Probiotics Plus Dietary Fiber Supplements Attenuate Olanzapine-Induced Weight Gain in Drug-Naïve First-Episode Schizophrenia Patients: Two Randomized Clinical Trials.
Antipsychotic-induced weight gain is associated with alterations to the composition of the gut microbiota. The purpose of this study was to determine the effect of probiotics plus dietary fiber on antipsychotic-induced weight gain. Two sequential, randomized clinical trials were conducted. In Study 1, 90 drug-naïve, first-episode schizophrenia patients were randomized to receive either olanzapine plus probiotics or olanzapine monotherapy for 12 weeks. In Study 2, 60 drug-naïve, first-episode schizophrenia patients were randomly assigned to receive either olanzapine plus probiotics and dietary fiber or olanzapine monotherapy for 12 weeks. In Study 1, no significant differences in weight gain were observed between the two groups. The insulin resistance index (IRI) was lower in the olanzapine plus probiotics group compared with the olanzapine monotherapy group at week 12 (estimated mean difference, -0.65, [95% confidence interval (CI), -1.10 to -0.20]; p = .005). In Study 2, weight gain was lower in the probiotics plus dietary fiber group than in the olanzapine monotherapy group at week 12 (estimated mean difference -3.45 kg, [95% CI, -5.91 to -1.00]; p = .007). At week 12, IRI increased significantly in the olanzapine monotherapy group (mean, 1.74; standard deviation (SD) = 1.11, p < .001), but not in the olanzapine plus probiotics and dietary fiber group (mean 0.47, SD = 2.16, p = .35) with an estimated mean difference of -0.95 between the two groups [95% CI, -1.77 to -0.14]; p = .022). These results provide support for the efficacy and safety of probiotics plus dietary fiber in attenuating antipsychotic-induced weight gain in drug-naïve, first-episode schizophrenia patients.


[Vascular ultrasonography].
Vascular ultrasound plays an important role in the visual depiction of arteries, veins, and changes of tissue in lymphatic diseases. In the case of arteries, this ranges from endothelial dysfunction over measuring the increase of intima media thickness to the detection of stenoses, occlusion, or aneurysm. Ultrasound helps to differentiate in functional arterial diseases such as primary and secondary Raynaud's syndrome as well as arterial compression syndromes like entrapment syndrome of different arterial regions or the chronic exceptional compartment syndrome of the lower leg. Ultrasound plays a central role in the diagnosis of rare arterial diseases like large vessel vasculitis, arterial dissection, cystic adventitial degeneration, and the differentiation of vascular malformation especially in children, thus, permitting ultrasound-guided intervention and follow-up controls. In venous thrombosis, sonography is the primary imaging method, while follow-up controls help in the prediction of recurrent venous thrombosis. Ultrasound is a tool to determine the cause and severity of chronic venous insufficiency and allows different therapeutic procedures for the treatment of varicose veins to be visually monitored.


Occlusal characteristics and prevalence of associated dental anomalies in the primary dentition.
Morphological variations in primary dentition are of great concern to a pediatric dentist as it may pose clinical problems like dental caries, delayed exfoliation and also anomalies in the permanent dentition, such as impaction of successors, supernumerary teeth, permanent double teeth or aplasia of teeth. The present study was conducted to investigate the presence of dental anomalies in the primary dentition of 1000 schoolchildren in the 3-5 year-old age group in Faridabad. One-thousand schoolchildren were examined using Type III examination (WHO, 1997) for primary molar relationship, occlusal characteristics, primate spaces, physiological spaces and other anomalies of teeth, including number and morphology. The prevalence of physiological spaces in maxillary and mandibular arches was 50.9% and 46.7%, respectively, whereas primate spaces were found in 61.7% of the children in the maxillary arch and 27.9% in the mandibular arch. The prevalence of unilateral anterior and posterior cross-bite was 0.1% and 0.8%, respectively, in the present study. The prevalence of hypodontia in the primary dentition was found to be 0.4% and the prevalence of fusion and gemination in the present study was 0.5%. Double teeth (fusion and gemination) and hypodontia were the most common dental anomalies found in the primary dentition in the present study.


Temporomandibular joint arterial variability.
The study aimed to investigate temporomandibular joint (TMJ) arterial variability. In this prospective study, the vasculature variability was studied using a 3D volume rendering CT angiography including random patients at two hospitals. A 16-quadrant (A1-D4) evaluation grid was developed using the Frankfurt plan as main reference. For each quadrant, the number of arterial ramus or branches was scored as clearly visible (2), partially visible (1), or not visible (0). A total of 50 patients were enrolled (mean age of 62.9 ± 16.0); 21 (42%) were men, and 29 (58%) were women. The authors observed bilaterally higher arterial density in the posterior aspect of the ascending ramus of the mandible (p < 0.0001), corresponding to quadrants B2 (5.92 ± 2.27 and 6.14 ± 2.56), B3 (9.76 ± 2.97 and 11.18 ± 2.86) and B4 (7.38 ± 2.78 and 8.10 ± 2.42). A strong correlation was found between the number of vessels and the variability of the region (r = 0.87, p = 0.00001). No differences were observed between men and women. Within the limitations of the study, arterial variability was observed in the TMJ territory. The posterior zone of the condyle and ramus is the most vascularized area, with great variability, representing an increased risk for surgical bleeding. Therefore, this knowledge seems to be particularly relevant for surgeons dedicated to TMJ and other facial surgery or facial/cerebral radiologic interventions. The authors encourage future studies to include larger samples and to identify thoroughly the arterial branches in this area.


Plasticity of hippocampal corticosteroid receptors during aging in the rat.
Aging is commonly associated with dysregulation of the hypothalamo-pituitary-adrenal axis and cognitive impairment. On the basis of suggestions that these disruptions ensue from changes in the hippocampal complement of corticosteroid (mineralocorticoid and glucocorticoid) receptors (MR and GR), we examined the availability of hippocampal MR and GR by measuring the in vivo uptake of 3H-aldosterone and 3H-dexamethasone (selective MR and GR agonists, respectively); MR and GR mRNA levels were also measured. We observed age-related declines in both the synthesis of MR and GR and the uptake of their respective ligands. Whereas MR mRNA levels and ligand uptake declined in parallel, GR binding declined more steeply than GR mRNA. This latter result, together with our finding that aged rats show impaired corticosteroid receptor mRNA and protein up-regulation after corticosteroid withdrawal, indicates decreased transcription of MR and GR genes and posttranslational modification of GR mRNA during aging. Given that corticosteroids can influence MR and GR synthesis and binding, and based on the finding that aged subjects show reduced basal secretion of corticosterone, we propose that this relative hypocorticalism may be responsible for the changes observed in MR and GR activity, which then leads to disturbances in neuroendocrine regulation and cognitive function in aged subjects.


Multiple Perspectives on Motivating Parents in Pediatric Primary Care to Initiate Participation in Parenting Programs.
To use multiple perspectives to identify the key components of pediatric primary care conversations for motivating parents to utilize parenting programs. We aim to develop an actionable framework that primary care clinicians (PCCs) can follow for effective conversations with parents. We conducted focus groups and interviews with researchers (n = 6) who have experience delivering parenting interventions through primary care, clinical personnel in federally qualified health centers (FQHCs) (n = 9), parents of 3-5-year olds who receive services at a FQHC pediatric clinic (n = 6), and parent educators (n = 5). Groups and interviews were informed by nominal group technique, and researchers triangulated consolidated strategies across the groups. Key strategies for PCCs to motivate parents to utilize parenting programs followed three steps: 1) learning about a parent's questions and concerns, 2) sharing resources, and 3) following up. PCCs can learn about parents' needs by empathizing, listening and responding, and asking questions that acknowledge parents' expertise. When sharing resources, PCCs can motivate participation in parenting programs by explaining each resource and its benefits, providing options that support parents' autonomy, and framing resources as strengthening rather than correcting parents' existing strategies or skills. Finally, PCCs can continue to engage parents by scheduling follow-up conversations or designating a staff member to check-in with parents. We provide examples for each strategy. Findings provide guidance from multiple perspectives on strategies to motivate parents in pediatric primary care setting for utilizing parenting programs.


Developmentally regulated addition of nucleotides within apocytochrome b transcripts in Trypanosoma brucei.
Production of the mitochondrial respiratory system and expression of mitochondrial genes are developmentally regulated in T. brucei. We have found three classes of apocytochrome b (CYb) transcripts. Two of these contain U's within their 5' sequence that are not found in the CYb gene. They occur in procyclic forms, which have a complete mitochondrial respiratory system, but are absent in bloodstream forms, which lack this respiratory system. The third transcript has the sequence predicted from the genomic sequence and is present in both life cycle stages. These findings suggest that there is developmentally regulated posttranscriptional addition of U's to CYb transcripts. This process may contribute to the developmentally regulated production of the mitochondrial respiratory system.


Can Factor V Leiden and prothrombin G20210A testing in women with recurrent pregnancy loss result in improved pregnancy outcomes?: Results from a targeted evidence-based review.
Women with recurrent pregnancy loss are offered Factor V Leiden (F5) and/or prothrombin G20210A (F2) testing to identify candidates for anticoagulation to improve outcomes. A systematic literature review was performed to estimate test performance, effect sizes, and treatment effectiveness. Electronic searches were performed through April 2011, with review of references from included articles. English-language studies addressed analytic validity, clinical validity, and/or clinical utility and satisfied predefined inclusion criteria. Adequate evidence showed high analytic sensitivity and specificity for F5 and F2 testing. Evidence for clinical validity was adequate. The summary odds ratio for association of recurrent pregnancy loss with F5 in case-controlled studies was 2.02 (95% confidence interval, 1.60-2.55), with moderate heterogeneity and suggestion of publication bias. Longitudinal studies in women with recurrent pregnancy loss or unselected cohorts showed F5 carriers were more likely to have a subsequent loss than noncarriers (odds ratios: 1.93 and 2.03, respectively). Results for F2 testing were similar. For clinical utility, evidence was adequate that anticoagulation treatments were ineffective (except in antiphospholipid antibody syndrome) and had treatment-associated harms. The certainty of evidence is moderate (high, moderate, and low) that anticoagulation of women with recurrent pregnancy loss and F5/F2 variants would currently lead to net harms.


