Correction of severe alar retraction with use of a cutaneous alar rotation flap.
Severe alar retraction is one of the most challenging problems to correct in nasal surgery. Management for severe alar retraction traditionally requires multiple stages and uses several surgical techniques. This article introduces a single-stage technique to correct severe alar retraction deformities using a cutaneous alar rotation flap in conjunction with alar batten grafts. Patients with severely retracted alae underwent ala reconstruction using a cutaneous alar rotation flap and autogenous cartilage batten grafts. Thirteen patients with severe alar retraction underwent alar reconstruction using cutaneous alar rotation flap and alar batten grafts. The alar retraction was corrected in all cases, achieving improvements functionally and aesthetically. No recurrence of alar retraction was noted. The incision sites for the patients healed with acceptable cosmetic results, with only one patient requiring scar revision. The cutaneous alar rotation flap is an effective and reliable surgical option to correct severe alar retraction. Advantages of this technique include a single-stage approach, ease of design, tissue match, and rich blood supply. Scar from the flap design can be kept inconspicuous by precise placement of the incision within the junction of the ala and the nasal dorsum, following principles of the aesthetic nasal subunits.


Transjugular intrahepatic portosystemic shunting versus paracentesis plus albumin for refractory ascites in cirrhosis.
The transjugular intrahepatic portosystemic shunt (TIPS) has been shown to be more effective than repeated paracentesis plus albumin in the control of refractory ascites. However, its effect on survival and healthcare costs is still uncertain. Seventy patients with cirrhosis and refractory ascites were randomly assigned to TIPS (35 patients) or repeated paracentesis plus intravenous albumin (35 patients). The primary endpoint was survival without liver transplantation. Secondary endpoints were complications of cirrhosis and costs. Twenty patients treated with TIPS and 18 treated with paracentesis died during the study period, whereas 7 patients in each group underwent liver transplantation (mean follow-up 282 +/- 43 vs. 325 +/- 61 days, respectively). The probability of survival without liver transplantation was 41% at 1 year and 26% at 2 years in the TIPS group, as compared with 35% and 30% in the paracentesis group (P = 0.51). In a multivariate analysis, only baseline blood urea nitrogen levels and Child-Pugh score were independently associated with survival. Recurrence of ascites and development of hepatorenal syndrome were lower in the TIPS group compared with the paracentesis group, whereas the frequency of severe hepatic encephalopathy was greater in the TIPS group. The calculated costs were higher in the TIPS group than in the paracentesis group. In patients with refractory ascites, TIPS lowers the rate of ascites recurrence and the risk of developing hepatorenal syndrome. However, TIPS does not improve survival and is associated with an increased frequency of severe encephalopathy and higher costs compared with repeated paracentesis plus albumin.


Progressive spinal muscular atrophy in a case of hypokalamic periodic paralysis.
A 47-year-old man with well-documented hypokalemic periodic paralysis demons-rated permanent myopathy as shown by biopsy. In addition there was clinical and biopsy evidence of progressive spinal muscular atrophy. The feature of the combination of these diseases is reported in a case and discussed.


Simultaneous determination of the nonlinear-elastic properties of skin and subcutaneous tissue in unconfined compression tests.
The compressive nonlinear-elastic properties of soft tissues are usually determined using unconfined compression tests. To determine the nonlinear-elastic behavior of skin and subcutaneous tissue using a conventional approach, the skin and subcutaneous tissue had to be separated before testing. Using such an approach, measurement errors may be increased as a consequence of the reduced specimen dimensions and cumulative experimental errors. In the present study, we propose a novel method to determine the nonlinear-elastic behaviors of the skin and the subcutaneous tissue simultaneously using specimens of skin/subcutaneous composites. The stress/strain curves of skin and subcutaneous tissues are derived from stress/strain curves of soft tissue specimens with different skin/subcutaneous height ratios. There is no need to separate the skin from the subcutaneous tissue in the tests, thereby improving the reliability and reducing measurement errors. In order to demonstrate the application of the proposed approach, unconfined compression tests with skin/subcutaneous tissues collected from the front paws of pigs were conducted. Using the proposed approach, stress/strain relationships of the skin and the subcutaneous tissue were derived from data determined in eight unconfined compression tests. The obtained stress/strain curves were consistent with published experimental data. Compared with conventional methods, the proposed approach is not only more efficient but also more reliable.


MiR-337-3p suppresses proliferation of epithelial ovarian cancer by targeting PIK3CA and PIK3CB.
Epithelial ovarian cancer (EOC) is responsible for nearly 140,000 deaths worldwide each year. MicroRNAs play critical roles in cancer development and progression. The function of microRNA miR-337-3p has been described in various cancers. However, the biological role of miR-337-3p and its molecular mechanisms underlying EOC initiation and progression have not been reported. Here, we reported that the expression of miR-337-3p is down-regulated in EOC tissues and low expression of miR-337-3p is correlated with advanced pathological grade for patients. Ectopic expression of miR-337-3p inhibited proliferation and induced apoptosis and cell cycle arrest in G0/G1 phase of EOC cells. PIK3CA and PIK3CB were revealed to be direct targets of miR-337-3p for reducing the activation of PI3K/AKT signaling pathway. PIK3CA and PIK3CB were discovered to affect cell proliferation of EOC cells in combination, and only when overexpressed simultaneously in miR-337-3p-expressing cells, could fully restore cell proliferation. In vivo investigation confirmed that miR-337-3p is a tumor suppressor that control expression of PIK3CA and PIK3CB encoded protein: p110α and p110β. Altogether, our results demonstrate that miR-337-3p is a tumor suppressor in EOC that inhibits the expression of PIK3CA and PIK3CB.


Adoptive cell therapy using regulatory T cells as individualized medicine to promote clinical transplantation tolerance.
Despite the success of organ transplantation, most transplant patients are susceptible to variety of infections and cancer due to the use of potent immunosuppressive drugs for life to prevent transplant rejection. Regulatory T cells are capable of preventing transplant rejection while leaving the immune system's function against infection intact. Thus, adoptive cell therapy using patient-specific regulatory T cells as individualized medicine could promote clinical transplantation tolerance without the use of nonspecific immunosuppressive agents.


NGALR is overexpressed and regulated by hypomethylation in esophageal squamous cell carcinoma.
Neutrophil gelatinase-associated lipocalin receptor (NGALR) mRNA level is reduced in isolated chronic myelogenous leukemia blasts but up-regulated in esophageal squamous cell carcinoma (ESCC). The mechanism of NGALR regulation is unknown. Here, we show the expression pattern of NGALR and examine the aberrant methylation of its gene in ESCC and esophageal carcinoma cell lines. The expression pattern of NGALR was analyzed by immunohistochemistry in 59 ESCCs and compared with noncancerous tissues. The DNA methylation status was investigated by methylation-specific PCR and by bisulfite genomic sequencing in esophageal carcinoma cell lines and surgically resected samples. Methylated cell lines were treated with a methylation inhibitor to restore NGALR expression. The expression of NGALR in ESCC was significantly higher in tumor cell membrane and cytoplasm than in normal esophageal epithelium (P < 0.01). Methylated alleles were detected in three NGALR-nonexpressing cell lines but were not detected in three NGALR-expressing cell lines. Treatment of methylated cell lines with 5-aza-2'-deoxycytidine, a methylation inhibitor, restored NGALR expression. In surgically resected samples, 31 of 77 (40.3%) primary esophageal carcinomas and 46 of 77 (59.7%) paired normal tissues contained methylated NGALR alleles (P < 0.05). Our results suggest that NGALR hypomethylation contributes to its expression in esophageal carcinomas and that this overexpression may play a role in the pathogenesis of esophageal carcinomas.


Studying colloidal aggregation using liposomes.
Colloidal aggregation using liposomes has been studied in this chapter. As criteria of stability, the stability factor, an extension of the DLVO theory of colloidal stability, the fractal dimension of the liposome aggregates and the different regimes of aggregation (RLCA and DLCA) and the temperature have been used.


Relation of age, race, and allotype to immunoglobulin subclass concentrations.
Concentrations of IgG1, IgG2, and total IgG were measured by a solid phase radioimmunoassay in sera from 36 healthy adults and 114 healthy children. As expected, IgG2 and total IgG had a positive correlation with age in children. In addition to age, several other factors were associated with significant differences in serum subclass concentrations. Female children had higher concentrations of IgG1 than males, and black subjects had significantly higher concentrations of IgG1, IgG2, and total IgG than whites. Although Km(1) and Gm(23) immunoglobulin allotypes had no relation to subclass concentrations when tested as single factors, the Km(1) allotype interacted significantly with race so that Km(1)-positive black children had higher IgG2 concentrations than other subjects. Our findings may explain, in part, recent observations of an association of the Km(1) allotype with altered immune responses of blacks to certain vaccines containing bacterial polysaccharides. In addition, our data indicate the need to control factors such as sex, race, and allotype in studies of subclass concentrations or immune responses.


The use of morphologic tissue examinations as novel technique for estimation of drug adverse reactions in hospitalized patients.
Morphologic evaluation of tissue specimens from a hospital population was used to identify and classify adverse reactions to drugs. With the use of this novel technique, the incidence of adverse tissue reactions was found to be 3.6% out of which 1.5% were found to be definitely caused by a specific pharmacological agent. Adverse tissue reactions were both sex- and age-related occurring more often in women and more frequently between the ages of 51-60 years. Although adverse tissue reactions were noted less frequently in males, a definite causative agent was identified in over 50% of males in which a tissue reaction was observed. Endometrium and liver were the predominant tissues altered morphologically in our hospital population. Estrogenic preparations and alcohol were found to be most frequently implicated in the observed adverse tissue reactions. In comparison to the observation of symptoms associated with drug use, our study provides an alternate means of relating an adverse reaction to pharmacological agent employed in that subjective bias can successfully be removed. Although the present system described appears to be more rigorous in identification of adverse reactions, evidence indicates that tissue adverse reaction technique may be advantageous in determination of an unwanted response in patients under 60 years of age. It is hoped that the tissue adverse reaction evaluation may provide a more accurate prediction of possible adverse effects and perhaps may be a more reliable, sensitive system for estimation of adverse effects in hospitalized patients.


