this MAOI to be a broadly used antidepressant drug.


KLF4α up-regulation promotes cell cycle progression and reduces survival time of patients with pancreatic cancer.
Krüppel-like factor 4 (KLF4) is a transcription factor associated with tumor suppression and oncogenesis. KLF4 suppresses pancreatic tumorigenesis by unknown mechanisms; we investigated alterations that might affect KLF4 function and lead to tumor formation. We identified different isoforms of KLF4 in pancreatic cancer cells by reverse-transcriptase polymerase chain reaction, cloning, and DNA sequence analyses. We constructed vectors to express the isoform KLF4α and characterize its function. Using real-time polymerase chain reaction, immunoprecipitation, and immunohistochemical analyses, we assessed expression of KLF4α in pancreatic cancer cell lines and tumor tissue samples; xenograft models were used to determine the effect of KLF4α on pancreatic tumorigenesis. We identified 4 KLF4 isoforms in human pancreatic cancer cells, designated KLF4α, KLF4β, KLF4γ, and KLF4δ. KLF4α localized primarily to the cytoplasm; its protein and messenger RNA were up-regulated in pancreatic cancer cell lines with high metastatic potential and human pancreatic tumors compared with normal pancreatic tissue. Transgenic expression of KLF4α reduced expression of p27(Kip1) and p21(Cip1), promoting cell cycle progression and in vivo tumor formation by pancreatic cancer cells. Increased expression of KLF4α in pancreatic tumor tissue was inversely correlated with overall time of survival in patients with stage II pancreatic ductal adenocarcinoma. We identified a splice variant of KLF4 (KLF4α) that is up-regulated in aggressive pancreatic cancer cells and human pancreatic tumor tissues. Increased expression promotes growth of pancreatic tumors in mice and is associated with reduced survival times of patients.


Efficient Activation of Apoptotic Signaling during Mitotic Arrest with AK301.
Mitotic inhibitors are widely utilized chemotherapeutic agents that take advantage of mitotic defects in cancer cells. We have identified a novel class of piperazine-based mitotic inhibitors, of which AK301 is the most potent derivative identified to date (EC50 < 200 nM). Colon cancer cells arrested in mitosis with AK301 readily underwent a p53-dependent apoptosis following compound withdrawal and arrest release. This apoptotic response was significantly higher for AK301 than for other mitotic inhibitors tested (colchicine, vincristine, and BI 2536). AK301-treated cells exhibited a robust mitosis-associated DNA damage response, including ATM activation, γH2AX phosphorylation and p53 stabilization. The association between mitotic signaling and the DNA damage response was supported by the finding that Aurora B inhibition reduced the level of γH2AX staining. Confocal imaging of AK301-treated cells revealed multiple γ-tubulin microtubule organizing centers attached to microtubules, but with limited centrosome migration, raising the possibility that aberrant microtubule pulling may underlie DNA breakage. AK301 selectively targeted APC-mutant colonocytes and promoted TNF-induced apoptosis in p53-mutant colon cancer cells. Our findings indicate that AK301 induces a mitotic arrest state with a highly active DNA damage response. Together with a reversible arrest state, AK301 is a potent promoter of a mitosis-to-apoptosis transition that can target cancer cells with mitotic defects.


Local control and survival from the Cooperative Osteosarcoma Study Group studies of the German Society of Pediatric Oncology and the Vienna Bone Tumor Registry.
The use of aggressive chemotherapy undoubtedly has brought about a dramatic increase in the cure rate of osteosarcoma. The authors' investigations have increased the authors' knowledge of chemotherapy for osteosarcoma, the differential efficacy of currently used agents, and the pronounced schedule dependency and relative route independency of their efficiency. The authors were able to confirm the prognostic significance of tumor response after preoperative chemotherapy. Preoperative chemotherapy in itself has facilitated and promoted limb-salvage surgery. Also, more patients can be cured today by use of aggressive thoracic surgery in case of primary or secondary pulmonary metastases. The authors' efforts to steadily increase metastasis-free survival rates by intensifying chemotherapy in this series of studies, however, have been only moderately successful. Still, chemotherapy-related acute toxicity is considerable and increases with aggressiveness of treatment, and the manifestations of late toxicity may continue to increase with follow-up time. Future trials should be targeted toward exploration of the minimum indispensable amount of toxic treatment yielding comparable or even better results than those currently attainable.