The Efficacy and Safety of Surufatinib Combined with Anti PD-1 Antibody Toripalimab in Neoadjuvant Treatment of Locally Advanced Differentiated Thyroid Cancer: A Phase II Study.
Surgery is the primary treatment for locally advanced differentiated thyroid cancer (DTC). However, some locally advanced patients are not candidates for R0/1 resection. There is limited evidence of neoadjuvant treatment in locally advanced DTC. Surufatinib targets multiple kinases, which is efficient, tolerable, and safe in patients with radioiodine-refractory DTC. In addition, surufatinib plus toripalimab (an anti-PD-1 antibody) showed encouraging antitumor activity in advanced solid tumors. This study was designed to evaluate the efficacy and safety of surufatinib plus toripalimab in locally advanced DTC in the neoadjuvant setting. In this single-arm, phase II study, patients with pathologically confirmed unresectable or borderline resectable DTC were eligible and received a combination of 250 mg of surufatinib (orally daily) with 240 mg of toripalimab (intravenous, every 3 weeks). Treatment continued until satisfied for curative surgery, disease progression, withdrawal of consent, unacceptable toxicity, or investigator decision. Primary endpoint was objective response rate (ORR). Secondary endpoints included R0/1 resection rate, adverse events (AEs), etc. RESULTS: Ten patients were enrolled and received at least 4 cycles of treatment. The ORR was 60%. Nine patients received R0/1 resections after neoadjuvant treatment. The median best percentage change in the sum of the target lesion diameter was 32%. Most adverse events (AEs) were grade 1 or 2. Surufatinib in combination with toripalimab as neoadjuvant therapy for locally advanced DTC was feasible, and the majority of patients achieved R0/1 resection. It represents a new option for locally advanced DTC and needs further investigation.


Abrogation of metastatic properties of tumour cells by de novo expression of H-2K antigens following H-2 gene transfection.
H-2 gene transfection was used to restore expression of H-2K antigens in metastatic and non-metastatic subclones of a murine fibrosarcoma that lack their major histocompatibility complex-encoded H-2K antigens. De novo expression of H-2K reduced tumorigenicity and abolished the formation of metastasis in syngeneic mice. Expression of H-2K may lead to effective recognition of the disseminating tumour cells by the host immune system.


Inversion of spatio-temporal distribution heat flux and reconstruction of transient temperature field of three-layered skin tissue during hyperthermia.
Hyperthermia (for example, high-intensity focused ultrasound, laser, radio-frequency) of cancerous cells from in vitro to in vivo requires accurately obtaining the heat distribution induced by external heating into the three-layered skin tissue. Obtaining the boundary heat flux into the three-layered skin tissue is a necessary condition to realize the measurement of tissue heat distribution. Considering the complexity of multiple boundary heat fluxes in spatio-temporal distribution, this study proposes an inversion scheme to predict the spatio-temporal distribution of multiple boundary heat fluxes into the three-layered skin tissue. In the inversion scheme, a multivariable prediction model is established to solve the spatio-temporal coupling problem between the inversed boundary heat flux and measurement temperature information. Furthermore, based on the dependence between the predicted temperature and inversed boundary heat flux, the inversion system is constructed to realize the simultaneous optimization inversion of multiple boundary heat fluxes in spatio-temporal distribution. To examine the feasibility and effectiveness of inversion scheme, numerical experiments are carried out to discuss the influence of future time steps and measurement errors on the inversion results of boundary heat flux. In addition, the transient temperature field of three-layered skin tissue is reconstructed by inversed boundary heat flux, which could provide an economical, effective, and non-invasive solution for the measurement of thermal field of three-layered skin tissue during hyperthermia.


Treatment of kala-azar in Brazil with Amphocil (amphotericin B cholesterol dispersion) for 5 days.
We have treated 10 patients suffering from kala-azar in Brazil with Amphocil (amphotericin B cholesterol dispersion) at a dose of 2 mg/kg/d for 5 d, following an earlier study in which this dosage for 7 d was found to cure all of 9 patients, with no relapse during 12 months. In the present study, all patients demonstrated initial resolution of disease. Parasites were absent upon bone marrow re-aspiration 2 weeks after therapy; no spleen extended beyond the costal margin 2 months after therapy; white blood cell counts, platelet counts, and serum levels of albumin rapidly returned to normal. Although one patient relapsed at 5 months, 8 of the other 9 patients had spleens of normal size (undetectable on deep palpation) at 12 months after therapy. Fever, sometimes accompanied by increased respiratory rate, occurred on the first day of drug infusion in 8 of 10 patients and was more severe in patients < 6 years old. Pre-medication with a non-steroidal anti-inflammatory agent (diclofenac potassium) before the next 4 infusions protected against this side effect in 5 of 6 patients. The results of this and our previous study suggest that the most appropriate regimen of Amphocil for kala-azar is 2 mg/kg/d for 7 d, with pre-medication each day, in patients aged > 5 years.


Absence of mutagenicity of Potomorphe umbellata and Potomorphe peltata in the Salmonella/mammalian-microsome mutagenicity assay.
The development of short term tests for measuring the mutagenic activity of genotoxic chemicals has been helpful in increasing security. Natural products from the flora are largely used in popular medicine. Using the Salmonella/mammalian-microsome assay, we investigated the genetic toxicity of two plant species popularly used in malaria treatment, Pothomorphe umbellata and Pothomorphe peltata. The data show the absence of genetic toxicity for both plant species.


Effect of hyperthermia on the function of thyroid gland.
Hyperthermia may be a consequence of environmental conditions, bacterial or viral infections and/or thyroid storm. This study investigates the acute effect of body temperature elevation on thyroid function and on its scintigraphy studies. Thyroid scintigraphy was performed on New Zealand White rabbits weighing approximately 3-3.5 kg. Each rabbit was injected with 115 MBq (3.1 mCi) technetium-99 m pertechnetate ((99m)Tc pertechnetate). Studies were performed using Gamma camera equipped with a low energy, high resolution, pinhole collimator interfaced with a computer. Static images were acquired 20 min after administration of the radiotracer. Two days later the same protocol was repeated for the same rabbit after increasing the body temperature by 2 degrees C. The experiment was repeated again after a 2-day interval at 3 degrees C, and then after another 2-day interval at 4 degrees C. Plasma free thyroxine (FT(4)), free triiodothyronine (FT(3)) and thyroid stimulating hormone (TSH) were measured at control and at different hyperthermic temperatures (+2, 3, 4 degrees C). We recorded isometric tension of rabbit thyroid artery strips in organ baths during stepwise temperature elevation. During hyperthermia the decrease in thyroid function and thyroid scintigraphy studies was proportional to body temperature elevation. The recording of isometric tension in rabbit thyroid artery strips in organ baths showed vasoconstriction during hyperthermia which is proportional to the heating temperature. Plasma FT(4) and FT(3) level were decreased while TSH levels were not affected by acute fever. Our results indicate that hyperthermia causes a transient decrease in thyroid gland function and scintigraphic patterns on radionuclide studies. Thus, body temperatures must be measured before radionuclide studies in order to ensure that interpretation of data is not influenced by hyperthermia.


Do younger women with elevated basal follicular stimulating hormone levels undergoing gonadotropin-stimulated intrauterine insemination cycles represent compromised reproductive outcomes?
To compare stimulation characteristics and reproductive outcomes in women representing elevated and normal day 3 FSH levels and to evaluate the prognostic significance of day 3 FSH on the reproductive outcomes of gonadotropin-stimulated IUI (GS-IUI) cycles in women <35 years. A cross-sectional study was designed. Unexplained infertility patients at the age ≤36 years, who underwent IUI, following gonadotropin stimulation (GS), were investigated. From 105 women with a day 3 FSH≥ 10U/L, 170GS/IUI cycles were assigned to Group EF; whereas a control group (Group NF, normal FSH) was constituted of 170 cycles with a day 3 FSH levels <10U/L. Demographic and stimulation characteristics as well as reproductive outcomes were compared. Primary outcome measure of this study was the biochemical, clinical and ongoing pregnancy rates. Secondary outcome measures were total gonadotropin dose, duration of gonadotropin stimulation, multiple pregnancy, miscarriage and cycle cancellation rates. β-hCG positivity, clinical and ongoing pregnancy rates did not differ between women with normal and elevated FSH levels (p=0.234, 0.282 and 0.388, respectively). Total gonadotropin dose, multiple pregnancy and miscarriage rates were not significantly different between the groups (p=0,181, 0.652 and 0.415, respectively). Duration of stimulation was significantly longer and cycle cancellation rate was significantly higher in Group EF than in Group NF (p=0.005 and 0.021, respectively). Younger women with elevated day 3 FSH represent comparable reproductive outcomes in GS-IUI cycles to those with normal FSH levels, although they may require longer periods of stimulation and are at higher risk of cycle cancellation. Thus, GS-IUI could be a possible treatment option in this patient group and should not be neglected.


Isolated hypogonadotrophic hypogonadism: a family with autosomal dominant inheritance.
A family is reported in which isolated hypogonadotrophic hypogonadism is inherited as an autosomal dominant condition with variable expression. In previous familial cases, inheritance was autosomal recessive. Comparison is made with the endocrine and genetic findings in Kallmann's syndrome, which should be considered a separate disorder. There is difficulty in drawing a sharp distinction between hypogonadotrophic hypogonadism and constitutional delay in puberty in this family.


Stereotaxic target calculation. Theory and practice.
Modern neuro-imaging techniques have significantly increased the accuracy of stereotactic procedures and have thereby generated a renewed interest in guided brain surgery. This paper describes the neuroradiological aspects of stereotaxic target calculation (x-, y-, z- coordinates) using the Riechert-Mundinger (Fisher) frame for computed tomography (CT). Selected cases are shown, illustrating patient positioning, CT technique, target identification and calculation. The importance of obtaining pre- and post-stereotaxic CT examinations is emphasized. Finally, future developments such as magnetic resonance (MR) guided stereotaxis and integrated functional-anatomical computer generated 3-dimensional maps, are briefly discussed.


Kalirin reduction rescues psychosis-associated behavioral deficits in APPswe/PSEN1dE9 transgenic mice.
Psychosis in Alzheimer's disease (AD+P) represents a distinct clinical and neurobiological AD phenotype and is associated with more rapid cognitive decline, higher rates of abnormal behaviors, and increased caregiver burden compared with AD without psychosis. On a molecular level, AD+P is associated with greater reductions in the protein kalirin, a guanine exchange factor which has also been linked to the psychotic disease, schizophrenia. In this study, we sought to determine the molecular and behavioral consequences of kalirin reduction in APPswe/PSEN1dE9 mice. We evaluated mice with and without kalirin reduction during tasks measuring psychosis-associated behaviors and spatial memory. We found that kalirin reduction in APPswe/PSEN1dE9 mice significantly attenuated psychosis-associated behavior at 12 months of age without changing spatial memory performance. The 12-month-old APPswe/PSEN1dE9 mice with reduced kalirin levels also had increased levels of the active, phosphorylated forms of p21 protein (Cdc42/Rac)-activated kinases (PAKs), which function in signaling pathways for maintenance of dendritic spine density, morphology, and function.