Sport-related concussive convulsions: a systematic review.
The incidence of sport-related concussion (SRC) continues to rise. Presentations of concussed athletes vary from subtle symptoms to notable signs. Between the 4th and 5th iterations of the Concussion in Sport Group (CISG) guidelines, concussive convulsions were removed as a modifying factor, but little evidence or discussion supported this change. While considerable research exists regarding post-traumatic epilepsy in moderate to severe traumatic brain injury, convulsions following SRC are relatively understudied. There is no clear consensus on the prevalence of convulsions, seizures, or the management of these entities following SRC. The aim of this review was to assess the state of the literature, describe the management trends of concussive convulsions and post-traumatic epilepsy in the SRC population, and provide evidence and guidance for the management of these athletes. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were adapted for a review of heterogeneous literature. English-language titles and abstracts published prior to June 2017 were searched systematically across four electronic databases. Primary peer-reviewed journal articles were included if they reported individuals of any age or gender who suffered a concussion or mild traumatic brain injury that was associated with seizure activity during a sports/recreational event. Of 852 records screened for review, 58 full-text articles were assessed for eligibility. Eight studies with 130 athletes total met the inclusion criteria. Of these individuals suffering a SRC convulsion or a post-concussive seizure, 0.8% received antiepileptic medications, 24.6% underwent electroencephalography, and 30.8% underwent brain imaging. The mean time until the participant returned to play was 14.8 days. Only 6.9% developed long-term sequelae over a mean follow-up time of 3.3 years. The current literature describing concussive convulsions and post-concussion seizure in sports is limited. A void of primary literature concerning the management of patients with concussive convulsions or seizures and the long-term sequelae among this population remains. However, the evidence available suggests that concussive convulsions do not need to be a primary modifying factor in the management of SRC.


Bifurcation structure of a chemostat model for an age-structured predator and its prey.
We model a chemostat containing an age-structured predator and its prey using a linear function for the uptake of substrate by the prey and two different functional responses (linear and Monod) for the consumption of prey by the predator. Limit cycles (LCs) caused by the predator's age structure arise at Hopf bifurcations at low values of the chemostat dilution rate for both model cases. In addition, LCs caused by the predator-prey interaction arise for the case with the Monod functional response. At low dilution rates in the Monod case, the age structure causes cycling at lower values of the inflowing resource concentration and conversely prevents cycling at higher values of the inflowing resource concentration. The results shed light on a similar model by Fussmann et al. [G. Fussmann, S. Ellner, K. Shertzer, and N. Hairston, Crossing the Hopf bifurcation in a live predator-prey system, Science 290 (2000), pp. 1358-1360.], which correctly predicted conditions for the onset of cycling in a chemostat containing an age-structured rotifer population feeding on algal prey.


In vitro antimicrobial properties and chemical composition of Santolina chamaecyparissus essential oil from Algeria.
The chemical composition of the essential oil obtained from the aerial parts of Santolina chamaecyparissus L., growing in Algeria, was investigated by GC-MS analyses. A total of 36 compounds were identified, accounting for 91.7% of the essential oil obtained. Camphor (31.1%) and cubenol (17.0%) were the predominant compounds. The potential of the antimicrobial activity was also investigated and the tested sample proved to be very active against Klebsiella pneumonia and Candida albicans (34.1 +/- 0.02 mm and 35.0 +/- 0.01 mm, respectively). Transverse sections of the leaf and stem of the plant suggest that the essential oil is localized in endogenous and exogenous sites.


Phytase from Citrobacter koseri PM-7: Enhanced production using statistical method and application in ameliorating mineral bioaccessibility and protein digestibility of high-phytate food.
The present study was aimed at enhancing phytase (Phy-Ck) production from Citrobacter koseri PM-7 using response surface methodology (RSM) and improving the bioaccessibility of minerals (Fe and Zn) and protein digestibility in high-phytate food using Phy-Ck. A five-variable and three-level central composite design of RSM using wheat bran (6.681%, w/v), inoculum level (2.5%, v/v), and triton X-100 (0.2%, v/v) resulted in up to 5.57-fold (1.047 U/ml) improvement in Phy-Ck yield from C. koseri PM-7 when compared with fermentation media I and II. The model was successfully validated in the design space by taking a random set of variable combinations. Treatment of high-phytate food with partially purified Phy-Ck showed improvement in mineral bioaccessibility maximally for defatted sesame flour (DSF) (Fe 45.5%; Zn 50.7%) followed by wheat flour (WF) (Fe 13.5%; Zn 14.4%), green gram flour (GGF) (Fe 0.7%; Zn 3.8%) and defatted groundnut flour (DGF) (Zn 5.6%). The in vitro protein digestibility (IVPD) of WF increased from 48.83 to 65.04%, GGF from 45.04 to 57.12%, and DSF from 47.34 to 55.7% after Phy-Ck treatment.


Can reporting more lead to less? The role of metrics in assessing liver transplant program performance.
Appropriate metrics for performance analysis is an active topic of debate within the transplant community. This study explores current proposals on metric expansion as well as potential metrics and prospective collaborations that have not received widespread discussion within the transplant community. The premature introduction of additional, nonvalidated metrics risks behaviors that may undermine donor utilization and patient access to transplantation.


[Ciaglia percutaneous dilatation tracheotomy with endoscopic control. Analysis of complication-fraught steps].
Since the first description by Ciaglia in 1985, percutaneous dilatational tracheostomy (PDT) has emerged worldwide to be a favored and frequently used technique for airway control. Advantages are the rapidity, simplicity and independence of the physician. These characteristics tempt clinicians to perform the procedure uncritically and thus produce complications. Based on our experiences with the technique and on a critical analysis of the literature the indications and optimal operative technique are discussed. Operative steps are illustrated and potential pitfalls (anatomic variations, injury to vital structures and bleeding) are defined. In our experience endoscopic control plays a crucial role in preventing intraoperative complications. ENT colleagues should know the technique because of their experience with tracheotomized patients and should offer their services to other disciplines.


Effects of benazepril on insulin resistance and glucose tolerance in uremia.
This study tested whether the angiotensin-converting enzyme inhibitor (ACEI) benazepril can improve the insulin resistance and glucose tolerance in uremia. Fifteen uremic hypertensive patients were treated with benazepril in a dose of 10-20 mg per day for ten weeks, and ten healthy subjects, matched in age, sex ratio and body mass index (BMI), served as the control group. Before and after the treatment, an oral 75 g glucose tolerance test (OGTT) and insulin release test (IRT) were performed in two groups above, and the blood glucose and serum insulin concentrations at 0, 60, 120 and 180 minutes after glucose load were examined, and the insulin glycoregulatory activity, including insulin sensitivity index (ISI), glucose uptake rate (M), total areas under the glucose and insulin curves during OGTTs (AUCG AUCINS), was calculated. The changes of serum potassium and renal function before and after treatment were observed. It showed that (1) benazepril could reduce blood pressure significantly (SBP decreased from 174.8 +/- 12.0 mmHg to 151.5 +/- 9.0 mmHg, p <0.001; DBP decreased from 108.0 +/- 8.2 mmHg to 95.3 +/- 9.0 mmHg, p <0.001). The total response rate was 86.7%. (2) After treatment with benazepril for ten weeks, the blood glucose and serum insulin concentrations after glucose load and AUCG, AUCINS values in the uremic patients were significantly lower than before treatment, but were still significantly higher than in the controls. The values of ISI and M in the uremic patients after treatment were much higher than before treatment, but were still significantly lower than in the control subjects. (3) The differences of serum potassium and creatinine levels before and after treatment were not significant. These findings indicate that benazepril can not only reduce blood pressure effectively and safely, but also partly improve insulin resistance, hyperinsulinemia and glucose intolerance in uremia.


Monte Carlo calculation of the dose distributions across a plane bone-marrow interface during diagnostic X-ray examinations.
The distribution of dose across a plane bone-marrow interface on irradiation with various diagnostic X-ray beams at a representative site have been determined using the Monte Carlo method. The site was in a dorsal vertebra near its surface and situated at a depth of 70 mm under the skin. The X-ray beams studied were generated at 100, 90, 80 and 70 kV with 2 mm aluminium added filter and at 55 kV with 1 mm aluminium added filter. It was found that the dose to bone marrow due to excess photoelectrons produced in bone falls off rapidly as the distance from the bone-marrow interface increases. Consequently, the percentage excess dose to a plane bone-marrow cavity, which is almost constant for the range of kV studied, is significant only if the cavity size is small.


Quantitative MR microscopy of enzymatically degraded articular cartilage.
Structural changes in bovine patellar articular cartilage, induced by component selective enzymatic treatments, were investigated by measuring tissue T(2) relaxation at 9.4 T. This MRI parameter was compared with Young's modulus, a measure of elastic stiffness and loadbearing ability of cartilage tissue. Collagenase was used to digest the collagen network and chondroitinase ABC to remove proteoglycans. Polarized light microscopy and digital densitometry were used to assess enzyme penetration after 44 hr of enzymatic digestion. T(2) relaxation in superficial cartilage increased significantly only in samples treated with collagenase. A statistically significant decrease in Young's modulus was observed in both enzymatically treated sample groups. These results confirm that T(2) of articular cartilage is sensitive to the integrity of collagen in the extracellular matrix. Nonetheless, it does not appear to be an unambiguous indicator of cartilage stiffness, which is significantly impaired in osteoarthrosis.


Bacterial vectors and delivery systems in cancer therapy.
Live bacterial vectors may be useful tools for the development of novel cancer therapies that can be added to the repertoire of existing drugs. Several bacterial strains effectively colonize solid tumors and act as antitumor therapeutics. The naturally occurring tumor-colonizing characteristics of bacterial species such as Salmonella sp, Clostridium sp and Escherichia coli can be further modified by genetic manipulations, making these bacterial systems excellent vehicles for the production and targeted delivery of therapeutic molecules into cancer cells. This feature review summarizes recent research on cancer therapy using genetically modified bacteria. Different approaches - bactofection, DNA vaccination, and bacterially mediated protein and RNAi delivery - in which modified bacteria are used as anticancer therapeutics, are discussed.


[Transmission of information concerning image brightness by neurons of the lateral geniculate body in the cat].
The response of the LGB neurons to moving stimuli consisting of 8 bars with stepwise increasing luminousness (by 0.47 lg units) revealed threshold intensities varying from neuron to neuron by 1.5--2.0 lg units. Frequency of the on- and off-central neurons activity depended on stimuli luminousness. Both on- and off-neurons increased their firing rate on increase of the stimuli luminousness. The probable mechanism of information transmission of the luminousness change (with constant contrast) and its place in the hypothesis of the point-to-point image description at the subcortical level of the visual system, are discussed.