Distribution of galanin-like immunoreactivity in the brain of Rana esculenta and Xenopus laevis.
The immunocytochemical distribution of galanin-containing perikarya and nerve terminals in the brain of Rana esculenta and Xenopus laevis was determined with antisera directed toward either porcine or rat galanin. The pattern of galanin-like immunoreactivity appeared to be identical with antisera directed toward either target antigen. The distribution of galanin-like immunoreactivity was similar in Rana esculenta and Xenopus laevis except for the absence of a distinct laminar distribution of immunoreactivity in the optic tectum of Xenopus laevis. Galanin-containing perikarya were located in all major subdivisions of the brain except the metencephalon. In the telencephalon, immunoreactive perikarya were detected in the pars medialis of the amygdala and the preoptic area. In the diencephalon, immunoreactive perikarya were detected in the caudal half of the suprachiasmatic nucleus, the nucleus of the periventricular organ, the ventral hypothalamus, and the median eminence. In the mesencephalon, immunoreactive perikarya were detected near the midline of the rostroventral tegmentum, in the torus semicircularis and, occasionally, in lamina A and layer 6 of the optic tectum. In the myelencephalon, labelled perikarya were detected only in the caudal half of the nucleus of the solitary tract. Immunoreactive nerve fibers of varying density were observed in all subdivisions of the brain with the densest accumulations of fibers occurring in the pars lateralis of the amygdala and the preoptic area. Dense accumulations of nerve fibers were also found in the lateral septum, the medial forebrain bundle, the periventricular region of the diencephalon, the ventral hypothalamus, the median eminence, the mesencephalic central gray, the laminar nucleus of the torus semicircularis, several laminae of the optic tectum, the interpeduncular nucleus, the isthmic nucleus, the central gray of the rhombencephalon, and the dorsolateral caudal medulla. The extensive system of galanin-containing perikarya and nerve fibers in the brain of representatives of two families of anurans showed many similarities to the distribution of galanin-containing perikarya and nerve fibers previously described for the mammalian brain.


[Population aging and institutionalization of elderly persons: some possible projections for Canada].
The consequences of population aging on the demand for institutional lodging will undoubtedly be considerable. The authors have estimated this future demand in relationship with the evolution of certain socio-demographic characteristics of tomorrow's elderly. Based on a multivariate analysis (logit model), their projections will demonstrate the need for an approach which takes into account the replacement of generations among the ranks of aged persons. In fact, in future the latter will be appreciably different from today's generations. Their sociodemographic characteristics will have an impact on the risk of living in an institution and, thus, on the proportion and the number of institutionalized elderly people. Furthermore, they will probably be in a position to be able to contribute towards a greater portion of the costs of institutional living. Certainly, the burden of institutionalization will be further weighed down by the arrival of the Baby Boomers into the 65 years and over age bracket. This article nevertheless distinguishes some significant nuances within the scope of this phenomenon.


Top-cited psoriasis authors in 4 high-impact dermatology journals: 2000-2012.
Psoriasis is a largely researched topic with abundant potential for publication in dermatologic journals. We used the Thomson Reuters' Web of Science citation database using the search term "psoriasis" in the titles of any literature published in 4 high-impact dermatology journals. We compiled a ranking of the top 25 cited first authors and top 25 cited authors overall on the subject of psoriasis between 2000-2012. We hope our analysis highlights the achievements of our colleagues and predecessors.


Cholesterol, cytokines and diseases.
A high level of cholesterol is associated with obesity, cardiovascular diseases and atherosclerosis. Immune response in atherosclerosis is mediated by chemokines which attract monocytes, leading to the innate immune response characterised by the production of cytokines. The immunoregulatory cytokines are an important bridge between innate and adductive immunity. TH1 cytokines are involved as effector T cells in inflammatory response, while TH2 cytokines can be anti-inflammatory such as IL-10 and IL-4. It is well known that statins enhance the production of TH2 cytokines whereas the secretion of TH1 cytokines is suppressed. For this purpose, we studied the significance of anti-inflammatory effect and suppression of inflammation by statins. In this paper we revisited the role of cholesterol and cytokines IL-18, IL-10, IL-12, TNF-α, interferon-γ, and chemokines in inflammatory diseases.