Grand Multiparous Women's Perceptions of Birthing, Nursing Care, and Childbirth Technology.
This qualitative descriptive study explored grand multiparous women's perceptions of the evolving changes in birthing, nursing care, and technology. A purposive sample of grand multiparous women (N = 13) from rural, eastern Washington State were interviewed as they shared their 105 birth stories. Eight themes were identified: (1) providing welcome care, (2) offering choices, (3) following birth plans, (4) establishing trust and rapport, (5) being an advocate, (6) providing reassurance and support, (7) relying on electronic fetal monitors and assessments versus nursing presence, and (8) having epidurals coupled with loss of bodily cues. Results from this study may be used to educate women, intrapartum nurses, and childbirth educators on nursing care and on the evolving use of technology to better manage intrapartum care in hospitals. The results can also add to the extant knowledge of childbirth nursing practices.


Modified double mandibular osteotomy for tumors of the parapharyngeal space.
In 1984, Attia et al described the double mandibular osteotomy as a more direct approach for tumors of the ptergomaxillary and parapharyngeal space. The procedure incorporates the traditional parasymphyseal osteotomy of the mandible with a horizontal osteotomy of the ascending ramus. Several modifications of this technique are described that increase the surgical exposure, while requiring less surgical dissection. The incorporation of rigid fixation with miniplates has improved postoperative recovery by avoiding maxillomandibular fixation and improving oral nutrition.


A Strep A vaccine global demand and return on investment forecast to inform industry research and development prioritization.
Investment in Strep A vaccine R&D is disproportionately low relative to the large burden of Strep A diseases globally. This study presents a novel Strep A vaccine global demand and financial forecast model with estimates of potential global demand and associated revenue and profits for a hypothetical Strep A vaccine as well as a net present value (NPV) analysis of return on capital investments required to develop the vaccine. A positive NPV was calculated for a variety of developer scenarios and target populations, including the global rollout of the vaccine in private and public markets by a multinational pharmaceutical corporation and a staged rollout by a developing country vaccine manufacturer for both infant and child populations. The results suggest there is a viable commercial market for a Strep A vaccine. It is hoped that this study will help to inform industry decision-making and drive increased prioritization of, and investment in, Strep A vaccine research and development.


Expressions of mass transfer coefficients of bubbles and free surface of culture tanks using the k-epsilon turbulence model.
For mammalian cell culture, getting a continuous supply of oxygen and extracting carbon dioxide are primary challenges even in the most modern biopharmaceutical manufacturing plants, due to the low oxygen solubility and excessive carbon dioxide accumulation. In addition, various independent flow and mass transfer characteristics in the culture tanks vessel make scale-up extremely difficult. One method for overcoming these and providing rational optimization is solving the fluid and mass transport equations by numerical simulation. To develop a simulation program, it is decisively important to know mass transfer coefficients of gaseous species in the culture tank. In this study, oxygen mass transfer coefficients are measured using a beaker with a sparger and impellers. In order to investigate the formulation of the mass transfer coefficients, the turbulent flow statistics is calculated by a CFD code for all cases, and the expressions of the mass transfer coefficients are established as functions of the statistics. Until now, the expression by Kawase is known in this field. This expression becomes a function only of energy dissipation rate epsilon. It does not coincide with the conventional experimental fact that mass transfer coefficient is proportional power 0.5 of impeller rotation speed. The new mass transfer coefficient is dependent on both of energy dissipation rate epsilon and turbulent flow energy k. It satisfies the relation of power of 0.5 of impeller rotation speed.


Experimental comparison of three monoclonal antibodies for the class-selective immunoextraction of triazines. Correlation with molecular modeling and principal component analysis studies.
The specificity of three immunosorbents (ISs) based on different monoclonal anti-triazine antibodies has been characterized by extraction recoveries studies and with step elution experiments. Both indicated that the anti-dichloroatrazine IS is specific of terbutylazine and cyanazine. The anti-atrazine IS is specific of the chlorotriazines, whereas the anti-ametryn IS can trap all the triazines. This confirms the great influence of the hapten design on the specificity of the resulting antibodies, even if the target molecules are small. Moreover, the anti-ametryn IS is suitable for class-selective extraction of triazines contained in complex matrices. An approach designed to learn more about the specificity for a group of structurally related compounds of antibodies produced with a given compound is proposed and evaluated. Molecular modeling followed by principal component analysis has been used to obtain distribution maps with the relative position of each immunoconjugate and all the triazines. In all three cases, conclusions on specificity made with the analysis of the maps fit well with the experimental results. Consequently, molecular modeling coupled with principal component analysis seems to be a unique, inexpensive, and rapid tool to select the appropriate hapten providing highly specific or class-specific antibodies according to the given problem.


Design, synthesis and evaluation of a series of novel long-acting dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes.
Type 2 diabetes mellitus (T2DM) is one of the most popular chronic diseases around the whole world. To improve the compliance of patients, long-acting antidiabetic drugs needed to be developed. Dipeptidyl peptidase-4 (DPP-4) inhibitors are becoming increasingly important in the T2DM treatment due to the favorable properties. In the present study, a series of new substituted dihydropyrido [4',3':3,4] pyrazolo [1,5-a] pyrimidin-9(10H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine were designed and synthesized as potent DPP-4 inhibitors. All compounds were characterized by 1H NMR, 13C NMR and HRMS and were evaluated in vitro. The inhibitory activity ranged from 0.43 to 12.70 μM while the inhibitory activity of positive control (omarigliptin) was 3.63 μM on DPP-4 in Caco-2 cells. Then pharmacokinetic studies were carried out in rats and compound 6c was finally selected for the further study because of its better pharmacokinetic profile. Additionally, preclinical pharmacological study of compound 6c exhibited extraordinary efficacy in vivo and good safety profile. In conclusion, compound 6c was considered as a promising DPP-4 inhibitor, which could be taken once a week or once every two weeks for the treatment of T2DM. More comprehensive researches will be carried out in the future for the further development of compound 6c.


Congenital heart disease in India: a status report.
Pediatric cardiac care in India is still in its infancy. We have no data on congenital heart disease (CHD) prevalence at birth or on proportional mortality from CHD. The resources are not only limited but also are at times improperly utilized. There are very few specialized pediatric cardiology training programs, those that are, are concentrated in certain regions of India and are often imparted through combined adult and pediatric programs. The existing number of trained personnel for pediatric cardiology and pediatric cardiac surgery is inadequate. Above all there is no national policy for pediatric heart care. Increasing awareness of the problem amongst the pediatricians through CMEs, seminars, symposia is likely to be most helpful in early diagnosis and timely referral of cases. Training programs exclusively dedicated to pediatric cardiology and pediatric cardiac surgery need to be established in centres with good standards of pediatric cardiac care.


Difference in the maintenance mechanism of atrial fibrillation perpetuated after pulmonary vein isolation between paroxysmal and persistent atrial fibrillation: Effects of subsequent stepwise ablation.
Neither the atrial fibrillation (AF) maintenance mechanism after pulmonary vein isolation (PVI) nor the mechanism of AF termination via stepwise ablation is clearly understood. Among 226 consecutive AF patients (154 paroxysmal (P-AF) and 72 persistent AF (Per-AF) patients), left atrial endocardial non-contact mapping was performed after PVI in the initial 10 P-AF and 16 Per-AF patients to define the AF maintenance mechanism. Subsequently, effect of stepwise catheter ablation (linear roof lesion and complex fractionated atrial electrogram (CFAE) following PVI) was evaluated in all patients. After PVI, AF was maintained by the activation around isolated PV/mitral annulus, focal discharge and disorganized activations mostly observed over residual CFAE region (pivoting activation, wave break and fusion). CFAE region in P-AF was smaller than Per-AF after PVI (1.6 ± 2.1 vs. 7.7 ± 2.5 cm(2), p<0.0001). The frequency of pivoting activation, wave break and fusion in P-AF were lower than those in Per-AF (1.9 ± 2.0 vs. 11.8 ± 5.0 times/s; p<0.0001, 0.1 ± 0.3 vs. 3.6 ± 2.5 times/s; p<0.001, 5.8 ± 3.6 vs. 9.8 ± 3.2 times/s; p<0.01). AF termination was more frequent in P-AF than Per-AF (94.8% vs 81.9%, p=0.0019). AF termination by PVI alone was more frequent in P-AF than Per-AF (85.6% vs. 18.6%, p<0.0001). However, AF termination via roof line and/or CFAE ablation was less frequent in P-AF than Per-AF (14.4 vs. 81.4%, p<0.0001). Disorganized activations after PVI, more prominent in Per-AF, were associated with residual CFAE region. Most P-AF was terminated by PVI alone, however additional roof line lesion and CFAE ablation were necessary to terminate Per-AF, consistent with mapping results.


Structural alteration of the target plasma membrane affects reception but not expression of the neural inductive signal.
We have previously reported that incubation of presumptive neuroectoderm in a solution of lectin (soybean agglutinin or garden pea agglutinin at 50 micrograms ml-1, 30 min) prior to its association with blastoporal lip inhibits neural induction (Duprat et al., 1982). We have also shown that incubation of presumptive ectoderm immediately after its association with blastoporal lip does not prevent neural induction. The same pattern of fluorescence on the ectodermal surface was observed when incubation with lectin was carried out before or after association of ectoderm with blastoporal lip. Although a particular molecular organization of the plasma membrane of the target ectoderm appears to be essential for reception or initiation of neural induction, the subsequent transmission and expression of this neural information does not appear to be affected by structural modifications of the target membrane. Similar studies performed using the inducer Con A indicated that the experimentally induced signal differed from the natural one.


[The role of peripheral capsulo-ligamentoplasties in the treatment of chronic anterior instability of the knee. Apropos of a series of 104 cases].
The authors have studied the results of 91 extra-articular ligamentoplasties amongst 104 knees treated surgically for chronic anterior laxity of the knee. The technique used in 40 cases was a Lemaire isolated lateral extra-articular ligamentoplasty using a strip of fascia lata and in 51 cases a double plasty, combining the same lateral plasty with a tightening of the posteromedial capsule and a forward transfer of the semimembranosus. The follow-up was from one to seven years, with a mean of four years. The results were assessed using the "ARPEGE" (Research Association for the Study of the Knee) scoring system, based on ability to undertake sports, functional stability, pain, resistance to fatigue, mobility and residual laxity. The overall results were excellent in 51 per cent, good in 10 per cent, fair in 10.5 per cent and bad in 28.5 per cent of cases. These results may seem to be unsatisfactory but a detailed study of the failures showed some errors in the indications for surgery which could have been avoided by a full appreciation of the type of laxity, the post-operative needs of the patient, his age and the level of sporting activity. Meniscectomy and lesions of the articular cartilage had a disturbing effect on the results. This study indicates a more precise place for extra-articular ligamentoplasties compared with in situ reconstructions of the anterior cruciate ligament.