[Ministernotomy improves the postoperative course in aortic valve replacement].
The advantages and the safety aspects of ministernotomy, in aortic valve replacement, are presently under investigation. The aim of this study was to compare the postoperative results between ministernotomy access and standard total sternotomy access. Between January 1997 and July 2002, 98 patients underwent elective aortic valve replacement. They were divided into two groups: group Gm (49 patients) undergoing a ministernotomy approach ("reversed C" or "reversed L") and group Gs (49 patients) undergoing conventional total sternotomy. The length of the skin incision was significantly shorter in group Gm (p < 0.001). The total operative time was significantly longer in group Gm (p = 0.02), but no significant differences were found in the cardiopulmonary bypass and aortic cross-clamping times. Mean mediastinal drainage, incidence of bleeding > 800 ml, mechanical ventilation time, intensive care unit stay and hospital stay were significantly greater in group Gs. Five days after the surgical procedure, spirometric analysis demonstrated a significant reduction in total lung capacity, and in maximum expiratory and inspiratory pressures in group Gs compared with group Gm (p = 0.003, p = 0.001, p = 0.01, respectively). Our results showed that in addition to cosmetic advantages, ministernotomy is also associated with a better outcome in terms of sternal stability, blood loss and transfusions, and postoperative pain. Ministernotomy also improved the recovery of respiratory function, with a shorter mechanical ventilation time and allowed an earlier hospital discharge.


[Diagnostic accuracy of FP-CIT SPECT in the evaluation of patients with clinically uncertain parkinsonian syndrome].
To determine diagnostic accuracy of FP-CIT SPECT in a subgroup of patients who clinically present nonconclusive or atypical characteristics of parkinsonism (Clinically Uncertain Parkinsonian Syndromes, CUPS), and assess the contribution of the quantitative analysis in this group of patients. We included 54 patients who make up the CUPS group. After a variable follow-up period, we evaluated the existence of a degenerative parkinsonism and compared it with the result of the FP-CIT SPECT, establishing the diagnostic accuracy of this procedure in the CUPS patient group. We obtained a high diagnostic accuracy of neurodegenerative Parkinsonism in the CUPS patient group (sensitivity: 85%; specificity: 93%). False positive results were obtained in patients with vascular parkinsonism and most of the false negative results in patients with Parkinson's disease. The quantitative evaluation did not contribute data of relevance to the qualitative evaluation. FP-CIT SPECT makes it possible to show the involvement of nigrostriatal dopaminergic pathway, also contributing with information of relevance to the clinician about the etiology of the extrapyramidal symptomatology in patients with nonconclusive signs and symptoms of the existence of a Parkinsonism.


[Basic concept of bone remodeling.]
Bone remodeling is a fundamental mechanism of bone metabolism in tissue level. Bone remodeling demonstrates sequential phase of activation, resorption, reversal, and formation. Bone histomorphometry can make the quantitative assessment of the turnover in bone remodeling.


The frequency and suppressor function of CD4+CD25highFoxp3+ T cells in the circulation of patients with squamous cell carcinoma of the head and neck.
Immune escape is a characteristic feature of head and neck squamous cell carcinoma (HNSCC). Regulatory T cells (Treg) might contribute to HNSCC progression by suppressing antitumor immunity, and their attributes in patients are of special interest. Multicolor flow cytometry was used to study the frequency and phenotype of Treg in peripheral blood lymphocytes of 35 patients with HNSCC and 15 normal controls (NC). CD4(+)CD25(high) T cells were purified by fluorescence-activated cell sorting and tested for regulatory function by coculture with carboxyfluorescein diacetate succinimidylester-labeled autologous CD4(+)CD25(-) responder cells. The percentages of circulating CD4(+)CD25(+) T cells were increased in HNSCC patients (5 +/- 3%) versus NC (2 +/- 1.5%). In patients, this cell subset largely contained CD4(+)CD25(high)Foxp3(+) T cells and only few CD25(low/interm) cells. In addition, the frequency of Treg positive for CD62L, CTLA-4, Fas, FasL, and Foxp3 was greater in the circulation of patients than in NC (P < 0.0001). In HNSCC patients, Treg mediated significantly higher suppression (78 +/- 7%) compared with Treg in NC (12 +/- 4%) with P < 0.0001. Surprisingly, higher Treg frequency (P < 0.0059) and levels of suppression (P < 0.0001) were observed in patients with no evident disease (NED) than in untreated patients with active disease (AD). The frequency of T cells with suppressor phenotype and function (Treg) was significantly greater in HNSCC patients who were NED after oncologic therapy relative to those with AD. This finding suggests that oncologic therapy favors expansion of Treg.


[Psychophysiological characteristics and metabolic indices of neurotransmitter metabolism in patients ill with endogenous depression].
Research was conducted upon 28 patients with a diagnosis of endogenous depression after their pharmacological treatment with imipramine or chlorimipramine. The investigation considered the interrelationship between psychophysiological parameters (heart rate, respiration rhythm, postural muscular tension) and the indices of the cholinergic and adrenergic systems (kinetic parameters of choline transport in the blood; Vmax, the activity of plasmic pseudocholinesterase, Che; blood acetylcholinesterase AChE, monoaminoxidase in blood platelets, MAO; and dopamine beta hydroxylase DBH). The results indicate that during relapse of endogenous depression there occurs an imbalance in the cholinergic-adrenergic systems which may be the result of some somatic symptoms typically found in the depression syndrome. The appearance, after pharmacotherapy, of a correlation between the indices of the activity of the cholinergic system with the respiratory rhythm suggest that the part played by the cholinergic mechanism in the regulation of autonomic processes normalizes itself during the course of successful therapy. The appearance of characteristic correlations between the activity of the cholinergic and adrenergic systems and the psychophysiological parameters in the presence of relatively low psychological stress seems to accompany successful treatment with imipramine and chlorimipramine.


Activities and well-being in older age: effects of self-concept and educational attainment.
The positive effect of activities on well-being is proposed to be mediated by self-conceptualizations and facilitated by socioeconomic status. The hypothesized processes were estimated with LISREL VIII using data from a large cross-sectional survey with a sample of 679 adults aged 65 and older who were representative of older adults living in the Detroit area. Findings indicate that the frequency of performing both leisure and productive activities yields an effect on physical health and depression and that these effects are mediated in part by a sense of self as agentic, but less clearly by a sense of self as social. Furthermore, socioeconomic status, operationalized as formal educational attainment, facilitates the effect of leisure to a greater extent than that of productive activities.


Surfactant protein d expression in chronic rhinosinusitis patients and immune responses in vitro to Aspergillus and alternaria in a nasal explant model.
Common fungi have been implicated in the pathogenesis of chronic rhinosinusitis (CRS) with eosinophilic mucus (EMCRS). Surfactant protein (SP)-D plays an important role in the immune response to Aspergillus fumigatus in the lungs. We sought to determine whether SP-D is expressed in nasal mucosa and investigated the response of SP-D in vitro to fungal allergens. 1) Nasal biopsies from 59 CRS and EMCRS patients, stratified into allergic fungal sinusitis (AFS), nonallergic fungal eosinophilic sinusitis (NAFES), and nonallergic nonfungal eosinophilic sinusitis (NANFES) were studied by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR), immunostaining and enzyme-linked immunosorbent assay (ELISA). 2) Nasal tissue from three CRS and three NANFES patients was cultured with fungal allergens in a nasal explant in vitro model for 24 hours at increasing concentrations and mRNA SP-D secreted SP-D protein levels in response to the fungi determined by qRT-PCR and ELISA. Staining for SP-D was detected in the submucosal glands from the nasal biopsies in all patient groups except for AFS. By ELISA, SP-D was undetectable in AFS and decreased in NAFES, NANFES, and CRS compared with controls. CRS patients in vitro cultured with Aspergillus and Alternaria allergens in a nasal tissue explant model induced up-regulation of SP-D by qRT-PCR. In contrast, NANFES nasal tissue explants cultured with Aspergillus allergens induced down-regulation of SP-D. We report for the first time the expression of SP-D in both diseased and normal nasal mucosa. SP-D expression in CRS patients is up-regulated by fungal allergens in an in vitro model. These results may provide potential novel therapy for treatment of CRS.


Mortality trends due to chronic obstructive pulmonary disease in Brazil.
The purpose of this study was to update and analyze data on mortality trend due to chronic obstructive pulmonary disease (COPD) in Brazil. Initially, the specific COPD mortality rates were calculated from 1989 to 2009 using data collected from DATASUS (Departamento de Informática do SUS - Brazilian Health System Database). Then, the polynomial regression models from the observed functional relation were estimated based on mortality coefficients and study years. We verified that the general mortality rates due to COPD in Brazil showed an increasing trend from 1989 to 2004, and then decreased. Both genders showed the same increasing tendencies until 2004 and decreased thereafter. The age group under 35 years old showed a linear decreasing trend. All other age groups showed quadratic tendencies, with increases until the years of 1998-1999 and then decreasing. The South and Southeast regions showed the highest COPD mortality rates with increasing trends until the years 2001-2002 and then decreased. The North, Northeast and Central-West regions showed lower mortality rates but increasing trend. This is the first report of COPD mortality stabilization in Brazil since 1980.


