Which Dengue Vaccine Approach Is the Most Promising, and Should We Be Concerned about Enhanced Disease after Vaccination? The Path to a Dengue Vaccine: Learning from Human Natural Dengue Infection Studies and Vaccine Trials.
Dengue virus (DENV) is the most common arthropod-borne viral disease of humans. Although effective vaccines exist against other flaviviral diseases like yellow fever and Japanese encephalitis, dengue vaccine development is complicated by the presence of four virus serotypes and the possibility of partial immunity enhancing dengue disease severity. Several live attenuated dengue vaccines are being tested in human clinical trials. Initial results are mixed, with variable efficacy depending on DENV serotype and previous DENV exposure. Here, we highlight recent discoveries about the human antibody response to DENV and propose guidelines for advancing development of safe and effective dengue vaccines.


The social cognitive and neural mechanisms that underlie social functioning in individuals with schizophrenia - a review.
In many individuals with a diagnosis of schizophrenia social functioning is impaired across the lifespan. Social cognition has emerged as one of the possible factors that may contribute to these challenges. Neuroimaging research can give further insights into the underlying mechanisms of social (cognitive) difficulties. This review summarises the evidence on the associations between social cognition in the domains of theory of mind and emotion perception and processing, and individuals' social functioning and social skills, as well as associated neural mechanisms. Eighteen behavioural studies were conducted since the last major review and meta-analysis in the field (inclusion between 7/2017 and 1/2022). No major review has investigated the link between the neural mechanisms of social cognition and their association with social functioning in schizophrenia. Fourteen relevant studies were included (from 1/2000 to 1/2022). The findings of the behavioural studies showed that associations with social outcomes were slightly stronger for theory of mind than for emotion perception and processing. Moreover, performance in both social cognitive domains was more strongly associated with performance on social skill measures than questionnaire-based assessment of social functioning in the community. Studies on the underlying neural substrate of these associations presented mixed findings. In general, higher activation in various regions of the social brain was associated with better social functioning. The available evidence suggests some shared regions that might underlie the social cognition-social outcome link between different domains. However, due to the heterogeneity in approaches and findings, the current knowledge base will need to be expanded before firm conclusions can be drawn.


The influence of graded distension and carbachol on the motor response to cholecystokinin in isolated guinea-pig antrum and fundus.
Graded distension increased the motor response to cholecystokinin and acetylcholine both in antral and fundal pouches. The increase became even more obvious when the pressure responses were converted into changes in wall tension. The responses to cholecystokinin were additive with low doses (10(-7)M) of carbachol, but diminished or abolished by prestimulation with higher doses. The results indicate that the increased response to cholecystokinin after distension is due to increased smooth muscle stretch.


trans-Aminoboration across Internal Alkynes Catalyzed by B(C6F5)3 for the Synthesis of Borylated Indoles.
We report here a facile B(C6F5)3 catalyzed trans-aminoboration of internal alkynes, furnishing 3-position borylated indoles at ambient temperature. This reaction proceeds with the breaking of a B-N bond and the formation of N-C and B-C bonds to produce indole and derivatives in one step. It works well for various boron reagents and alkynyl-anilines. The borylated indoles can be further derivatized to give column stable organoboron compounds that can be used for future functionalization.


Cavity approach to the Sourlas code system.
The statistical physics properties of regular and irregular Sourlas codes are investigated in this paper by the cavity method. At finite temperatures, the free-energy density of these coding systems is derived and compared with the result obtained by the replica method. In the zero-temperature limit, the Shannon's bound is recovered in the case of infinite-body interactions while the code rate is still finite. However, the decoding performance as obtained by the replica theory has not considered the zero-temperature entropic effect. The cavity approach is able to consider the ground-state entropy. It leads to a set of evanescent cavity fields propagation equations which further improve the decoding performance as confirmed by our numerical simulations on single instances. For the irregular Sourlas code, we find that it takes the trade-off between good dynamical property and high performance of decoding. In agreement with the results found from the algorithmic point of view, the decoding exhibits a first-order phase transition as occurs in the regular code system with three-body interactions. The cavity approach for the Sourlas code system can be extended to consider first-step replica symmetry breaking.