Ergonomic principles of task alignment, visual display, and direction of execution of laparoscopic bowel suturing.
Laparoscopic suturing is technically a demanding skill in laparoscopic surgery. Ergonomic experimental studies provide objective information on the important factors and variables that govern optimal endoscopic suturing. Our objective was to determine the optimum physical alignment, visual display, and direction of intracorporeal laparoscopic bowel suturing using infrared motion analysis and telemetric electromyography (EMG) systems. Ten surgeons participated in the study; each sutured 50-mm porcine small bowel enterotomies toward and away from the surgeon in the vertical and horizontal bowel plane with either isoplanar (image display corresponds with actual lie of the bowel) or nonisoplanar (bowel displayed horizontally but mounted vertically in the trainer and vice versa) display. The end points were the placement error score, execution time, leakage pressure, motion analysis, and telemetric EMG parameters of the surgeon's dominant upper limb. Suturing was demonstrably easier in the vertical than in the horizontal plane, resulting in a better task quality (placement error score, p < 0.0001; leakage pressure, p < 0.005) and shorter execution time (p < 0.05). Nonisoplanar display of the surgical anatomy degrades performance in terms of both task efficiency and task quality. On motion analysis, a wider angle of excursion and lower angular velocity were observed during the vertical suturing with isoplaner display. Compared to horizontal suturing, supination at the wrist was significantly greater during vertical than horizontal suturing (p < 0.05). Within each category (vertical vs horizontal suturing), the direction of suturing (toward/away from the surgeon) did not influence the extent of pronation/ supination at the wrist. In line with the degraded performance, significantly more muscle work was expended during horizontal suturing. This affected the forearm flexors (p < 0.05), arm flexors and extensors (p < 0.005 and p < 0.05, respectively), and deltoid muscles (p < 0.005) and was accompanied by significantly more fatigue in the related muscles. Small bowel enterotomies sutured toward the surgeon in both the vertical and the horizontal planes exhibited less placement error score than when sutured away from the surgeon, with no significant difference in the motion analysis and EMG parameters. Optimal laparoscopic suturing (better task quality and reduced execution time) is achieved with vertical suturing toward the surgeon with isoplanar monitor display of the operative field. The poorer task performance observed during horizontal suturing is accompanied by more muscle work and fatigue, and it is not improved by monitor display of the enterotomy in the vertical plane.


Characterization of a translation inhibitory protein from Luffa aegyptiaca.
A protein with a molecular weight of about 30,000 was purified from the seeds of Luffa aegyptiaca. This protein inhibited cell free translation at pM concentrations. In spite of functional similarity to other ribosomal inhibitory proteins, the NH2-terminal analysis did not show any significant homology. Competitive inhibition studies indicate no immunological crossreactivity between the inhibitory protein from Luffa aegyptiaca, pokeweed antiviral protein (PAP) and recombinant ricin A chain. Chemical linkage of the protein to a monoclonal antibody reactive to transferrin receptor resulted in a highly cytotoxic conjugate.


Inflammatory pseudotumor of the spleen: report of a case with emphasis on contrast-enhanced ultrasound findings.
Splenic inflammatory pseudotumor is a rare pathology, and the literature stresses the difficulty of preoperative diagnosis. There are no previous reports of contrast-enhanced ultrasound findings for this tumor in the literature. Our case appears to be the first to be examined using this technique. In our case, contrast-enhanced ultrasound showed the mass to be homogeneously and less enhanced than the surrounding parenchyma in all phases, and it included fine enhanced spots. We also briefly review the literature.


One turn more: threshold superiority of 3-turn versus 2-turn screw-in myocardial electrodes.
Epicardial electrodes are an alternative for patients in whom the transvenous approach presents technical difficulties. We have had clinical experience with two types of myocardial sutureless electrodes inserted in the anterior left ventricular wall: the 3-turn screw-in electrode (Medtronic 6917) was used in 209 patients from 1974 to 1977 and the 2-turn screw-in lead (Medtronic 6917 A) was used in 61 patients from 1978 to 1981. The initial threshold was equal and acceptable with both types of electrodes. During a follow-up period (up to 48 months), critical elevation of the pacing threshold resulting in exit block was found in 12% (25) of the patients with the 3-turn screw-in electrode and in 20% (12) of the patients with the 2-turn electrode (p less than 0.05). Elevation of the pacing threshold developed fairly early, usually within 6 months, with the 2-turn screw-in electrode, but much later, within 2-4 years, with the 3-turn electrode. During a longer follow-up time of up to 96 months the frequency of exit block increased up to 16% with the 3-turn electrode. Our results indicate that late critical elevation of the pacing threshold is surprisingly frequent with screw-in electrodes inserted into the left ventricular myocardium, and it is especially common with the 2-turn screw-in electrode.


Molecular mechanism for the initial process of visual excitation. IV. Energy surfaces of visual pigments and photoisomerization mechanism.
Using the twisted conformations of the chromophores for visual pigments and intermediates which were theoretically determined in the previous paper, energy surfaces of the pigment at - 190 degrees C were obtained as functions of the torsional angles theta 9-10 and theta 11-12 or of the torsional angles theta 9-10 and theta 13-14. In these calculations, the existence of specific reaction paths between rhodopsin (R) and bathorhodopsin (B), between isorhodopsin I (I) and bathorhodopsin, and between isorhodopsin II (I') and bathorhodopsin were assumed. It was shown that the total energy surfaces of the excited states had minima C1 at theta 9-10 approximately -10 degrees and theta 11-12 approximately -80 degrees, C2 at theta 9-10 approximately -85 degrees and theta 11-12 approximately -5 degrees, and C3 at theta 9-10 approximately -0 degree and theta 13-14 approximately -90 degrees. These minima are considered to correspond to the thermally barrierless common states as denoted by Rosenfeld et al. Using the total energy surfaces in the ground and excited states, the molecular mechanism of the photoisomerization reaction was suggested. Quantum yields for the photoconversions among R, I, I' and B were related to the rates of vibrational relaxations, radiationless transitions and thermal excitations. Some discussion was made of the temperature effect on the quantum yield. Similar calculations of the energy surfaces were also made at other temperatures where lumirhodopsin or metarhodopsin I is stable. Relative energy levels of the pigments and the intermediates were discussed.


Peripheral blood parameter abnormalities precede therapy-related myeloid neoplasms after autologous transplantation for lymphoma.
Therapy-related myeloid neoplasms (t-MN) are a leading cause of nonrelapse mortality after autologous peripheral blood stem cell transplantation (aPBSCT) in patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphomas (NHL). t-MN patients treated at an earlier stage of disease evolution have a better prognosis, and this presents a need to identify patients at risk for t-MN. Using a prospective longitudinal study design, this study evaluated peripheral blood parameters pre-aPBSCT and on day 100, at 6 months, 1 year, 2 years, and 3 years in 304 patients treated with aPBSCT. The relation between peripheral blood parameters and subsequent development of t-MN was examined, and nomograms were developed to identify patients at risk for t-MN. Twenty-one patients developed t-MN at a median of 1.95 years post-aPBSCT. Hemoglobin, hematocrit, white blood cell, and platelet counts were lower among patients who developed t-MN compared to those who did not; these differences appeared soon after aPBSCT, persisted, and preceded development of t-MN. Older age at aPBSCT (hazard ratio [HR]per_year_increase = 1.08, P = .007), exposure to total body irradiation (TBI) (HR = 2.90, P = .04), and low 100-day platelet count (HRincrease_per_unit_decline_in_PLT = 1.01, P = .002) predicted subsequent t-MN. These parameters and primary diagnosis allowed identification of patients at high risk of t-MN (eg, an HL patient undergoing aPBSCT at the age of 70 years with TBI and with a day 100 PLT between 100,000 and 150,000 would have a 62% probability of developing t-MN at 6 years post-aPBSCT). Abnormalities in peripheral blood parameters can identify patients at high risk for t-MN after aPBSCT for HL or NHL, allowing opportunities to personalize close surveillance and possible disease-modifying interventions.


The Ca2+ affinity of the plasma membrane Ca2+ pump is controlled by alternative splicing.
The plasma membrane Ca2+ pump is a calmodulin-regulated P-type ATPase that is an essential element in controlling intracellular Ca2+ concentration. Studies on the gene structure of this pump have revealed an alternate splice option that changes the structure of the calmodulin-binding domain. This change in the structure of the enzyme results in a reduced calmodulin affinity. Tests of the enzyme's activity in the presence of a high calmodulin concentration, approximating that found inside living cells, show that this reduced calmodulin affinity causes a reduced apparent affinity of the enzyme for Ca2+. This shift in the Ca2+ activation occurs in a Ca2+ concentration range crucial to cellular function and is probably the physiologically important consequence of the alternate splice.


Role of ERAB/L-3-hydroxyacyl-coenzyme A dehydrogenase type II activity in Abeta-induced cytotoxicity.
Endoplasmic reticulum-associated amyloid beta-peptide (Abeta)-binding protein (ERAB)/L-3-hydroxyacyl-CoA dehydrogenase type II (HADH II) is expressed at high levels in Alzheimer's disease (AD)-affected brain, binds Abeta, and contributes to Abeta-induced cytotoxicity. Purified recombinant ERAB/HADH II catalyzed the NADH-dependent reduction of S-acetoacetyl-CoA with a Km of approximately 68 microM and a Vmax of approximately 430 micromol/min/mg. The contribution of ERAB/HADH II enzymatic activity to Abeta-mediated cellular dysfunction was studied by site-directed mutagenesis in the catalytic domain (Y168G/K172G). Although COS cells cotransfected to overexpress wild-type ERAB/HADH II and variant beta-amyloid precursor protein (betaAPP(V717G)) showed DNA fragmentation, cotransfection with Y168G/K172G-altered ERAB and betaAPP(V717G) was without effect. We thus asked whether the enzyme might recognize alcohol substrates of which the aldehyde products could be cytotoxic; ERAB/HADH II catalyzed oxidation of a variety of simple alcohols (C2-C10) to their respective aldehydes in the presence of NAD+ and NAD-dependent oxidation of 17beta-estradiol. Addition of micromolar levels of synthetic Abeta(1-40) to purified ERAB/HADH II inhibited, in parallel, reduction of S-acetoacetyl-CoA (Ki approximately 1.6 microM), as well as oxidation of 17beta-estradiol (Ki approximately 3.2 microM) and (-)-2-octanol (Ki approximately 2.6 microM). Because micromolar levels of Abeta were required to inhibit ERAB/HADH II activity, whereas Abeta binding to ERAB/HADH II occurred at much lower concentrations (Km approximately 40-70 nM), the latter more closely simulating Abeta levels within cells, Abeta perturbation of ERAB/HADH II was likely to result from mechanisms other than the direct modulation of enzymatic activity. Cells cotransfected to overexpress ERAB/HADH II and betaAPP(V717G) generated malondialdehyde-protein and 4-hydroxynonenal-protein epitopes, which were detectable only at the lowest levels in cells overexpressing either ERAB/HADH II or betaAPP(V717G) alone. Generation of such toxic aldehydes was not observed in cells contransfected to overexpress Y168G/K172G-altered ERAB and betaAPP(V717G). We conclude that the generalized alcohol dehydrogenase activity of ERAB/HADH II is central to the cytotoxicity observed in an Abeta-rich environment.