Assessment of ventriculo-vascular properties in repaired coarctation using cardiac magnetic resonance-derived aortic, left atrial and left ventricular strain.
In patients with repaired coarctation of aorta (CoA), we assessed ventriculo-vascular characteristics using CMR-derived aortic area strain (AAS), left atrial (LA) and left ventricular (LV) longitudinal and circumferential strain (LS, CS). Seventy-five subjects including 50 with repaired CoA divided into hypertensive (n = 25), normotensive (n = 25) and 25 controls were studied. AAS was measured at 3 levels: ascending aorta, proximal descending and descending aorta. LA and LV LS were measured using CMR-feature tracking. LA and LV end-diastolic volumes, ejection fraction (EF) and mass were measured. Mean patient age was 19.7 ± 6.7 and controls 23 ± 15 (years). All strains (LA, LV, ascending and descending aortic) were lower in CoA subgroups compared to controls except the AAS at diaphragm, which was not different. Comparisons between hypertensive and normotensive CoA showed no differences in LV mass, LV volumetric indices, and LA and LV strain indices; however, ascending AAS was lower in hypertensive subgroup (p = 0.02). Ascending AAS was correlated with LV mass (r = -0.4, p = 0.005), LVEF (r = -0.4, p = 0.004), systolic blood pressure (r = -0.5, p = 0.0001) and LVLS (r = 0.5, p = 0.001). Ascending AAS correlated with LV mass, EF and LVLS. In hypertensive CoA, ascending AAS was reduced compared to normotensive CoA and controls, indicating vascular remodelling differences influenced by ongoing hypertension. • Impaired arterial strain is a measure of increased stiffness in arteries • Ascending aorta strain correlates with left ventricular mass and longitudinal strain • Ascending aorta strain is significantly lower in hypertensive coarctation patients • Hypertension may be a consequence of vascular pathology persisting despite repair.


The effect of problem-based learning with cooperative-learning strategies in surgery clerkships.
Cooperative learning is used often as part of the problem-based learning (PBL) process. But PBL does not demand that students work together until all individuals master the material or share the rewards for their work together. A cooperative learning and assessment structure was introduced in a PBL course in 10-week surgery clerkship, and the difference was evaluated between this method and conventional PBL in an acute abdominal pain module. An experimental design was used. No significant differences in achievement were found between the study and control group. Both the study and control group students who scored low on the pretest made the greatest gains at the end of the education. Students in the cooperative learning group felt that cooperation helped them learn, it was fun to study and expressed satisfaction, but they complained about the amount of time the groups had to work together, difficulties of group work, and noise during the sessions. This study evaluated the impact of a cooperative learning technique (student team learning [STL]) in PBL and found no differences. The study confirms that a relationship exists between allocated study time and achievement, and student's satisfaction about using this technique.


New non competitive AMPA antagonists.
New halogen atom substituted 2,3-benzodiazepine derivatives condensed with an azole ring on the seven membered part of the ring system of type 3 and 4 as well as 5 and 6 were synthesized. It was found that chloro-, dichloro- and bromo-substitutions in the benzene ring and additionally imidazole ring condensation on the diazepine ring can successfully substitute the methylenedioxy group in the well known molecules GYKI 52466 (1) and GYKI 53773 (2) and the 3-acetyl-4-methyl structural feature in 2, respectively, preserving the highly active AMPA antagonist characteristic of the original molecules. From the most active compounds (3b,i) 3b (GYKI 47261) was chosen for detailed investigations. 3b revealed an excellent, broad spectrum anticonvulsant activity against seizures evoked by electroshock and different chemoconvulsive agents indicating a possible antiepileptic efficacy. 3b was found to be highly active in a transient model of focal ischemia predictive of a therapeutic value in human stroke. 3b also reversed the dopamine depleting effect of MPTP and antagonized the oxotremorine induced tremor in mice indicating a potential antiparkinson activity.


Effects of maternal smoking during pregnancy on body composition in offspring.
The aim of the present cross-sectional study was to use objective methods to assess the association between maternal smoking and body composition in offspring. A total of 2508 grade 4 school children were enrolled; all underwent lifestyle disease and passive smoking screening. Children were classified into four groups according to their urinary cotinine level and maternal smoking status during or before pregnancy. Items measured on lifestyle disease screening were compared among the four groups. Only degree of obesity (DO) and body mass index (BMI) were significantly associated with maternal smoking during pregnancy. The prevalence of both DO >20% and DO >30%, and BMI >22% and BMI >25% was highest in children of mothers who smoked during pregnancy. These children had a tendency toward shorter height and increased weight although it was not statistically significant. There were no significant differences between maternal smoking status and lipid profile among groups. Confounders such as food, exercise and sleep were able to be eliminated. Maternal smoking during pregnancy may be an independent risk factor of changing body composition in offspring, that is, shorter height and increased weight.


Deficient passive and one-way active avoidance acquisition following medial forebrain bundle lesions in rats.
Cathodal electrolytic lesions of the medial forebrain bundle (MFB) at posterior hypothalamic levels in male hooded rats produced a mild, transient hypodipsia and lowered jump thresholds to footshock. The lesions produced marked deficits in passive avoidance performance in a paradigm that paired discrete, linearly incrementing footshock intensities with contact of a water spout following 48 hr of water deprivation. Intraperitoneal injections of DL-5-hydroxytryptophan (75 mg/kg), the immediate metabolic precursor of serotonin, had no effect on the passive avoidance performance of either experimental or operated control subjects. Lesions of the MFB also resulted in deficient acquisition in a one-trial step-through passive avoidance paradigm not using motivation to drink and caused a severe acquisition deficit in a one-way active avoidance task. Lesions of the septal nuclei produced lowered jump thresholds but did not affect acquisition in the first passive avoidance task. The results are interpreted as indicating a lesion-induced deficiency in fear learning, independent of the serotonergic functions of the MFB.


Cabazitaxel: more than a new taxane for metastatic castrate-resistant prostate cancer?
The taxanes are recognized as a major class of chemotherapeutic agents; however, mechanisms of innate and acquired resistance can limit their usefulness. Cabazitaxel, a novel taxane with microtubule-stabilizing potency similar to docetaxel, exhibits activity against tumor cell lines resistant to paclitaxel and docetaxel. Cabazitaxel showed linear pharmacokinetics and a terminal elimination half-life comparable with that of docetaxel, findings which support dosing as a single infusion in three-week treatment cycles. Dose-ranging studies recommended doses of 20 or 25 mg/m(2) every three weeks. Antitumor activity was shown in patients with advanced cancer and chemotherapy failure (including taxane failure). Other early studies investigated the efficacy of cabazitaxel in pretreated metastatic breast cancer, either as a single agent or in combination with capecitabine. Objective antitumor response rates of up to 24% and sustained tumor stabilizations were also observed. The TROPIC phase III study, conducted in patients with metastatic castrate-resistant prostate cancer previously treated with docetaxel, established cabazitaxel as the first chemotherapeutic agent to offer a survival advantage in this patient population. Across these studies, the dose-limiting hematologic toxicity was neutropenia (including febrile neutropenia), usually controllable with colony-stimulating factor/granulocyte-colony stimulating factor support.


Exenatide (exendin-4) improves insulin sensitivity and {beta}-cell mass in insulin-resistant obese fa/fa Zucker rats independent of glycemia and body weight.
The effects of the incretin mimetic exenatide (exendin-4) on metabolic parameters, insulin sensitivity, and beta-cell mass were examined in nondiabetic, insulin-resistant obese fa/fa Zucker rats. After 6 wk of treatment, ad libitum-fed exenatide-treated (EX) and pair-fed vehicle control (PF) rats had comparable food intake, body weight, hemoglobin A(1c) (HbA(1c)), and fasting plasma concentrations of glucose, insulin, and lipids. Concurrent decreases in food intake and weight gain were observed in EX and PF rats, compared with ad libitum-fed vehicle control (CON) rats (P < 0.001). The increases in HbA(1c) and fasting plasma insulin concentrations that occur during the normal progression of this disease model were significantly reduced in EX and PF rats, compared with CON rats (P < 0.001). The insulin sensitivity index (ISI; glucose infusion rate to plasma insulin concentration) measured during a hyperinsulinemic euglycemic clamp was 224% higher in EX rats than CON rats (P < 0.001) and 61% higher in EX rats than PF rats (P < 0.004). The latter difference was despite comparable HbA(1c), fasting glucose, fasting insulin, total cholesterol, high-density lipoprotein, and daily food consumption between EX and PF animals. In the absence of exenatide, beta-cell mass was hyperbolically related to ISI (beta-cell mass * ISI was constant). Analogous to the disposition index, the beta-cell mass * ISI product was 63% greater in EX than PF rats (P < 0.05). Thus, exenatide increased beta-cell mass to a greater extent than would be expected in animals of comparable insulin resistance, suggesting a direct trophic effect on islet neogenesis in obese fa/fa rats independent of body weight and glycemia.


lncRNA in the liver: Prospects for fundamental research and therapy by RNA interference.
Long non-coding RNAs constitute the most abundant part of the transcribed mammalian genome. lncRNAs affect all essential processes in the living cell including transcription, splicing, translation, replication, shaping of chromatin and post translational modification of proteins. Alterations in lncRNA expression have been linked to a number of diseases; thus, modulation of lncRNA expression holds a huge potential for gene-based therapy. In this review we summarize published data about lncRNAs in the context of hepatic carcinogenesis and liver fibrosis, and the corresponding potential targets for gene therapy. Recent advancements in targeted delivery to the liver made RNA interference an invaluable tool to decipher hepatic lncRNA function and to develop lncRNA-oriented therapies for liver-involved diseases in the future. Different approaches for RNA delivery that can be used for functional studies in the lab and for clinical lncRNA based applications are critically discussed in this review.


Pre-emptive treatment of hepatitis B infection by lamivudine in two Tunisian renal transplant recipients.
Infection with hepatitis B virus has a major implication for transplant recipients due to the risk of reactivation under immunosuppression, progression to chronic liver disease, development of liver cirrhosis and hepatocellular carcinoma. We report two cases of renal transplantation patients who were hepatitis B surface antigen positive before transplantation and were treated by Lamivudine.


[De novo distal superior cerebellar artery aneurysm after embolization of a ruptured aneurysm at the bifurcation of the contralateral basilar and superior cerebellar arteries].
The formation of de novo aneurysms in the posterior fossa after successful treatment of a previous aneurysm in the same fossa is rare. Here we describe a case of a de novo generated aneurysm at the distal superior cerebellar artery(SCA)7 years after the successful obliteration of an aneurysm at the contralateral basilar artery(BA)-SCA bifurcation. The treatment of the original posterior fossa aneurysm may lead to hemodynamic changes that may contribute to the formation of a de novo aneurysm at another vulnerable point in the posterior fossa circulation. We conclude that a close surveillance is required after the initial treatment of posterior fossa aneurysms in order to detect the possible formation of de novo aneurysms.