The HLA-A*31:01 allele: influence on carbamazepine treatment.
Carbamazepine (CBZ) is an effective anticonvulsant that can sometimes cause hypersensitivity reactions that vary in frequency and severity. Strong associations have been reported between specific human leukocyte antigen (HLA) alleles and susceptibility to CBZ hypersensitivity reactions. Screening for HLA-B*15:02 is mandated in patients from South East Asia because of a strong association with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). HLA-A*31:01 predisposes to multiple phenotypes of CBZ hypersensitivity including maculopapular exanthema, hypersensitivity syndrome, and SJS/TEN in a range of populations including Europeans, Japanese, South Koreans and Han Chinese, although the effect size varies between the different phenotypes and populations. Between 47 Caucasians and 67 Japanese patients would need to be tested for HLA-A*31:01 in order to avoid a single case of CBZ hypersensitivity. A cost-effectiveness study has demonstrated that HLA-A*31:01 screening would be cost-effective. Patient preference assessment has also revealed that patients prefer pharmacogenetic screening and prescription of alternative anticonvulsants compared to current standard of practice without pharmacogenetic testing. For patients who test positive for HLA-A*31:01, alternative treatments are available. When alternatives have failed or are unavailable, HLA-A*31:01 testing can alert clinicians to 1) patients who are at increased risk of CBZ hypersensitivity who can then be targeted for more intensive monitoring and 2) increase diagnostic certainty in cases where hypersensitivity has already occurred, so patients can be advised to avoid structurally related drugs in the future. On the basis of the current evidence, we would favor screening all patients for HLA-A*31:01 and HLA-B*15:02 prior to starting CBZ therapy.


Concordance of opinions between patients and physicians and their relationship with symptomatic control and future risk in patients with moderate-severe asthma.
Differences between the opinions of patients and physicians on the impact of asthma are common. We hypothesised that patient-physician discordance may negatively affect asthma outcome. A total of 2902 patients (61% women, mean age 47 years) with moderate-severe asthma and 231 physicians participated in a prospective study. At the baseline visit, data on demographics, clinical variables, degree of asthma control according to the Asthma Control Test (ACT), basic spirometry and the Hospital Anxiety and Depression Scale (HADS) were collected and an ad hoc questionnaire was completed that allowed the degree of concordance between doctors and patients to be assessed. A scheduled telephone call after 3 months was used to elicit the ACT score and the future risk of asthma. At the final visit at 6 months, the following data were recorded: ACT score, spirometry, HADS score and an ad hoc questionnaire to assess the agreement between the doctor and the patient. Changes in study variables according to patient-physician concordance or discordance were analysed. The rate of patient-physician discordance was 27.2%, with overestimation of disease impact by the physician in 12.3% and underestimation in 14.9%. Patient-physician opinion discordance, particularly in the case of physicians underestimating the impact of asthma, showed worse results with statistically significant differences in ACT score, a higher percentage of patients with poor asthma control and lower HADS scores. The need for hospital and emergency department admissions was also higher. Patient-physician opinion discordance may be contributing to lower symptomatic control and increased future risk, with a higher impact when physicians underestimate the impact of asthma on their patients.


Joint estimation of population density functions and the location of the central business district.
"In this paper we [propose] a new procedure for estimating population density functions under conditions that the exact location of the CBD [central business district] is unknown or uncertain. As such it can also be utilized as a method for identifying the location of the CBD....[We apply] this method to cross-sectional data from Tel-Aviv-Yafo [Israel] during 1961 through 1990...."


Hyponatremia: mechanisms and newer treatments.
To review the neural and renal mechanisms of osmotic homeostasis, provide a rationale for the sensitivity of the central nervous system to hyponatremia, and outline modern approaches to therapy of acute and chronic hyponatremia. Review of relevant literature with focus on physiologic mechanisms. With careful monitoring, acute hyponatremia can be managed, while minimizing risks both of continued hyponatremia and the osmotic demyelination that can occur with overly rapid correction of severe hyponatremia. Chronic hyponatremia due to disorders of volume regulation (congestive heart failure or cirrhosis) or to syndrome of inappropriate antidiuretic hormone release can be managed effectively with vasopressin V2 receptor antagonists, but there is no evidence that controlling the hyponatremia enhances survival associated with the underlying diseases. Therapy in the acute setting balances the risk of the osmotic disturbance with the risk of overly rapid correction. The V2 receptor antagonist tolvaptan has enhanced our ability to improve chronic hyponatremia in conditions such as congestive heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormone hypersecretion.