Sex-related impelling cues uniquely predict event-level alcohol-related sexual behavior that poses heightened risk for negative consequences among college women.
The occurrence of sexual behavior that poses heightened risk for negative outcomes (e.g., condomless sex, sex with new or unfamiliar partners) often involves drinking alcohol for social and enhancement purposes, with female college students being particularly at-risk for resulting consequences. This study examined whether alcohol use, drinking motives, and sex-related impelling cues (i.e., cues that may impel one toward engaging in sexual activity) could predict sexual behaviors that pose heightened risk for negative consequences among female undergraduates. A total of 251 drinking episodes from 56 female college students (M age = 19.66) were obtained via surveys assessing alcohol use, drinking motives, sex-related impelling cues, and sexual behaviors at the event level. Relationships between variables were examined via main effect and factorial generalized estimating equations for social, enhancement, coping, and conformity drinking motives. In each main effects model, sex-related impelling cues were the only significant predictor. Significant three-way interactions were found in the social and enhancement factorial models, such that sexual behaviors that pose heightened risk for negative consequences occurred 58.81% and 55.81% of the time, respectively, under conditions of high drinks, motives, and sex-related impelling cues. This study provides a more nuanced understanding of the circumstances under which these sexual behaviors are most likely to occur, necessitating the consideration of sex-related impelling cues in addition to previously known predictors (i.e., alcohol use and drinking motives). This knowledge may assist in developing targeted interventions designed to reduce sexual behavior that poses heightened risk for negative consequences and ultimately improve the lives of college women. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Validation of Frail Scale and comparison with hospital frailty risk score to predict hospital use in a cohort of older Australian women.
With no standard frailty tool for clinical care, research and policymaking, identifying frail older people is a challenge. This study aimed to compare two validated scales, which are the Frail Scale and Hospital Frailty Risk Score (HFRS) for their ability in identifying frailty in older Australian women and predicting hospital use. This study included older Australian women aged 75-95 years, who had unplanned overnight hospital admission as an index admission between 2001 and 2016. Data from the Australian Longitudinal Study on Women's Health (ALSWH) were linked with administrative hospital data to calculate HFRS (using the International Statistical Classification of Diseases, Australia Modification (ICD-10-AM) diagnostic codes) and the Frail Scale (using the ALSWH self-reported survey). The Frail Scale identified a higher proportion of older frail women (30.54%) compared to the HFRS (23.0%). Frail older women, classified by Frail Scale, were at higher risk of long hospital stay (adjusted odds ratio = 1.28, 95% CI = 1.02-1.60), repeated admission (adjusted hazard ratio [AHR] = 1.30, 95% CI = 1.03-1.41) and death (AHR = 1.70, 95% CI = 1.45-2.01). HFRS was associated with longer hospital stay and mortality. The proportion of older women classified as frail by the Frail Scale tool was higher than women classified as frail by HFRS. The Frail Scale and HFRS were not significantly associated with each other. While both tools were associated with the risk of long hospital stay and mortality, only the Frail Scale predicted the risk of repeated admission.


Intrabiliary Ascariasis: A Case Report of an Uncommon Cause of Acute Abdomen and Obstructive Jaundice in Children.
Intrabiliary ascariasis is an uncommon cause of biliary colic and obstructive jaundice among children due to the small size of the ampullary orifice. A high index of suspicion for patients living in an endemic area and radiologic examination are crucial for diagnosis and treatment. A 12-year-old male Ethiopian child presented with colicky right upper quadrant pain, nausea, and vomiting for 3 days. Physical examination showed slightly icteric sclera and slightly tender hepatomegaly. Laboratory and ultrasound examinations were suggestive of obstructive jaundice secondary to intra-biliary ascariasis. The child was admitted and followed by conservative management including maintenance fluid, nil per mouth, and analgesics. The abdominal pain and icterus resolved on his second and third day of admission, respectively. A follow-up ultrasound showed that the worm had migrated from the common bile duct. The patient was dewormed with a single dose of oral albendazole 400mg and discharged home. Currently, the patient is well and attending school. Although biliary ascariasis is an uncommon cause of acute abdomen and obstructive jaundice, it should be suspected among patients from endemic areas presenting with suggestive clinical and laboratory features. Conservative treatment is the treatment of choice for uncomplicated biliary ascariasis patients.


Iron-deficiency anaemia enhances red blood cell oxidative stress.
Oxidative stress associated with iron deficiency anaemia in a murine model was studied feeding an iron-deficient diet. Anaemia was monitored by a decrease in hematocrit and haemoglobin. For the 9 week study an increase in total iron binding capacity was also demonstrated. Anaemia resulted in an increase in red blood cells (RBC) oxidative stress as indicated by increased levels of fluorescent heme degradation products (1.24-fold after 5 weeks; 2.1-fold after 9 weeks). The increase in oxidative stress was further confirmed by elevated levels of methemoglobin for mice fed an iron-deficient diet. Increased haemoglobin autoxidation and subsequent generation of ROS can account for the shorter RBC lifespan and other pathological changes associated with iron-deficiency anaemia.