[Aortitis due to Salmonella].
A 72-year-old man received treatment with amoxicillin/clavulanic acid because of fever and abdominal pain as an outpatient setting. Salmonella enteritidis infection was confirmed by a positive blood culture. The febrile patient showed abdominal tenderness on palpation. CT and PET scans revealed an aneurysmatic soft tissue inflammation which was interpreted as infectious aortitis in the context of salmonella bacteraemia. After several weeks of antibiotic treatment with ceftriaxone, an elective reconstruction using xenopericard with replacement of the mesenterial vessels was performed. After a postoperative course of antibiotics the patient recovered completely. In patients with positive blood cultures for Salmonella in combination with fever, back or abdominal pain a workup for infectious aortitis and a rapid treatment is recommended.


Intrapeptide regulation of protein kinase C.
Protein kinase C is allosterically activated by diacylglycerol and phosphatidylserine. The enzyme is also activated by surprisingly dissimilar compounds such as short chained phosphatidylcholines and protamine sulfate. Here we show that conventional and nonconventional activators of protein kinase C beta II produce the same structural alteration. They expose Arg19 of the autoinhibitory pseudosubstrate domain to proteolysis. Molecular modeling of protein kinase C beta II's catalytic domain, based on the structure of the cAMP-dependent kinase's catalytic domain, indicates that Arg19 is shielded by a cluster of acidic residues when the pseudosubstrate occupies the substrate-binding site. Our biochemical data and structural modeling indicate a common mechanism of intrapeptide regulation of protein kinase C by all activators that involves release of the pseudosubstrate from the active site.


Neurofibromatosis: bladder involvement with malignant degeneration.
A solitary neurofibroma of the urinary tract is rare. More rare in the urinary tract are neurofibromas associated with the neurofibromatosis of Von Recklinghausen's disease. A case of multiple neurofibromas of the bladder degenerating into neurofibrosarcoma is described.


Analysis on internal mechanism of zedoary turmeric in treatment of liver cancer based on pharmacodynamic substances and pharmacodynamic groups.
Zedoary tumeric (Curcumae Rhizoma, Ezhu in Chinese) has a long history of application and has great potential in the treatment of liver cancer. The antiliver cancer effect of zedoary tumeric depends on the combined action of multiple pharmacodynamic substances. In order to clarify the specific mechanism of zedoary tumeric against liver cancer, this paper first analyzes the mechanism of its single pharmacodynamic substance against liver cancer, and then verifies the joint anti liver cancer mechanism of its "pharmacodynamic group". By searching the research on the antihepatoma effect of active components of zedoary tumeric in recent years, we found that pharmacodynamic substances, including curcumol, zedoarondiol, curcumenol, curzerenone, curdione, curcumin, germacrone, β-elemene, can act on multi-target and multi-channel to play an antihepatoma role. For example, curcumin can regulate miR, GLO1, CD133, VEGF, YAP, LIN28B, GPR81, HCAR-1, P53 and PI3K/Akt/mTOR, HSP70/TLR4 and NF-κB. Wnt/TGF/EMT, Nrf2/Keap1, JAK/STAT and other pathways play an antihepatoma role. Network pharmacological analysis showed that the core targets of the "pharmacodynamic group" for anti-life cancer are AKT1, EGFR, MAPK8, etc, and the core pathways are neuroactive live receiver interaction, nitrogen metabolism, HIF-1 signaling pathway, etc. At the same time, by comparing and analyzing the relationship between the specific mechanisms of pharmacodynamic substance and "pharmacodynamic group", it is found that they have great reference significance in target, pathway, biological function, determination of core pharmacodynamic components, formation of core target protein interaction, in-depth research of single pharmacodynamic substance, increasing curative effect and so on. By analyzing the internal mechanism of zedoary tumeric pharmacodynamic substance and "pharmacodynamic group" in the treatment of liver cancer, this paper intends to provide some ideas and references for the deeper pharmacological research of zedoary tumeric and the relationship between pharmacodynamic substance and "pharmacodynamic group".


Correction to: Blood transcriptomic discrimination of bacterial and viral infections in the emergency department: a multi-cohort observational validation study.
An amendment to this paper has been published and can be accessed via the original article.


Antimicrobial activity of Ro 19-5247 (T-2525), a new oral cephalosporin, tested against 7,745 recent clinical isolates.
The susceptibility testing of 7,745 recent clinical isolates from four medical centers showed Ro 19-5247 to be eight- to greater than 64-fold more active than cephalexin against the Enterobacteriaceae. Ro 19-5247 was comparable with cephalexin in anti-staphylococcal activity (MIC50, 4.0 micrograms/ml) and fourfold more active than cefixime. None of the oral cephalosporins were effective (MIC50, greater than 32 micrograms/ml) against enterococci, Pseudomonas aeruginosa and P. maltophilia. beta-lactamase hydrolysis experiments failed to demonstrate significant Ro 19-5247 inactivation by ten commonly encountered chromosomal- or plasmid-mediated enzymes (P99, K1, K14, TEM, CARB, OXA).


Proline can have opposite effects on fast and slow protein folding phases.
Proline isomerization is well known to cause additional slow phases during protein refolding. We address a new question: does the presence of prolines significantly affect the very fast kinetics that lead to the formation of folding intermediates? We examined both the very slow (10-100 min) and very fast (4 micro s-2.5 ms) folding kinetics of the two-domain enzyme yeast phosphoglycerate kinase by temperature-jump relaxation. Phosphoglycerate kinase contains a conserved cis-proline in position 204, in addition to several trans-prolines. Native cis-prolines have the largest effect on folding kinetics because the unfolded state favors trans isomerization, so we compared the kinetics of a P204H mutant with the wild-type as a proof of principle. The presence of Pro-204 causes an additional slow phase upon refolding from the cold denatured state, as reported in the literature. Contrary to this, the fast folding events are sped up in the presence of the cis-proline, probably by restriction of the conformational space accessible to the molecule. The wild-type and Pro204His mutant would be excellent models for off-lattice simulations probing the effects of conformational restriction on short timescales.


NMDA receptors and metaplasticity: mechanisms and possible roles in neuropsychiatric disorders.
N-methyl-D-aspartate receptors (NMDARs) are key components of neural signaling, playing roles in synaptic transmission and in the synaptic plasticity thought to underlie learning and memory. NMDAR activation can also have neurotoxic consequences contributing to several forms of neurodegeneration. Additionally, NMDARs can modulate neuronal function and regulate the ability of synapses to undergo synaptic plasticity. Evidence gathered over the past 20 years strongly supports the idea that untimely activation of NMDARs impairs the induction of long-term potentiation (LTP) by a form of metaplasticity. This metaplasticity can be triggered by multiple stimuli including physiological receptor activation, and metabolic and behavioral stressors. These latter findings raise the possibility that NMDARs contribute to cognitive dysfunction associated with neuropsychiatric disorders. This paper examines NMDAR metaplasticity and its potential role in cognition. Recent studies using NMDAR antagonists for therapeutic purposes also raise the possibility that metaplasticity may contribute to clinical effects of certain drugs.


Technical Aspects and Benefits of Experimental Mouse Lung Transplantation.
In recent years, the number of lung transplantations performed as the last option for many respiratory diseases has grown considerably, both in adults and children. However, the causes for the relatively short survival of lungs compared to other organ transplants still need to be studied. Techniques have improved since the 1950s when experimental lung transplantation began, and the different animal species used now include rodents. The advantage of using these small species is that the surgical model has been expanded and standardized, and different respiratory problems can be studied. In this review we examine the different technical strategies used in experimental transplantation in rats and mice, focusing on surgical techniques and anesthesia and monitoring methods, and highlighting the major contributions of mouse lung transplantation to the field.


Characterization of calcium uptake into rough endoplasmic reticulum of rat pancreas.
ATP-dependent Ca2+ uptake into isolated pancreatic acinar cells with permeabilized plasma membranes, as well as into isolated endoplasmic reticulum prepared from these cells, was measured using a Ca2+ -specific electrode and 45Ca2+. Endoplasmic reticulum was purified on an isopycnic Percoll gradient and characterized by marker enzyme distribution. When compared to the total homogenate, the typical marker for the rough endoplasmic reticulum RNA was enriched threefold and the typical marker for the plasma membrane Na+,K+(Mg2+)ATPase was decreased 20-fold. When different fractions of the Percoll gradient were compared, 45Ca2+ uptake correlated with the RNA content and not with the Na+,K+(Mg2+)ATPase activity. The characteristics of nonmitochondrial Ca2+ uptake into leaky isolated cells and 45Ca2+ uptake into isolated endoplasmic reticulum were very similar: Calcium uptake was maximal at 0.3 and 0.2 mmol/liter free Mg2+, at 1 and 1 mmol/liter ATP, at pH 6.0 and 6.5, and free Ca2+ concentration of 2 and 2 mumol/liter, respectively. Calcium uptake decreased at higher free Ca2+ concentration. 45Ca2+ uptake was dependent on monovalent cations (Rb+ greater than K+ greater than Na+ greater than Li+ greater than choline+) and different anions (Cl- greater than Br- greater than SO4(2-) greater than NO3- greater than I- greater than cyclamate- greater than SCN-) in both preparations. Twenty mmol/liter oxalate enhanced 45Ca2+ uptake in permeabilized cells 10-fold and in vesicles of endoplasmic reticulum, fivefold. Calcium oxalate precipitates in the endoplasmic reticulum of both preparations could be demonstrated by electron microscopy. The nonmitochondrial Ca2+ pool in permeabilized cells characterized in this study has been previously shown to regulate the cytosolic free Ca2+ concentration to 0.4 mumol/liter. Our results provide firm evidence that the endoplasmic reticulum plays an important role in the regulation of the cytosolic free Ca2+ concentration in pancreatic acinar cells.


Modification of chloride flux across brain membranes by inhibitory amino acids in developing and adult mice.
The influx of 36Cl- was studied in membrane vesicles prepared from different brain regions from 3-day-old and adult mice. In both age groups the influx was enhanced about threefold by gamma-aminobutyric acid (GABA), which effect was blocked by bicuculline and picrotoxin but not by baclofen, characteristic of a GABAA receptor-mediated event. In samples from the adult brain stem the GABA stimulation was smaller than in samples from the other brain regions. Most of the compounds studied apparently act at the same receptor site with the following order of efficacy: muscimol greater than GABA greater than beta-alanine greater than hypotaurine greater than taurine. A number of anticonvulsant taurine derivatives were not effective and glycine only in the brain stem. The weak modulatory effects of taurine could be of significance in vivo since depolarizing stimuli release massive amounts of taurine in developing brain tissue.