The development and integration of fine motor sequences in 12- to 18-month-old children: a test of the modular theory of motor skill acquisition.
According to the modular model, skill development proceeds through the development of stable units of action called subroutines. The development of these programmed units frees the child to attend to those parts of the action not yet mastered. Once consolidated they can be applied to many different contexts. Thus, complex skill sequences can be produced. The theory generates several predictions, most fundamental being an association between increasing proficiency and increasing consistency. Experiment 1 was a longitudinal study in which six 12-month-old children were observed over a period of eight months. Various manipulative tasks were used, notably the placement of rods in corresponding holes. Experiment 2 was a cross-sectional study of performance consistency in rod placement (N = 30). Results showed that consistency decreases as proficiency increases. It is concluded therefore that the programmed components of complex actions are not characterized by the invariance predicted by modular theory.


On-line monitoring of a microwave-assisted chemical reaction by nanolitre NMR-spectroscopy.
We report the use of a nanolitre nuclear magnetic resonance (NMR) spectroscopy microfluidic chip hyphenated to a continuous-flow microlitre-microwave irradiation set-up, for on-line monitoring and rapid optimization of reaction conditions.


Leaf water relations of Eucalyptus cloeziana and Eucalyptus argophloia in response to water deficit.
Leaf water relations responses to limited water supply were determined in 7-month-old plants of a dry inland provenance of Eucalyptus argophloia Blakely and in a humid coastal provenance (Gympie) and a dry inland provenance (Hungry Hills) of Eucalyptus cloeziana F. Muell. Each provenance of E. cloeziana exhibited a lower relative water content at the turgor loss point, a lower apoplastic water content, a smaller ratio of dry mass to turgid mass and a lower bulk modulus of elasticity than the single provenance of E. argophloia. Osmotic potential at full turgor and water potential at the turgor loss point were significantly lower in E. argophloia and the inland provenance of E. cloeziana than in the coastal provenance of E. cloeziana. There was limited osmotic adjustment in response to soil drying in E. cloeziana, but not in E. argophloia. Between-species differences in water relations parameters were larger than those between the E. cloeziana provenances. Both E. cloeziana provenances maintained turgor under moderate water stress through a combination of osmotic and elastic adjustments. Eucalyptus argophloia had more rigid cell walls and reached lower water potentials with less reduction in relative water content than either of the E. cloeziana provenances, thereby enabling it to extract water from dryer soils.


A Fisher scoring algorithm for the weighted regression method of QTL mapping.
An improved weighted least square (LS) method for quantitative trait loci (QTL) mapping using the estimating equation (EE) algorithm was developed recently. The method is more efficient than both the LS and the weighted LS methods and slightly less efficient than the mixture model maximum likelihood (ML) method. The iteration process of the EE algorithm is implicit. We developed a Fisher-scoring algorithm for the weighted LS method. The iteration process is explicit and easy to program. In addition, the method automatically provides an approximate variance-covariance matrix for the estimated QTL parameters as a by-product of the iteration process. As a consequence, a W-test statistic can be used for testing the significance of QTL. To compare the Fisher scoring algorithm with the expectation maximization (EM)-based ML method, we also developed a slightly simplified method to compute the variance-covariance matrix of the estimated parameters under the EM algorithm.


Numerical modeling of drug delivery in a dynamic solid tumor microvasculature.
The complicated capillary network induced by angiogenesis is one of the main reasons of unsuccessful cancer therapy. A multi-scale mathematical method which simulates drug transport to a solid tumor is used in this study to investigate how capillary network structure affects drug delivery. The mathematical method involves processes such as blood flow through vessels, solute and fluid diffusion, convective transport in extracellular matrix, and extravasation from blood vessels. The effect of heterogeneous dynamic network on interstitial fluid flow and drug delivery is investigated by this multi-scale method. The sprouting angiogenesis model is used for generating capillary network and then fluid flow governing equations are implemented to calculate blood flow through the tumor-induced capillary network and fluid flow in normal and tumor tissues. Finally, convection-diffusion equation is used to simulate drug delivery. Three approaches are used to simulate drug transport based on the developed mathematical method: without a vascular network, using a static vascular network, and a dynamic vascular network. The avascular approach predicts more uniform and higher drug concentration than vascular approaches since the simplified assumptions are implemented in this method. The dynamic network which uses more realistic assumptions predicts more irregular blood vessels, high interstitial pressure, and more heterogeneity in drug distribution than other two approaches.


The Q-CHAT (Quantitative CHecklist for Autism in Toddlers): a normally distributed quantitative measure of autistic traits at 18-24 months of age: preliminary report.
We report a major revision of the CHecklist for Autism in Toddlers (CHAT). This quantitative CHAT (Q-CHAT) contains 25 items, scored on a 5 point scale (0-4). The Q-CHAT was completed by parents of n = 779 unselected toddlers (mean age 21 months) and n = 160 toddlers and preschoolers (mean age 44 months) with an Autism Spectrum Condition (ASC). The ASC group (mean (SD) = 51.8 (14.3)) scored higher on the Q-CHAT than controls (26.7 (7.8)). Boys in the control group (27.5 (7.8)) scored higher than girls (25.8 (7.7)). The intraclass correlation for test-retest reliability was 0.82 (n = 330). The distribution in the control group was close to normal. Full examination of the clinical validity of the Q-CHAT and test properties is underway.


[Secular trends of height in adulthood of children born in the city of São Paulo, Brazil from 1950-1976].
The purpose of this study was to estimate the secular trend/change in the height of young males born in the city of S. Paulo between 1950 and 1976 and measured in the year they turn 18 years. A random and representative sample (6,942 individuals) was evaluated in military draft. Statistical analyses included Shapiro-Wilk test for normality of height distribution in each birth cohort, and linear regression analysis for trend on heights. Stature has increased 3.42 centimeters during the 27 years covered by the study (1.26 cm/decade). The trend was not linear: in the 50s, there was a statistically significant increase (0.84 cm/decade); in the 60s, a smaller but non-significant increase (0.5 cm/decade) was seen; in the period of 1970-76, a greater increase in heights (2.9 cm/decade) was observed. The secular change rate observed was comparable to the rate seen in other countries. The most recent birth cohorts (1975 and 1976) achieved the higher statures in the study (approximately 175 cm). Despite these height increments, deficits of 1.8 e 6.2 cm were seen when the taller cohorts of the study were compared to American young males born in 1961 (NCHS) and Dutch men born in 1972. If there won't be any changes in the accelerated rates of the 70s, young people of São Paulo may overcome these deficits in about one or three decades.


Psychometric testing of the Revised Humane Caring Scale for adult patients in Singapore.
In this study, we examined the validity and reliability of the Revised Humane Caring Scale as used by adult patients in a tertiary hospital in Singapore. A three-phase descriptive quantitative study was conducted. In phase I, an expert panel of nurses and inpatients examined the content validity of the scale; phase II comprised a pilot study on 20 patients; and in phase III, a large-scale study on 235 patients was implemented to test the internal consistency of the scale. The results revealed that the content validity index of the scale ranged from 0.856 to 1, and the scale had a high inter-rater agreement kappa value of 0.940. Cronbach's alpha ranged from 0.798 to 0.877 in phase II, and from 0.579 to 0.760 in phase III, respectively. The Revised Humane Caring Scale revealed good content validity and an acceptable level of internal consistency. The scale is an acceptable measurement tool for evaluating adult patients' satisfaction during hospitalization.


[A comparison of the analgesic effect of ketanov and tramal in postoperative pain].
The efficacy of postoperative pain relief by ketanov and tramal was assessed in 42 patients operated on the abdominal organs and lower limb arteries. The time of development of the analgesic effect and duration and depth of analgesia were compared. The drug effects were compared from protocols of clinical examination, hemodynamic changes, and time course of external respiration and blood saturation with oxygen. The findings confirm a high analgesic effect of ketanov, which is not inferior to tramal, and by some parameters even higher.


Noninvasive imaging with thallium-201 scintigraphy may not correlate with survival in patients with osteosarcoma.
Histologic response to preoperative chemotherapy is a strong prognostic factor for osteosarcoma (OS). Thallium-201 (Tl-201) scintigraphic response to initial chemotherapy has previously been described as a predictor of histologic response. In the current study, the authors re-examined a series of patients studied using Tl-201 scintigraphy to determine the correlation between changes observed on Tl-201 scintigraphy and event-free survival (EFS). A total of 22 patients with biopsy-proven OS of the extremity underwent Tl-201 imaging before and immediately after preoperative chemotherapy. The maximum pixel counts taken over the tumor divided by those taken of a background region yielded a tumor-to-background ratio (TBR). The percentage of change in the TBR before and after adjuvant chemotherapy, defined as the alteration ratio (AR), was correlated with EFS. The median AR was 85% (range, 28-100%). The 3-year EFS was 0.72 (95% confidence interval [95% CI], 0.48-0.86) and the 5-year EFS was 0.67 (95% CI, 0.43-0.86). There was no association between AR and EFS detected in this cohort (hazard ratio, 0.99; 95% CI, 0.95-1.02 [Somers rank correlation coefficient, 0.15]). Although Tl-201 scintigraphy was used as a tool for the assessment of response to chemotherapy in patients with OS, the AR did not appear to be predictive of EFS in this small group of patients. It is necessary to use the outcome variables of ultimate interest-EFS and overall survival- and not rely on surrogates for outcome to evaluate potential prognostic factors.


Defining the Role of the MADS-Box Gene, Zea Agamous-like1, a Target of Selection During Maize Domestication.
Genomic scans for genes that show the signature of past selection have been widely applied to a number of species and have identified a large number of selection candidate genes. In cultivated maize (Zea mays ssp. mays) selection scans have identified several hundred candidate domestication genes by comparing nucleotide diversity and differentiation between maize and its progenitor, teosinte (Z. mays ssp. parviglumis). One of these is a gene called zea agamous-like1 (zagl1), a MADS-box transcription factor, that is known for its function in the control of flowering time. To determine the trait(s) controlled by zagl1 that was (were) the target(s) of selection during maize domestication, we created a set of recombinant chromosome isogenic lines that differ for the maize versus teosinte alleles of zagl1 and which carry cross-overs between zagl1 and its neighbor genes. These lines were grown in a randomized trial and scored for flowering time and domestication related traits. The results indicated that the maize versus teosinte alleles of zagl1 affect flowering time as expected, as well as multiple traits related to ear size with the maize allele conferring larger ears with more kernels. Our results suggest that zagl1 may have been under selection during domestication to increase the size of the maize ear.