[Materials and technics in root canal treatments in Switzerland--a determination of their status].
No data is available on either the materials nor techniques used by Swiss clinicians when doing root canal therapy (RCT). Consequently, in January 1993 questionnaires were posted to all dentists registered with the Swiss Dental Association, excluding those known not to practice RCT. Sixteen questions were answered detailing the disinfecting and obturating materials used, which types of files, preparation and obturation techniques were used and which radiographs were taken during RCT. Demographic details were also answered. Of the 3353 questionnaires posted, 2091 (62.4%) were completed and returned. Major results showed that 50.6% of the responding clinicians used AH26 to obturate canals, 45% Endomethasone and 36.6% N2. Canals were disinfected using Ledermix (81.2%), Asphaline (67.6%), Ca(OH)2 (60.2%). Clinicians used H2O2 and NaOCl equally frequently (75%). Hedstroem files, reamers and flexofiles were used by 52%, 29% and 26% of the clinicians, respectively. Canals were obturated by single-cone technique (68%), lateral condensation (34%), or by using only a paste or sealer (23%). 86.4% take a diagnostic radiograph, 69.2% determine working length from radiographs, and 91.5% take a final radiograph as well. Too many Swiss clinicians still use formaldehyde-containing products in root canal therapy coupled with a "single cone" or a "no cone" obturation technique.


Pals1/Mpp5 is required for correct localization of Crb1 at the subapical region in polarized Muller glia cells.
Mutations in the human Crumbs homologue-1 (CRB1) gene cause retinal diseases including Leber's congenital amaurosis (LCA) and retinitis pigmentosa type 12. The CRB1 transmembrane protein localizes at a subapical region (SAR) above intercellular adherens junctions between photoreceptor and Müller glia (MG) cells. We demonstrate that the Crb1-/- phenotype, as shown in Crb1-/- mice, is accelerated and intensified in primary retina cultures. Immuno-electron microscopy showed strong Crb1 immunoreactivity at the SAR in MG cells but barely in photoreceptor cells, whereas Crb2, Crb3, Patj, Pals1 and Mupp1 were present in both cell types. Human CRB1, introduced in MG cells in Crb1-/- primary retinas, was targeted to the SAR. RNA interference-induced silencing of the Crb1-interacting-protein Pals1 (protein associated with Lin7; Mpp5) in MG cells resulted in loss of Crb1, Crb2, Mupp1 and Veli3 protein localization and partial loss of Crb3. We conclude that Pals1 is required for correct localization of Crb family members and its interactors at the SAR of polarized MG cells.


Effect of Water Stress on the Carbohydrate Metabolism of Citrullus lanatus Seeds during Germination.
Gluconeogenesis in Citrullus lanatus seeds is a post germinative event. Increases in isocitrate lyase activity and incorporation of radioactivity from [2-(14)C]acetate into sugars occur only after radicle emergence. During germination, the seeds appear to rely on carbohydrate as the respiratory substrate. At this time, glycolysis, the pentose phosphate pathway, and the tricarbocyclic acid cycle seem to be functional. Utilization of raffinose during germination appears to be important.Water stress, which completely inhibits germination, has a marked effect on carbohydrate metabolism. The rate of (14)CO(2) release from [2-(14)C]acetate, [1-(14)C]glucose, and [6-(14)C]glucose is lower in the stressed seeds than the control seeds during the respiratory lag phase. However, in the stressed seeds neither glycolysis, the pentose phosphate pathway, nor the tricarboxylic acid cycle is completely inhibited. In contrast to the control seeds in which raffinose content sharply declines after 12 h of incubation, raffinose content in the stressed seeds remains fairly constant.The respiratory lag phase of the control seeds coincides with a lower reducing substance content, glucose content, and fructose content than in the stressed seeds during the corresponding incubation period.