Chromosomal analysis of sperm from men with idiopathic infertility using sperm karyotyping and fluorescence in situ hybridization.
To determine if idiopathic infertile men having oligozoospermia, asthenozoospermia, or teratozoospermia have an elevated risk of transmitting chromosomal abnormalities to their offspring. Sperm chromosomal complements from five somatically normal infertile men were assayed using the human sperm-hamster oocyte fusion system and the disomy frequencies for chromosomes 1, 12, and the sex chromosomes were determined using fluorescence in situ hybridization. Infertile men and normal donors were volunteers in an academic research environment. Five men with the appropriate semen characteristics were recruited among patients concerned about their infertility. Sperm fused with hamster oocytes resulting in sperm chromosomes or the sperm nuclei were prepared for fluorescence in situ hybridization. Structural and numerical abnormalities assessed by sperm karyotypes and the disomy frequency determined by fluorescence in situ hybridization analysis. The infertile men showed increased frequencies of numerical abnormalities and total abnormalities as determined by sperm karyotyping. Analysis of sperm nuclei by fluorescence in situ hybridization indicated a significant increase in the frequency of disomy for chromosome 1 and XY disomy. Sperm from infertile men may contain an increased frequency of chromosomal abnormalities.


How Bases Catalyze Diels-Alder Reactions.
We have quantum chemically studied the base-catalyzed Diels-Alder (DA) reaction between 3-hydroxy-2-pyrone and N-methylmaleimide using dispersion-corrected density functional theory. The uncatalyzed reaction is slow and is preceded by the extrusion of CO2 via a retro-DA reaction. Base catalysis, for example, by triethylamine, lowers the reaction barrier up to 10 kcal mol-1 , causing the reaction to proceed smoothly at low temperature, which quenches the expulsion of CO2 , yielding efficient access to polyoxygenated natural compounds. Our activation strain analyses reveal that the base accelerates the DA reaction via two distinct electronic mechanisms: i) by the HOMO-raising effect, which enhances the normal electron demand orbital interaction; and ii) by donating charge into 3-hydroxy-2-pyrone which accumulates in its reactive region and promotes strongly stabilizing secondary electrostatic interactions with N-methylmaleimide.


First Reported Case of a Clinically Nonresponsive-to-Itraconazole Alternaria alternata Isolated from a Skin Infection of a Nonimmunocompromised Patient from Romania.
Alternaria alternata is a melanic fungus capable of causing a wide variety of infections, some of which have lethal potential. It is a ubiquitous fungus and a well-known plant pathogen. Cutaneous infections with Alternaria alternata most often occur in the extremities of patients who perform conventional agriculture, thus being exposed to occupational hazards leading to the disruption of the skin barrier. This paper presents the first case report from Romania of an itraconazole nonresponsive cutaneous alternariosis in a patient without any type of immunosuppression. After an initial misdiagnosis regarding the etiology of the patient's skin infection, two successive punch biopsies, followed by mycologic examination, lead to the final diagnosis of cutaneous alternariosis. Treatment guided by antifungal susceptibility testing has been instituted, leading to the gradual healing of the patient's skin ulcerations. The ability of Alternaria alternata to infect immunocompetent human hosts and to develop resistance to antifungal drugs highlight the importance of correctly diagnosing the etiology of skin ulcerations and instituting appropriate treatment guided by antifungal susceptibility testing whenever the suspicion of a fungal skin infection is plausible.


Whole brain apparent diffusion coefficient histogram: a new tool for evaluation of leukoaraiosis.
To test whole brain apparent diffusion coefficient histogram analysis as an alternative approach to visual score for the assessment of leukoaraiosis (LA). T2 and diffusion weighted images were obtained in 15 elderly patients. LA extension was assessed on T2 weighted images by two observers using a semiquantitative visual score. Apparent diffusion coefficient (ADC) maps of the entire brain were generated and, after exclusion of the skull with manual tracing and of the cerebrospinal fluid (CSF) by application of a threshold value, whole brain (WB)-ADC histogram was obtained. Moreover, a brain volume index (BVI) was calculated on ADC maps as (intracranial volume - CSF volume) /intracranial volume. The kappa inter-observer agreement for LA scoring was 0.69. Manual segmentation of the skull showed a mean inter-operator coefficient of variation below 3%. The median value of whole brain ADC histogram directly correlated with LA extension (P = 0.013). Moreover a significant inverse correlation (P = 0.002) was found between WB-ADC median value and BVI. WB-ADC histogram is a reproducible alternative tool for assessing LA extension and severity.


Synthesis, cloning and expression in Escherichia coli of the gene coding for the trypsin inhibitor from Cucurbita pepo.
A chemically synthesized gene coding for the serine proteinase inhibitor CPTI II was cloned in E. coli and its expression was investigated in cytoplasmic and secretion systems. Under all conditions investigated the biologically active form of the inhibitor was found only in the latter system, although the yield was rather low.


Noninvasive estimation of human radiation dosimetry of 18F-FDG by whole-body small animal PET imaging in rats.
Small animal PET provides the biodistribution of administrated radiotracer in vivo and have a potential to contribute on dosimetry study. The aim of this study is to investigate the effect of region-of-interest (ROI)-delineation in whole-body rat PET image toward non-invasive estimation of human dosimetry of 18F-FDG. After administration of 18F-FDG (averaged 11.7 MBq), 3.5-h PET and 20-min CT scans were sequentially performed for three rats by Clairvivo PET/CT system. Seven source organs, and the remainder of the body, were studied to extrapolate %ID(t) and estimate time-integrated activity coefficients [kBq-h/MBq] in human. The mean absorbed dose in each target organ and the effective dose were estimated by MIRD method. Effects of ROI-definitions on both extrapolated %ID(t) in human and estimated doses were also investigated by using (i) small ROIs of high uptake region and (ii) whole organ ROIs. Averaged effective doses of 18F-FDG in human by using high-uptake and whole-organ ROIs were 27.8 ± 6.54 and 19.3 ± 2.72 μSv/MBq, respectively. The use of small animal PET scanner, which allows repeatedly PET scans, have a potential to contribute on the reduction of the number of experimental animals. However, the ways of ROI drawing influences on the estimated effective dose and safe-side ROI definition may be preferred.


Cognition and Hemodynamics.
The relationship between cerebral hemodynamics and cognitive performance has increasingly become recognized as a major challenge in clinical practice for older adults. Both diabetes and hypertension worsen brain perfusion and are major risk factors for cerebrovascular disease, stroke and dementia. Cerebrovascular reserve has emerged as a potential biomarker for monitoring pressure-perfusion-cognition relationships. Endothelial dysfunction and inflammation, microvascular disease, and mascrovascular disease affect cerebral hemodynamics and play an important role in pathohysiology and severity of multiple medical conditions, presenting as cognitive decline in the old age. Therefore, the identification of cerebrovascular vascular reactivity as a new therapeutic target is needed for prevention of cognitive decline late in life.


Bleeding during enoxaparin treatment more common with age over 75 years and severe renal insufficiency.
Severe renal insufficiency, defined as a creatinine clearance <30 mL/min, increases the risk for bleeding in elderly patients receiving enoxaparin (enoxaparin sodium) treatment. The risk/benefit ratios of enoxaparin and unfractionated heparin (UFH) in patients with acute myocardial infarction (AMI) aged >75 years were determined by investigating the parameters of efficacy (ischaemic event, lethal outcome), safety (bleeding events, renal insufficiency) or both (composite endpoint: ischaemic event or lethal outcome or bleeding event). The study included 113 patients (59 male, 52.2%) with AMI aged >75 years; 36 of these patients received enoxaparin. In the patients who had severe renal insufficiency, bleeding events were more frequent in those receiving enoxaparin than in those patients who received UFH (3 vs 1, respectively; p = 0.024). Irrespective of the presence of renal insufficiency, bleeding events occurred more often in patients who received enoxaparin than in those who received UFH (13 vs 8, respectively; p = 0.007). The composite endpoint showed a nonsignificantly better profile in patients who received enoxaparin than in those who received UFH. Although the use of enoxaparin (compared with UFH) and the presence of severe renal insufficiency significantly increased the occurrence of bleeding in patients with AMI aged >75 years, the risk/benefit difference in this population was not significant.


Impact of delays in radiotherapy of head and neck cancer on outcome.
In head and neck cancer (HNC), the relationship between a delay in starting radiotherapy (RT) and the outcome is unclear. The aim of the present study was to determine the impact of the amount of time before treatment intervention (TTI) and the growth kinetics of individual tumors on treatment outcomes and survival. Two hundred sixty-two HNC patients with 273 primary tumors, treated with definitive (chemo) RT, were retrospectively analyzed. The TTI was defined as the time interval between the date of histopathologic diagnosis and the first day of the RT course. Volumetric data on 57 tumors were obtained from diagnostic and RT planning computer tomography (CT) scans in order to calculate the tumor growth kinetic parameters. No significant association between locoregional control or cause-specific hazards and TTI was found. The log hazard for locoregional recurrence linearly increased during the first 40 days of waiting for RT, although this was not significant. The median tumor volume relative increase rate and tumor volume doubling time was 3.2%/day and 19 days, respectively, and neither had any impact on locoregional control or cause-specific hazards. The association between a delay in starting RT and the outcome is complex and does not harm all patients waiting for RT. Further research into imaging-derived kinetic data on individual tumors is warranted in order to identify patients at an increased risk of adverse outcomes due to a delay in starting RT.


Biologic and prognostic significance of hepatocyte hepatitis B core antigen expressions in the natural course of chronic hepatitis B virus infection.
To elucidate the biologic significance of hepatocyte hepatitis B core antigen (HBcAg) expression and its relation to the natural course of hepatitis B virus (HBV) infection, the patterns of HBcAg were correlated with HBV virus replication state and the disease activity in 598 needle liver biopsies performed on 569 hepatitis B surface antigen (HBsAg) carriers aged 1-81 years. A good correlation of liver HBcAg with serum HBeAg and HBV DNA status was demonstrated. HBcAg was present in the hepatocyte nuclei (nHBcAg) or cytoplasm (cHBcAg), or in both (mixed). Pure nHBcAg was seen mainly in children and young adults; 86% of the patients had non-aggressive disease, but rare cases of chronic active hepatitis (CAH) and HBeAg seroconversion were observed. In contrast, cHBcAg was predominantly associated with CAH (52%) and accompanied by a significantly higher HBeAg seroconversion rate (27%). The HBeAg-negative group, particularly the liver HBcAg-negative subgroup, had a lower frequency of CAH, but an increased incidence of non-aggressive disease as well as cirrhosis and/or hepatocellular carcinoma, indicating that HBeAg seroconversion to anti-HBe does not necessarily mean a favorable prognosis. The results suggest that expression of HBcAg correlates with the liver pathology and the three phases of chronic HBV infection: (1) the early immune tolerance phase is characterized by nHBcAg, mild disease and low HBeAg seroconversion rate; (2) the virus replication/elimination phase by cHBcAg or negative HBcAg, frequent CAH, and high HBeAg seroconversion rate; and (3) the inactive virus replication phase by negative HBcAg and a bipolar disease spectrum.