A new technique of concealed penis repair.
Phimosis associated with concealed penis is not amenable to ordinary circumcision. To our knowledge we describe a new technique to repair concealed penis. From September 2003 to January 2008, 57 consecutive patients with concealed penis were treated using our technique. Median age at surgery was 33 months (range 7 months to 34 years). The technique consists of 3 steps. Step 1 is a ventral incision to slit the narrow ring of the prepuce and expose the glans. Step 2 is a circumferential skin incision made between 2 edges of the ventral diamond-shaped skin defect, followed by midline incision of the dorsal inner prepuce to make 2 skin flaps connected to the glans. Step 3 is skin coverage. Two skin flaps are brought down and sutured together on the ventral side of the penis. The suture line between the penile shaft skin and the flap eventually becomes elliptical. Medical records were reviewed for voiding function, scar formation, and replies from older patients and the parents of younger children about impressions of the surgical results. Median followup was 26 months. No patient had voiding problems. Lymphedema persisted due to suture line constriction in 2 patients who underwent incision of the constriction. All older patients and the parents of younger children were satisfied with the surgical results. Our new method is easy to design and perform to correct concealed penis. It provides a good cosmetic appearance and seems to be applicable in all cases with deficient penile shaft skin.


Alcohol usage predicts holistic perception: A novel method for exploring addiction.
Holistic perception is a special form of automatic and experience dependent processing that prioritises objects of interest through the visual system. We therefore speculated that higher levels of alcohol consumption may be associated with enhanced holistic perception for alcohol cues. In our first experiment, we confirmed this hypothesis by showing that increasing regular alcohol usage was associated with greater holistic perception of alcohol, but not non-alcohol, cues. We replicated this finding in a second experiment, but confirmed drink-specific holistic perception for lager cues was not predicted by experience with that drink, but general alcohol usage. In our final experiment when alcohol images were absent from the task, higher levels of alcohol consumption predicted decreased holistic perception for non-rewarding cues. Alcohol use is therefore linked to inverse alterations in holistic perception for alcohol versus non-alcohol cues, with the latter's effects context dependent. We hypothesise that such inverse relationships may be due to limited cortical resources becoming reutilised for alcohol cues at the expense of other stimuli. Future work will be required to determine holistic perception's role in maintaining addiction, its predictive value in successful abstinence, and its relationship with characteristics of addiction such as cue reactivity, attentional biases and personality traits.


Comparisons of different stages of chick embryonic development by the physiological regulatory response to hyposmotic challenge.
Cardiac myocytes isolated and cultured from 11 day chick embryos present a Ca(2+)-dependent regulatory volume decrease (RVD) when exposed to hyposmotic stimulus. The RVD of myocytes from different embryonic stages were analyzed to evaluate their physiological performance through development. Among the several embryonic stages analyzed (6, 11, 16 and 19 days) only 19 day cardiac myocytes present a greater RVD when compared with 11 day (considered as control), the other ages showed no difference in the regulatory response. As it is known that RVD is Ca(2+) dependent, we decided to investigate the transient free Ca(2+) response during the hyposmotic swelling of the 11 and 19 day stages. The 11 day cardiac myocyte showed a transient 40% increase in intracellular free Ca(2+) when submitted to hyposmotic solutions, and the free Ca(2+) returned to baseline levels while the cells remained in hyposmotic buffer. However, the intracellular free Ca(2+) transient in the 19 day cells during hyposmotic challenge increases 100% and instead of returning to baseline levels, declines to 55% above control, well after the 11 day transient has returned to baseline. Also, quantitative fluorescence microscopy revealed that 19 day cardiac myocytes have more sarcoplasmic reticulum (SR) Ca(2+) ATPase sites per cell as compared to the 11 day cells. Our findings suggest that 19 day cells have more developed intracellular Ca(2+) stores (SR). By evoking the mechanism of Ca(2+) induced Ca(2+) release, the cells have more free Ca(2+) available for signaling the RVD during hyposmotic swelling.


[Reorganization of the interdisciplinary emergency unit at the university clinic of Göttingen].
Configuration of the interdisciplinary emergency unit within the university clinic of Göttingen was successfully reorganized during the past two years. All emergencies except traumatologic, gynecologic and pediatric emergencies are treated within this functional unit which is guided by the center of internal medicine. It is organized in a three shift operation manner over a period of 24 hours. Due to a close interdisciplinary collaboration between different departments patients receive optimal diagnostic and therapeutic treatment within a short period of time. To improve processes within the emergency department a series of measures were taken including the -establishment of an intermediate care unit for unstable patients, setting up of special diagnostic and therapeutic units for the acute coronary syndrome as well as stroke, implementation of standardized clinical pathways, establishment of an electronic data processing network in close communication with all diagnostic entities, introduction of a quality assurance system and reduction of medical costs. Reorganization measures lead to a substantial optimization and acceleration of emergency proceedings and thus, provides optimal patient care around the clock. In addition, medical costs could clearly be reduced at the interface between preclinical and clinical emergency medicine.


[Oxygen consumption and aging in longterm cultures of lens epithelia].
By means of the described technique lens epithelia were cultured in 40 subcultures; at the same time, both the morphological aging processes and oxygen consumption of the cells, were observed using the Warburg respirometer. To date comparable studies are not available. Morphologically, cell enlargement took place in conjunction with signs of degeneration. Oxygen consumption of 2 microliter per hour per 10(5) cells +/- 0.8 remained at a constant level without any significant diurnal rhythm up to subculture 39 and then suddenly fell to about one-fourth of the initial value. As the cells died of an unknown cause, it was concluded that the aerobic metabolism of lens epithelia seemed to be linked to survival without being age related.


Break-up, coalescence and catastrophic phase inversion in turbulent contactors.
When a low concentration of immiscible phase is dispersed, break-up in the impeller region controls the drop size. The traditional application of Kolmogoroff's theory of local isotropic turbulence has been moderately successful in relating equilibrium drop sizes to the physical properties and the turbulent flow, with low power number impellers giving smaller drops at equal mean specific energy dissipation rates, [Formula: see text] However, to explain the reduction in drop size at equal [Formula: see text] on scale-up, the concept of intermittency must be introduced leading to a scale-up rule close to constant tip speed. With increasing concentration, coalescence generally becomes important and drop sizes increase. Modelling of coalescence involves collision frequency and coalescence efficiency. The latter is dependent on the type of drop interface, the establishment of which type for a particular system being difficult. The difficulty is compounded since in clean systems, at concentrations of the aqueous phase > approximately 20% by volume, droplets of oil appear in the aqueous drops whilst the converse is not found. At sufficiently high concentrations, where the concept of collision frequency is questionable, catastrophic phase inversion (CPI) occurs because coalescence becomes so high. Anything that enhances coalescence, e.g. surfactants, particles that bridge interfaces, wettable surfaces, bulk flow patterns, encourages CPI to occur at lower concentrations of dispersed phase. Satisfactory models for CPI are not available.


Prediction of tumor response to experimental radioimmunotherapy with 90Y in nude mice.
To identify those factors that predict variability in tumor response to 90Y-radioimmunotherapy based on measurement of incorporated activity and physical dimensions of individual tumors and to apply the concept of effective dose to radioimmunotherapy. Human colon carcinoma xenografts growing in nude mice were treated with anti-CEA antibodies labeled with 90Y directly or through a bispecific antibody/labeled hapten system. Tumor response was measured as the delay in growth to eight times the treatment volume. Noninvasive activity (based on bremsstrahlung radiation) and dimension measurements were made in these animals at several times after label injection. The following parameters were compared for their ability to predict individual tumor response: (a) injected activity, (b) injected activity times a factor based on average uptake as a function of volume, (c) in vivo activity per volume measured in each animal at a single time, (d) the integral over time of in vivo activity per volume in each animal, and (e) the minimum dose for each animal in a uniformly active ellipsoid whose total activity and dimensions varied over time the same as the tumor. After correcting for differences in injected activity, two parameters account for much of the variability in tumor response. One of these is the general trend of larger tumors to take up less activity per volume. Additional variability can be accounted for by the in vivo activity per volume measurements. The minimum dose as introduced here is likely to be useful in estimating the biologically effective dose delivered by each treatment.


New neptunium(V) borates that exhibit the alexandrite effect.
A new neptunium(V) borate, K[(NpO(2))B(10)O(14)(OH)(4)], was synthesized using boric acid as a reactive flux. The compound possesses a layered structure in which Np(V) resides in triangular holes, creating a hexagonal-bipyramidal environment around neptunium. This compound is unusual in that it exhibits the Alexandrite effect, a property that is typically restricted to neptunium(IV) compounds.


Structure and Function of the Stressosome Signalling Hub.
The stressosome is a multi-protein signal integration and transduction hub found in a wide range of bacterial species. The role that the stressosome plays in regulating the transcription of genes involved in the general stress response has been studied most extensively in the Gram-positive model organism Bacillus subtilis. The stressosome receives and relays the signal(s) that initiate a complex phosphorylation-dependent partner switching cascade, resulting in the activation of the alternative sigma factor σB. This sigma factor controls transcription of more than 150 genes involved in the general stress response. X-ray crystal structures of individual components of the stressosome and single-particle cryo-EM reconstructions of stressosome complexes, coupled with biochemical and single cell analyses, have permitted a detailed understanding of the dynamic signalling behaviour that arises from this multi-protein complex. Furthermore, bioinformatics analyses indicate that genetic modules encoding key stressosome proteins are found in a wide range of bacterial species, indicating an evolutionary advantage afforded by stressosome complexes. Interestingly, the genetic modules are associated with a variety of signalling modules encoding secondary messenger regulation systems, as well as classical two-component signal transduction systems, suggesting a diversification in function. In this chapter we review the current research into stressosome systems and discuss the functional implications of the unique structure of these signalling complexes.


Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6-dihydropyrimidin-2-yl)amide derivatives as PI3Kβ inhibitors.
From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3Kβ isoform. The structure of compound 1 in PI3Kγ was solved revealing a binding mode in agreement with the SAR observed on PI3Kβ. These compounds displayed inhibition in the nanomolar range in the biochemical assay and were also potent p-Akt inhibitors in a PTEN-deficient PC3 prostate cancer cell line. Optimization of in vitro pharmocokinetic properties led to compound 25 exhibiting 52% bioavailability in mice and target engagement in an acute PK/PD study.