Process for nutrient recycling from intensive aquaculture through microalgae-bacteria consortium.
This work studies a biological process based on a microalgae-bacteria consortium for recycling nutrients in a recirculating aquaculture system (RAS) implanted in an intensive marine aquaculture farm. Additionally, some techniques were used for microalgae biomass harvesting and tested the effectiveness of filtration by a column with multi-layer sand to reduce the solids concentrations in the effluent. The consortium was grown in photobioreactors in batch and semi-continuous operation modes using the solids concentrated stream generated in the RAS system. The semi-continuous operation showed a high percentage of TDN and TDP removal, achieving final concentrations of 1.09 ± 0.02 mg·L-1 and 0.01 ± 0.01 mg·L-1, respectively, while DOC was reduced to 3.87 ± 0.06 mg·L-1. The values of productivity 44 ± 9 mg TSS·L-1 indicated that the studied stream is a suitable culture medium for the growth of the microalgae-bacteria consortium. A combination of harvesting techniques was studied, coagulation-flocculation-settling and coagulation-flocculation-flotation. The first step was to optimise the dose of FeCl3 through the coagulation-flocculation test to pre-concentrate the biomass generated, achieving an optimal dose of 0.106 mg Fe·mg TSS-1. Then, two separation processes were applied to the stream and compared: settling and flotation. The maximum removal efficiency (90.2 ± 0.3 %) was obtained in the settling process, so the coagulation-flocculation-settling was select as the best combination of harvesting techniques. Finally, sand filtration was studied as an effluent refining process to improve solids reduction of the water obtained in the harvesting step resulting in an effluent with 17.18 ± 1.49 mg TSS·L-1. The proposed sequence process is capable of recycling nutrients from an intensive marine aquaculture farm by using these resources via transformation into microalgae biomass and generating quality effluent.


[Quality and outcome assessment in gastrointestinal endoscopy: study of 202 colonoscopies].
The aim of this study was to evaluate the quality of the medical care associated with the colonoscopies performed in our gastrointestinal endoscopy unit. This 6-month prospective, comparative study used process and result indicators. Its long-term objective was to improve the quality of care and to select a few pertinent quality indicators for continual monitoring. An audit was conducted of all total colonoscopies performed at our general hospital from November 2005 through May 2006. It assessed the principal published process and result indicators for the medical aspects of the procedure as well as patient satisfaction (indication, procedure itself, results, complications, satisfaction). These indicators were also compared between endoscopists. During the 6-month study period, 202 total colonoscopies were performed. Waiting time for the procedure, appropriateness of the indication, proportion of colonoscopies completed, proportion of neoplastic lesions found, adequacy of bowel preparation, frequency of complications, and patient satisfaction were similar to and even above the standard values. However, patient information and the completeness of the legal documents were insufficient. Although the mean values were satisfactory, detailed individual analysis showed statistically significant differences between endoscopists. For example, the proportion of withdrawal times exceeding 6 minutes was 16.3%, 25.0% and 86.4% according to endoscopist. The mean number of polyps each removed per procedure was respectively 1, 2, and 3 (p<0.05). An improvement plan was implemented in view of these results, and appropriate simple indicators were selected for prospective monitoring. Despite the overall results, which essentially complied with standard guidelines, our prospective and comparative audit of colonoscopies pointed out significant variations between individual endoscopists and helped us to define improvement actions and indicators.


TRH regulates Kv1.5 gene expression through a Galphaq-mediated PLC-independent pathway.
Thyrotropin-releasing hormone (TRH) decreases transcription of the Kv1.5 K(+) channel gene in GH(3) pituitary cells. Here, we examine whether TRH utilizes Gq activated phospholipase C, Gs or Gi to produce this response. We report that expression of constitutively active Galphaq mimicked and occluded the TRH effect. In contrast, expression of activated Galpha(S) or Galpha(i2) had no effect on Kv1. 5 mRNA expression. Furthermore, pertussis and cholera toxins failed to block the TRH-induced decrease in channel mRNA. Surprisingly, despite the role of Gq, the phospholipase C inhibitor U73122 did not alter down-regulation of channel mRNA by TRH, although it abolished the TRH-induced increase in intracellular [Ca(2+)] and up-regulation of c-fos mRNA. Furthermore, depletion of an intracellular Ca(2+) pool or inhibition of protein kinase C did not block the TRH-induced decrease in Kv1.5 mRNA. These results indicate that TRH-induced down-regulation of Kv1.5 gene expression is mediated by Galphaq proteins, but does not require PLC activation.


Focal epileptogenic lesions.
The spectrum of focal epileptogenic lesions and their clinical manifestations in children differ substantially from those seen in adults. In adults, mesial temporal sclerosis is the common lesion in surgical series; but in children, MTS is uncommon, and when it does occur, it exists frequently as dual pathology. The most common lesions in pediatric epilepsy surgery candidates are malformations of cortical development, developmental tumors, or encephalomalacia from infarction, hypoxia, trauma, or infection. Careful analysis of the lesion characteristics on brain MRI is sufficiently predictive of pathology in most cases. Histopathological evaluation remains the gold standard for diagnosis of mass lesions. The electroclinical phenotype of epilepsy in adults is largely determined by the anatomical location of the lesion and its connectivity. In children, in addition to the location of the lesion, the age at onset of the lesion and the age at onset of epilepsy have a major impact on the electroclinical phenotype. Children with congenital or early acquired lesions may manifest with generalized features on EEG and seizure semiology. Experience from various centers has demonstrated that a subset of these children benefit from epilepsy surgery despite a generalized epilepsy phenotype. All children with medically refractory epilepsy and a focal lesion should undergo evaluation for potential epilepsy surgery irrespective of the EEG findings and seizure semiology.


Phosphorylation of eukaryotic translation initiation factor 2Bepsilon by glycogen synthase kinase-3beta regulates beta-adrenergic cardiac myocyte hypertrophy.
Glycogen synthase kinase 3beta (GSK-3beta) negatively regulates cardiac hypertrophy. A potential target mediating the antihypertrophic effect of GSK-3beta is eukaryotic translation initiation factor 2Bepsilon (eIF2Bepsilon). Overexpression of GSK-3beta increased the cellular kinase activity toward GST-eIF2Bepsilon in neonatal rat cardiac myocytes, whereas LiCl (10 mmol/L) or isoproterenol (ISO) (10 micromol/L), a treatment known to inhibit GSK-3beta, decreased it. Immunoblot analyses using anti-S535 phosphospecific eIF2Bepsilon antibody showed that S535 phosphorylation of endogenous eIF2Bepsilon was decreased by LiCl or ISO, suggesting that GSK-3beta is the predominant kinase regulating phosphorylation of eIF2Bepsilon-S535 in cardiac myocytes. Decreases in eIF2Bepsilon-S535 phosphorylation were also observed in a rat model of cardiac hypertrophy in vivo. Overexpression of wild-type eIF2Bepsilon alone moderately increased cell size (+31+/-11%; P<0.05 versus control), whereas treatment of eIF2Bepsilon-transduced myocytes with LiCl (+73+/-22% versus eIF2Bepsilon only; P<0.05) or ISO (+84+/-33% versus eIF2Bepsilon only; P<0.05) enhanced the effect of eIF2Bepsilon. Overexpression of eIF2Bepsilon-S535A, which is not phosphorylated by GSK-3beta, increased cell size (+107+/-35%) as strongly as ISO (+95+/-25%), and abolished antihypertrophic effects of GSK-3beta, indicating that S535 phosphorylation of eIF2Bepsilon critically mediates antihypertrophic effects of GSK-3beta. Furthermore, expression of eIF2Bepsilon-F259L, a dominant-negative mutant, inhibited ISO-induced hypertrophy, indicating that eIF2Bepsilon is required for beta-adrenergic hypertrophy. Interestingly, expression of eIF2Bepsilon-S535A partially increased cytoskeletal reorganization, whereas it did not increase expression of atrial natriuretic factor gene. These results suggest that GSK-3beta is the predominant kinase mediating phosphorylation of eIF2Bepsilon-S535 in cardiac myocytes, which in turn plays an important role in regulating cardiac hypertrophy primarily through protein synthesis.


Flexible protective gloves: the emperor's new clothes?
The risk of developing skin cancer is estimated for interventional radiologists who do and do not wear thin, flexible protective leaded gloves. The use of these gloves is extremely expensive in terms of dollars per potential cancer prevented. Good radiographic practice without the use of flexible protective gloves provides adequate protection.


[Observation on effect of double filtration plasmapheresis on patients with active rheumatoid arthritis in active stage].
To investigate the effect of filtration plasmapheresis (DFPP) on blood contents of rheumatoid factor (RF), C reactive protein (CRP), and erythrocyte sedimentation rate (ESR) in patients with rheumatoid arthritis (RA) in active stage, and to appraise the therapeutic effect of DFPP on RA. The changes in contents of blood RF, CRP, ESR before and after DFPP were compared. The treatment was given for 2-3 times, and the activity of RA and the appearance of filtrate plasma were compared before and after the treatment. There were dramatic reductions of the levels of RF, CRP, ESR after single DFPP by 22.55%, 57.08% and 50.48%, respectively, compared with those before the treatment (all P<0.001). The color of the filtrate was green in RA in active stage. The cases with dark green filtrate had higher active indexes (pain, tenderness, swelling) and blood contents of CRP and ESR than those with green or yellow-green ones (all P<0.001). DFPP can remarkably reduce the level of RF, CRP, ESR of blood. The filtrate of RA in active stage appeared green. There is a relationship between the activity of RA and the color of filtrates.