Application of laser Doppler flowmetry to measure cerebral microvascular perfusion in the fetal sheep.
Laser Doppler flowmetry (LDF) has been used to measure flow in various organs of the adult, but has not been applied to the mammalian fetus. The purpose of this study was to apply LDF to measure cerebral blood flow of the fetal sheep and to assess the possible errors and artifacts of the method caused by myometrial, fetal, and maternal movements. By three days after probe placement, the flow signal had decreased 55% from initial post surgical readings and thereafter it became stable. During fetal hypoxia, the signal increased 48% and during hypercarbia it increased 59%. After fetal death, the signal decreased to 48% of control level. After maternal death, it decreased to 9% and electrical zero could not be reached. LDF is useful to measure changes of fetal cerebral microvascular perfusion because it can provide continuous signals but care is required in data handling and probe fixation when used for the mammalian fetus.


[The Involvement of Cardiomyocyte-Specific Transcription Factors Meis in Adipocyte Differentiation].
Homeodomain transcription factors play a significant role in adipocyte differentiation. The role of Pbx1 and Prep1, proteins of the TALE family (the three amino acid loop extension), was previously established in adipocyte differentiation of mesenchymal stromal cells and 3T3-L1 cell line. In this study, with the use of RNA interference technology we show that another transcription factor from the same family, Meis1, which is a core protein of mature cardiomyocytes, represses adipogenesis to a greater degree than its paralog Meis2. A number of Meis target genes, markers of adipocytes, are identified. This may indicate the transcriptional mechanism of the effect of Meis1 on the adipocyte differentiation of mouse preadipocytes.


Capsaicin pretreatment modifies hydrogen sulphide-induced pulmonary injury in rats.
One of the major target organs of hydrogen sulphide gas is the lung. Exfoliation of upper respiratory epithelia and pulmonary edema are prominent effects. Various neuropeptides contained in afferent C-fibres are intimately associated with the epithelia of the conducting airways and are liberated upon exposure to noxious gases. We sought to determine their role in the pathogenesis of hydrogen-sulphide-induced pulmonary injury by pretreating rats with the neurotoxin, capsaicin, which is known to ablate a subpopulation of vagal afferent C-fibres. Groups of capsaicin and saline (control) pretreated Fischer 344 rats were exposed to an edemogenic concentration of hydrogen sulphide (525-559 mg/m3) for 4 hr. Mortality was significantly greater (p less than 0.01) in the capsaicin treated rats (12/12) compared to the control animals (2/12). Pulmonary injury was also more severe in the capsaicin pretreated animals as assessed by lung water content, histological grade of pulmonary edema and protein in the broncho-alveolar fluid. Animals depleted of substance P exhibited a significantly greater (p less than 0.01) degree of bronchial epithelial cell exfoliation and ulceration following exposure to hydrogen sulphide. These experiments indicate that capsaicin sensitive sensory nerves may play a major role in pulmonary defense against the effects of inhaled toxic gases such as hydrogen sulphide.


Human exposure to mercury in a compact fluorescent lamp manufacturing area: By food (rice and fish) consumption and occupational exposure.
To investigate human Hg exposure by food consumption and occupation exposure in a compact fluorescent lamp (CFL) manufacturing area, human hair and rice samples were collected from Gaohong town, Zhejiang Province, China. The mean values of total mercury (THg) and methylmercury (MeHg) concentrations in local cultivated rice samples were significantly higher than in commercial rice samples which indicated that CFL manufacturing activities resulted in Hg accumulation in local rice samples. For all of the study participants, significantly higher THg concentrations in human hair were observed in CFL workers compared with other residents. In comparison, MeHg concentrations in human hair of residents whose diet consisted of local cultivated rice were significantly higher than those who consumed commercial rice. These results demonstrated that CFL manufacturing activities resulted in THg accumulation in the hair of CFL workers. However, MeHg in hair were mainly affected by the sources of rice of the residents.


Exposure to 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDT) in relation to bone mineral density and rate of bone loss in menopausal women.
The organochlorine pesticide 2,2-bis(p-chlorophenyl)-1,1,1,-trichloroethane (DDT) and its metabolite 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) are examples of an environmental contaminant that may have hormonal properties. Bone metabolism is both estrogen- and androgen-dependent. Exposures to various environmental endocrine disrupters can affect bone metabolism in animals, but there are no published data concerning the effect of DDE exposure on bone metabolism in humans. We hypothesized that high levels of DDE would be associated with lower bone density in peri- and postmenopausal women than in premenopausal women. Study subjects were drawn from the cohort of women who had participated in the Mount Sinai Medical Center Longitudinal Normative Bone Density Study (1984-1987). We used serum samples obtained at study entry to measure DDE levels in 103 (50 black, 53 white) women (mean age = 54.5 y [standard deviation = 5 y]). Measurements of bone mineral density at the lumbar spine and radius were made at 6-mo intervals during a 2-y period. DDE concentrations were significantly (p < .001) higher in blacks (13.9 ng/ml) than in whites (8.4 ng/ml), but there was no correlation between DDE concentration and bone density at the spine (mean levels = 1.065 g/cm2 and 1.043 g/cm2 in the lowest and highest quartiles, respectively, of DDE [trend p value = .85]) or at the radius (mean levels = 0.658 g/cm and 0.664 g/cm in the lowest and highest quartiles, respectively, of DDE [trend p value = .34]). Longitudinal analyses revealed no correlation between DDE and the rate of bone loss at either bone site. Similar results were seen in race-stratified analyses, as well as in analyses in which we controlled for lactation history and other potential confounders. We found little evidence that chronic low-level DDT exposure is associated with bone density in peri- and postmenopausal women.


Erythrocyte binding preference of 16 subtypes of low pathogenic avian influenza and 2009 pandemic influenza A (H1N1) viruses.
All 16 subtypes of avian influenza viruses of low pathogenicity (LPAIV) as well as their hemagglutinin (H) antigens, and four 2009 pandemic influenza A (H1N1) virus isolates were assayed for hemagglutinating activity against 5 erythrocyte species: goose, guinea pig, human group O, chicken and horse. Of all viruses and antigens assayed, the highest hemagglutination (HA) titers were obtained with goose and guinea pig erythrocytes. Hemagglutinating activity of replicating LPAIV and LPAIV antigens decreased, in order, with chicken and human group O; meanwhile, horse erythrocytes yielded lowest or no HA titer. Moreover, the 2009 pandemic viruses did not agglutinate both horse and chicken erythrocytes. Our study concluded that goose and guinea pig erythrocytes are the best in HA assay for all subtypes of influenza viruses.


Meningitis due to Neisseria mucosa: case report and review.
Neisseria mucosa is a species of gram-negative cocci that has a characteristic mucoid, adherent colonial morphology and includes pigmented and nonpigmented morphotypes. The ability of N. mucosa to reduce nitrates distinguishes it from other Neisseria species. N. mucosa is part of the normal human nasopharyngeal flora and infrequently causes human infections, including meningitis. We report a unique case of a patient with a cerebrospinal fluid shunt infection due to N. mucosa and review five other reports of cases of meningitis caused by this organism. Seven additional previously reported cases of presumed N. mucosa meningitis have been excluded from this review on the basis of the current criteria for identification of the organism. In the reports of established cases, female infants and children who often had predisposing conditions predominate. Although the outcome for such patients has been favorable, no clinical or laboratory findings are helpful in distinguishing meningitis due to N. mucosa from that due to other bacteria.


Effect of nitric oxide synthesis modification on renal function in gentamicin-induced nephrotoxicity.
We evaluated the effect of acute or chronic nitric oxide (NO) synthesis activation or inhibition in rats with gentamicin-induced acute renal failure. Rats received gentamicin 100 mg/kg per day for 6 days, or isotonic saline. Some animals of each group also received N(G)-monomethyl-l-arginine (l-NAME, 4 mg/kg per day) or l-arginine (1%) in the drinking water for 6 days (chronic NO synthesis modification). In another experimental set, animals were treated with gentamicin or saline for 6 days and glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured before and after the infusion of l-NAME (50 mg/h per kg) or l-arginine (60 mg/h per kg) (acute NO synthesis modification). Acute l-NAME administration induced a decrease in GFR and RPF both in control and gentamicin treated animals. Chronic l-NAME treatment induced an impairment in GFR only in gentamicin-treated animals. Acute l-arginine administration did not modify renal function in any experimental group whereas chronic l-arginine administration improved renal function only in gentamicin-treated animals. Urinary excretion of N-acetyl-β-d-glucosaminidase and alkaline phosphatase was increased by chronic treatment with l-NAME in both groups, whereas l-arginine had no effect. In conclusion, NO synthesis inhibition aggravates gentamicin-induced renal damage. However, chronic NO synthesis stimulation partially prevents against gentamicin nephrotoxicity, thus suggesting that increased renal NO synthesis during gentamicin-induced nephrotoxicity plays a protector role on renal function.


An elderly diabetic case of ochronosis with depression and chronic pain.
Alkaptonuria (ochronosis) is a rare autosomal recessive disorder featuring a genetic error in the amino acid metabolism. A defect in the tyrosine metabolism results in the accumulation and deposition of homogentisic acid in connective tissue, causing a blue-black discolouration. Degenerative arthropathy of the spine, knee, and hip are common signs of ochronosis in older age. An association between ochronosis and depression has not previously been discussed in the literature. This case report describes a 69 year-old woman with diabetes mellitus, ochronosis, depression and chronic pain.


Dissolution rate improvement of poorly water-soluble drugs obtained by adsorbing solutions of drugs in hydrophilic solvents onto high surface area carriers.
The dissolution rate of the model drugs carbamazepine and nifedipine was improved by adsorbing solutions of the drugs in hydrophilic non-volatile or volatile solvents onto carriers with a large surface area. This was accomplished by dissolving the drug in methanol or the non-toxic hydrophilic liquids PEG 400 or 2-pyrrolidone, and adsorbing these solutions onto the surface of silica (Aerosil) or crosslinked polyvinylpyrrolidone (Kollidon CL-M). The solvent binding capacities decreased in the order of methanol, PEG 400, 2-pyrrolidone for Aerosil 200, 300, 380 and for Kollidon CL-M. Kollidon bound less liquid than Aerosil because of the smaller surface area. Differential scanning calorimetry measurements showed higher interactions between drugs and Kollidon compared to Aerosil, suggesting a low aggregation of precipitated drug particles. The drug release from the adsorbent systems was enhanced when compared to micronized drug and independent of the drug loading in the investigated range. The drugs were also dissolved in various liquid, paste-like or solid solubilisers (polyoxyl-40-hydrogenated castor oil (Cremophor RH 40), macrogol-15-hydroxystearate (Solutol HS), poloxamers (Lutrol F68, Pluronic F87NF and Pluronic L44NF) and adsorbed onto Kollidon. These adsorbent systems also exhibited an increased dissolution rate when compared to pure drug.


Aromatase and its inhibitors.
Inhibitors of aromatase (estrogen synthetase) have been developed as treatment for postmenopausal breast cancer. Both steroidal substrate analogs, type I inhibitors, which inactivate the enzyme and non-steroidal competitive reversible, type II inhibitors, are now available. 4-hydroxyandrostenedione (4-OHA), the first selective aromatase inhibitor, has been shown to reduce serum estrogen concentrations and cause complete and partial responses in approximately 25% of patients with hormone responsive disease who have relapsed from previous endocrine treatment. Letrozole (CGS 20, 269) and anastrozole (ZN 1033) have been recently approved for treatment. Both suppress serum estrogen levels to the limit of assay detection. Letrozole has been shown to be significantly superior to megace in overall response rates and time to treatment failure, whereas anastrozole was found to improve survival in comparison to megace. Both were better tolerated than the latter. The potential of aromatase within the breast as a significant source of estrogen mediating tumor proliferation and which might determine the outcome of inhibitor treatment was explored. Using immunocytochemistry and in situ hybridization, aromatase and mRNAarom was detected mainly in the epithelial cells of the terminal ductal lobular units (TDLU) of the normal breast and also in breast tumor epithelial cells as well as some stromal cells. Increase in proliferation, measured by increased thymidine incorporation into DNA and by PCNA immunostaining in response to testosterone was observed in histocultures of breast cancer samples. This effect could be inhibited by 4-OHA and implies that intratumoral aromatase has functional significance. An intratumoral aromatase model in the ovariectomized nude mouse was developed which simulated the hormone responsive postmenopausal breast cancer patient. This model also allows evaluation of the efficacy of aromatase inhibitors and antiestrogens in tumors of estrogen receptor positive, human breast carcinoma cells transfected with the human aromatase gene. Thus, the cells synthesized estrogen which stimulated tumor formation. Both aromatase inhibitors and antiestrogens were effective in suppressing tumor growth in this model. However, letrozole was more effective than tamoxifen. When the aromatase inhibitors were combined with tamoxifen, tumor growth was suppressed to about the same extent as with the aromatase inhibitors alone. Thus, there was no additive or synergistic effects of combining tamoxifen with aromatase inhibitors. This suggests that sequential treatment with these agents is likely to be more beneficial to the patient in terms of longer response to treatment.


Factors Affecting Early Death and Survival of Patients With Acute Promyelocytic Leukemia Treated With ATRA-Based Therapy Regimens.
To perform a retrospective analysis of the prognostic relevance of clinicopathologic parameters in a well-documented cohort of patients treated with all-trans-retinoic acid (ATRA)-based induction regimens in order to discover which indicators can predict a high risk of early death (ED) and patient survival. We analyzed data of 288 newly diagnosed adult acute promyelocytic leukemia patients in Hangzhou, China. The median follow-up time was 32 months (range, 6-78 months). The 3-year disease-free and overall survival rates were 90.83% and 91.69%, respectively. In the multivariable analysis, older age (≥ 60 years) was the only independent risk factor for ED (hazard ratio [HR] = 15.057; P = .004). High white blood cell count was not a risk factor for ED (P = .055), but it was for relapse (HR = 2.7; P = .009). FLT3 mutation (HR = 3.9; 95% confidence interval, 1.4 to 10; P = .007) and older age (≥ 60 years) (HR = 5.3; 95% confidence interval, 2.4 to 11; P < .001) were prognostic factors for poorer disease-free and overall survival. Interestingly, CD15 negativity (HR = 0.23; P = .049) was a prognostic factor for relapse. The ED rate was 5.9% (17/288 patients). The perceived impact of the identification of these high-risk factors should be described in order to decide whether any modifications to treatment strategy should be entertained.


The lived experience of mothering after prison: the preliminary study.
The purpose of this interpretive phenomenological preliminary study was to gain a better understanding of the experience of mothering after prison. In-depth interviewing was conducted with two participants for a period of 4 months after their release from prison. All interviews were focused on the research question, "What has been your experience of mothering since your release from prison?" Data were analyzed using thematic analysis. The following four themes emerged: "always the mother,""separation anxiety,""new demands: divided loyalties," and "the honeymoon is over."


Interventional trials in atypical parkinsonism.
Atypical parkinson disorders (APD) are rapidly progressive neurodegenerative diseases with a variable clinical presentation that may even mimic Parkinson's disease. Multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are commonly summarized under this umbrella term. Significant developments in research have expanded knowledge and have broadened available symptomatic treatments, particularly for the treatment of neurogenic orthostatic hypotension. Nonetheless, symptomatic support still remains limited in all of these disorders. Currently, there exists no effective treatment to delay disease progression and disease-modifying trials have failed to provide coherent and convincing results. Recent trials of rasagiline (in MSA), rifampicin (in MSA), tideglusib (in PSP) and davunetide (in PSP) reported negative results. Nevertheless, large cohorts of patients were recruited for interventional studies in the last few years which improved our understanding of trial methodology in APDs immensely. In addition, remarkable progress in basic research has been reported recently and will provide a solid foundation for future therapeutic trials. In this review, we will summarize published randomized, placebo-controlled clinical trials (RCTs) in APDs. Additionally, the design of ongoing and unpublished interventions will be presented.


Laryngeal Verrucous Carcinoma.
Objective Laryngeal verrucous carcinoma (LVC) is a rare, locally invasive neoplasm comprising 1% to 3.4% of laryngeal carcinomas. Management strategies are a topic of ongoing conversation, and no definitive treatment protocol based on T stage and presentation exists. This review examines characteristics, treatment modalities, and patient outcomes of LVC. Data Sources PubMed, MEDLINE, EMBASE, and Web of Science. Methods Databases were searched through October 29, 2015, for literature detailing individual patient cases of LVC. Variables analyzed included patient demographics, tumor characteristics, tumor size, treatment, and outcomes. Results Thirty-seven articles with 369 cases were included. LVC was found more commonly in males (13.8:1), at an average age of 58.7 years, and located in the glottis (74.0%). Most patients had local disease at presentation (94.9%). The most common presenting symptom was hoarseness (92.3%). The most common primary treatment was surgery alone (72.3%), with local excision as the most common technique (56.8%). In patients with data available on both surgical modality and T stage, most patients who presented as T1 and were managed surgically underwent local excision (79.2%). Surgical treatment alone led to high rates of disease-free survival at follow-up (86.8%). A large number of patients presenting with T1 disease were disease free at follow-up (88.6%). Overall survival was 80.3%. Conclusion LVC is most often managed surgically. The extent of surgical resection may be guided by T stage, with smaller tumors resected via local excision and larger tumors via partial or total laryngectomy. Regardless of T stage or therapy, LVC has a good posttreatment prognosis.


Characterization of human liver microsomal cytochrome P450 involved in the reductive metabolism of zonisamide.
Zonisamide (1,2-benzisoxazole-3-methanesulfonamide) was metabolized to 2-sulfamoylacetylphenol (SMAP) in human liver microsomes under anaerobic conditions. The formation of SMAP was remarkably inhibited by cimetidine, n-octylamine, ketoconazole, and carbon monoxide, indicating that a cytochrome P450 is involved in the metabolism of zonisamide to SMAP in human liver microsomes. The SMAP-producing activity did not correlate with the spectrally determined amount of cytochrome P450. In contrast, the SMAP-producing activity from zonisamide correlated closely with the activity of testosterone 6 beta-hydroxylase (r2 = 0.96) and correlated slightly but significantly with the activity of imipramine 2-hydroxylase (r2 = 0.28), but not with those of aniline hydroxylase (r2 = 0.09) or benzphetamine N-demethylase (r2 = 0.20). In addition, immunoquantitation of cytochrome P450 enzymes in 21 human liver microsomal samples revealed that SMAP formation correlated closely with the amount of P450 3A enzyme and correlated moderately well with that of P450 2D6 but not with that of P450 2C enzyme in human liver microsomes. P450 3A4 exhibited SMAP-producing activity in a reconstituted monooxygenase system. The metabolism of zonisamide to SMAP was almost completely inhibited by anti-P450 3A4 antibody but not by anti-P450 2C9 or anti-P450 2D6 antibodies, suggesting that the amount of P450 3A enzyme may be a major factor influencing the level of metabolism of zonisamide to SMAP in human liver microsomes.


Inhibitory synaptogenesis in the rat anteroventral cochlear nucleus.
Spherical cells in the anteroventral division of the cochlear nucleus, which relay excitatory inputs from the auditory nerve, also receive both GABAergic and glycinergic inhibitory synapses. Inhibition mediated by GABA and glycine fulfils essential roles in the processing abilities of these and other auditory neurons. However, the developmental program leading to a mature complement of GABAergic and glycinergic synapses and microcircuits is largely unknown. Because of their relatively simple geometry, spherical cells provide an excellent model for unraveling basic developmental patterns of inhibitory synaptogenesis. Using a combination of high resolution immunocytochemical methods, we report that, in the rat, synapses containing GABA or glycine are deployed on spherical cell bodies over a time period extending well beyond hearing onset. Such postnatal developmental recruitment of inhibitory endings is progressive, although there are two distinct leaps in their numbers. The first occurs by the end of the first postnatal week, prior to hearing onset, and the second, during the third postnatal week, after hearing onset. This pattern suggests that adjustments in inhibition could be driven by acoustic experience. While GABAergic and glycinergic endings are maturing and growing in number and size, their neurotransmitter content also appears to be developmentally regulated. Quantitative ultrastructural immunocytochemistry with colloidal gold suggests that GABA and glycine accumulation in synaptic endings follows a staggered pattern, with labeling stabilizing at adult levels by postnatal day 21. This may account for adjustments in synaptic efficacy and strength.