Discrete positive and negative thyroid hormone-responsive transcription regulatory elements of the rat growth hormone gene.
We have recently shown that a thyroid hormone-responsive transcription stimulatory element exists in the 5'-flanking DNA near the rat growth hormone (rGH) gene (Crew, M. D., and Spindler, S. R. (1986) J. Biol. Chem. 261, 5018-5022). Progressive deletion-transfection analysis of the 5' end of the gene has led to the identification of two genetic elements responsive to thyroid hormone. The first of these is a thyroid hormone-responsive transcription stimulatory element, or TSE. The TSE induced a thyroid hormone-dependent induction-attenuation transcription cycle similar to that of the natural rGH gene. Deletion of sequences between positions -254 and -241 in the rGH 5'-flanking DNA eliminated TSE activity. The second regulatory element is a thyroid hormone-responsive transcription inhibitory element (TIE). When this element was active, thyroid hormone strongly but transiently inhibited rGH promoter utilization. Deletion of sequences between nucleotides -46 and -21 abolished the effects of the TIE. To determine whether the TSE and TIE are enhancer-like, we ligated various regions of rat growth hormone 5'-flanking DNA containing these elements to a chimeric test gene containing the Herpes simplex virus thymidine kinase promoter. Thyroid hormone activated heterologous promoter utilization when a rat growth hormone 5'-flanking DNA fragment containing the TSE (-520 to -115) was linked in cis, regardless of the distance or orientation of the TSE with respect to the promoter. These data suggest that the TSE is a thyroid hormone-dependent enhancer. In contrast, when the TIE was placed immediately 5' to the thymidine kinase promoter, transcription was not effected by 3,5,3'-L-triiodothyronine, suggesting that the TIE is not enhancer-like.


Using Flame-Assisted Printing to Fabricate Large Nanostructured Oxide Thin Film for Electrochromic Applications.
Flame spray pyrolysis was a process to produce oxide nanoparticles in a self-sustaining flame. When the produced nanoparticles were deposited on a substrate, nanostructured oxide thin films could be obtained. However, the size of the thin film was usually limited by the fixed substrate. Here, we demonstrated that thin film with a large area could be deposited by using the moving substrate, which was precisely controlled by servo motors. As a result, the flame tip could scan over the substrate and deposit the nanoparticles on it line by line, analogues to a printing process called flame-assisted printing (FAP). As an example, nanostructured bismuth-oxide thin films with a size of up to 20 cm × 20 cm were deposited with the FAP process. The bismuth-oxide thin film exhibited a stable electrochromic property with a high modulation of 70.5%. The excellent performance could be ascribed to its porous nanostructure formed in the FAP process. The process can be extended to deposit other various oxides (e.g., tungsten-oxide) thin films with a large size for versatile applications.


Conversion of spent mushroom substrate to biofertilizer using a stress-tolerant phosphate-solubilizing Pichia farinose FL7.
To develop high-efficient biofertilizer, an environmental stress-tolerant phosphate-solubilizing microorganism (PSM) was isolated from agricultural wastes compost, and then applied to spent mushroom substrate (SMS). The isolate FL7 was identified as Pichia farinose with resistance against multiple environmental stresses, including 5-45°C temperature, 3-10 pH range, 0-23% (w/v) NaCl and 0-6M ammonium ion. Under the optimized cultivation condition, 852.8 mg/l total organic acids can be produced and pH can be reduced to 3.8 after 60 h, meanwhile, the soluble phosphate content reached 816.16 mg/l. The P. farinose was used to convert SMS to a phosphate biofertilizer through a semi-solid fermentation (SSF) process. After fermentation of 10 days, cell density can be increased to 5.6 × 10(8)CFU/g in biomass and pH in this medium can be decreased to 4.0. SMS biofertilizer produced by P. farinose significantly improved the growth of soybean in pot experiments, demonstrating a tremendous potential in agricultural application.


Neurodegeneration in D-bifunctional protein deficiency: diagnostic clues and natural history using serial magnetic resonance imaging.
We report serial neurodegenerative changes on neuroimaging in a rare peroxisomal disease called D-bifunctional protein deficiency. The pattern of posterior to anterior demyelination with white matter disease resembles X-linked adrenoleukodystrophy. We feel this case is important to (1) highlight that D-bifunctional protein deficiency should be considered in cases where the neuroimaging resembles X-linked adrenoleukodystrophy, (2) to show different stages of progression to help identify this disease using neuroimaging in children, and (3) to show that neuroimaging suggesting a leukodystrophy can warrant peroxisomal beta-oxidation studies in skin fibroblasts even when plasma very long chain fatty acids are normal.


Regulation of localized corrosion of 316L stainless steel on osteogenic differentiation of bone morrow derived mesenchymal stem cells.
Localized corrosion has become a concerning issue in orthopedic implants as it is associated with peri-implant adverse tissue reactions and implant failure. Here, the pitting corrosion of 316 L stainless steels (316 L SSs) was initiated by electrochemical polarization to simulate the in vivo localized corrosion of orthopedic implants. The effect of localized corrosion on osteogenic differentiation of bone marrow derived mesenchymal stem cells (BMSCs) was systematically studied. The results suggest that pitting corrosion of 316 L SS reduced the viability, adhesion, proliferation, and osteogenic differentiation abilities of BMSCs, especially for the cells around the corrosion pits. The relatively high concentrations of metallic ions such as Cr3+ and Ni2+ released by pitting corrosion could cause cytotoxicity to the BMSCs. The inhomogeneous electrochemical environment resulted from localized corrosion could promote reactive oxygen species (ROS) generation around the corrosion pits and cause oxidative stress of BMSCs. In addition, localized corrosion could also electrochemically interact with the cells and lead to cell membrane depolarization. The depolarized cell membranes and relatively high levels of ROS mediated the degradation of the osteogenic capacity of BMSCs. This work provides new insights into corrosion-mediated cell function degeneration as well as the material-cell interactions.


Immune responses to SARS-CoV-2 infection and vaccination in children.
During the three years since SARS-CoV-2 infections were first described a wealth of information has been gathered about viral variants and their changing properties, the disease presentations they elicit and how the many vaccines developed in record time protect from COVID-19 severe disease in different populations. A general theme throughout the pandemic has been the observation that children and young people in general fare well, with mild symptoms during acute infection and full recovery thereafter. It has also become clear that this is not universally true, as some children develop severe COVID-19 hypoxic pneumonia and even succumb to the infection, while another group of children develop a rare but serious multisystem inflammatory syndrome (MIS-C) and some other children experience prolonged illness following acute infection, post-COVID. Here I will discuss some of the findings made to explain these diverse disease manifestations in children and young people infected by SARS-CoV-2. I will also discuss the vaccines developed at record speed and their efficacy in protecting children from disease.


Energy and macronutrient intake over the course of the day of German adults: A DEDIPAC-study.
The aim of the study was to analyze the energy and macronutrient intake over the course of the day of selected population groups in Germany defined by sex, age, BMI, SES, and diet quality. The study was based on food consumption data from the German National Nutrition Survey II (2005-2007) assessed by two 4-day dietary weighing records of 662 women and men aged between 18 and 80 years. Energy and macronutrient intake were calculated using the German Nutrient Database 3.02 and summarized for the periods 'morning', 'midday', 'afternoon', 'evening', and 'night'. Generalized estimating equation models were used to examine differences in energy and macronutrient intake. For women and men, a three-main-meal pattern ('morning', 'midday', and 'evening') was observed, indicated as peaks in energy intake at 08:00 to 09:00, 13:00 and 19:00 o'clock. The distributions of carbohydrate, protein, and fat intake mirror the distribution of energy intake over the course of the day. The highest energy intake was found in the 'evening' period, especially in young adults, overweight persons, persons with a high SES, and men with a low diet quality. Women of the oldest age group showed a similar energy intake across the three-main-meals in contrast to young adults, who had lower peaks in the 'morning' and 'midday' periods as well as a shift to later meal times. Young adults seem to have a higher variability in energy intake and a less distinct meal pattern, while seniors have a more structured day. Because a high energy intake in the 'evening' period is associated with negative health-related factors, the distribution of energy intake should be considered by recommendations for a healthy nutritional behavior.


Development of a Standardized Set of Patient-centered Outcomes for Advanced Prostate Cancer: An International Effort for a Unified Approach.
There are no universally monitored outcomes relevant to men with advanced prostate cancer, making it challenging to compare health outcomes between populations. We sought to develop a standard set of outcomes relevant to men with advanced prostate cancer to follow during routine clinical care. The International Consortium for Health Outcomes Measurement assembled a multidisciplinary working group to develop the set. We used a modified Delphi method to achieve consensus regarding the outcomes, measures, and case mix factors included. The 25 members of the multidisciplinary international working group represented academic and nonacademic centers, registries, and patients. Recognizing the heterogeneity of men with advanced prostate cancer, the group defined the scope as men with all stages of incurable prostate cancer (metastatic and biochemical recurrence ineligible for further curative therapy). We defined outcomes important to all men, such as overall survival, and measures specific to subgroups, such as time to metastasis. Measures gathered from clinical data include measures of disease control. We also identified patient-reported outcome measures (PROMs), such as degree of urinary, bowel, and erectile dysfunction, mood symptoms, and pain control. The international multidisciplinary group identified clinical data and PROMs that serve as a basis for international health outcome comparisons and quality-of-care assessments. The set will be revised annually. Our international group has recommended a standardized set of patient-centered outcomes to be followed during routine care for all men with advanced prostate cancer.


Alterations of RNA metabolism in sea urchin embryos by an inhibitor of protein synthesis initiation.
An inhibitor of the initiation of protein synthesis, 2-(4-methyl-2,6 dinitroanilino)-N-methyl propionamide, (MDMP), inhibits incorporation of amino acids by 85--95% without altering the rate of incorporation of uridine into sea-urchin-hatched blastula embryos. Since the inhibition is readily reversible up to at least 90 min after addition, extensive secondary effects are unlikely. Newly synthesized RNA accumulates in polyribosome-like structures in amount and with a size distribution very similar to the control. The polyadenylation of total, cytoplasmic and polyribosomal RNA are only slightly different from the controls. While the size distribution of 9-S of approx. 30-S RNA is about the same, there is relatively less low molecular weight RNA (approx. 4-S). There is also a greater accumulation of greater than 30-S RNA in the cytoplasm of treated embryos due either to leakage and/or improper processing of nuclear RNA. The latter possibility is consistent with the decrease in 4-S RNA which is a presumed degradation product of nuclear HnRNA. While the initial rate of RNA synthesis and much of the accumulation of RNA in polyribosomes are not affected, the inhibition of protein synthesis per se or a secondary effect of MDMP results in altered patterns of RNA transport and processing.


Otitis media.
Otitis media is a disease involving the inflammation and infection of the middle ear. Despite modern medical therapy, its widespread incidence in all age groups makes it one of the most common illnesses seen by physicians. The advent of a wide range of antibiotics has helped to decrease the number of complications resulting from the disease. Nevertheless, the large number of missed school and work days and the hearing losses and related problems that accompany otitis media make it a perpetual menace to public health.


A case of Miller Fisher syndrome: atypical findings and therapeutic considerations.
The Miller Fisher syndrome (MFS) is generally considered to be a disease of the peripheral nervous system. In some cases contemporary involvement of the central nervous system has been described (CNS). We report a case in which it was possible to prove involvement of cranial nerves VII, VIII, IX and X and to exclude CNS involvement. We discuss the possible role of early plasmapheresis treatment on disease evolution.