[Expectations of obstetrics from the viewpoint of women].
Motherhood is predominantly perceived as a coping process with social, physical, and emotional adaptation. Pregnancy care as an interdisciplinary task is, therefore, of utmost importance in supporting women during this process. Generally, women have concrete ideas and wishes regarding an optimal service: information, dialogue, and different kinds of assistance during the preparation for birth and parenthood. The results of several longitudinal studies have shown that the real experiences of women during pregnancy is essential respects differ from the expectations. Psychological and psychotherapeutical interventions in pregnant women with problems and disturbances are discussed as well.


Bone formation around titanium implants in the rat tibia: role of insulin.
Clinical and experimental studies show, with few exceptions, that type 1 diabetes mellitus is associated with a delay in bone repair around endosseous implants. The effect of insulin in bone repair/remodeling is not completely understood. The aim of this study was to investigate the course of histological and ultrastructural changes of the osseointegration process under the influence of insulin. Titanium implants were inserted into the tibiae of male Wistar rats. Animals were divided into three groups: 1) rats with alloxan-induced diabetes; 2) diabetic rats treated with isophane insulin (2 IU/day); and 3) matching controls. Histological and histomorphometric analysis of bone-implant sections were performed 10 and 21 days after implant placement. Relative to control values, rats with alloxan-induced diabetes exhibited a 50% reduction in the area of formed bone (P < 0.001) and in the surface of contact between bone and implant (P < 0.01) 21 days after implant placement. There were no significant differences between groups 10 days after surgery. Values returned to normal levels in diabetic rats after insulin treatment. Presence of chondrocyte-like cells surrounded by a cartilaginouslike matrix in diabetic rats suggests a delay in the process of bone repair. Ultrastructural characteristics of bone-implant interface in diabetic rats treated with insulin resembled those observed in controls. The data presented suggest that bone repair around endosseous implants is regulated, at least in part, by insulin. The results imply that the control of the metabolic status of the diabetic patient is essential for a successful osseointegration.


A Growing Disconnection From Nature Is Evident in Cultural Products.
Human connection with nature is widely believed to be in decline even though empirical evidence is scarce on the magnitude and historical pattern of the change. Studying works of popular culture in English throughout the 20th century and later, we have documented a cultural shift away from nature that begins in the 1950s. Since then, references to nature have been decreasing steadily in fiction books, song lyrics, and film storylines, whereas references to the human-made environment have not. The observed temporal pattern is consistent with the explanatory role of increased virtual and indoors recreation options (e.g., television, video games) in the disconnect from nature, and it is inconsistent with a pure urbanization account. These findings are cause for concern, not only because they imply foregone physical and psychological benefits from engagement with nature, but also because cultural products are agents of socialization that can evoke curiosity, respect, and concern for the natural world.


The novel peptide DR4penA attenuates the bleomycin- and paraquat-induced pulmonary fibrosis by suppressing the TGF-β/Smad signaling pathway.
Pulmonary fibrosis (PF), which is caused by continuous alveolar epithelial cell injury and abnormal repair, is referred to as a difficult disease of the lung system by the World Health Organization due to its rapid progression, poor prognosis, and high mortality rate. However, there is still a lack of ideal therapeutic strategies. The peptide DR8 (DHNNPQIR-NH2 ), which is derived from rapeseed, exerted antifibrotic activity in the lung, liver, and kidney in our previous studies. By studying the structure-activity relationship and rational design, we introduced an unnatural hydrophobic amino acid (α-(4-pentenyl)-Ala) into DR8 and screened the novel peptide DR4penA (DHNα-(4-pentenyl)-APQIR-NH2 ), which had higher anti-PF activity, higher antioxidant activity and a longer half-life than DR8. Notably, DR4penA attenuated bleomycin- and paraquat-induced PF, and the anti-PF activity of DR4penA was equivalent to that of pirfenidone. Additionally, DR4penA suppressed the TGF-β/Smad pathway in TGF-β1-induced A549 cells and paraquat-induced rats. This study demonstrates that the novel peptide DR4penA is a potential candidate compound for PF therapy, and its antifibrotic activity in different preclinical models of PF provides a theoretical basis for further study.


A case of gastric cancer manifesting as a solitary brain metastasis in the cerebellopontine angle that mimicked acoustic neuroma.
At the time of diagnosis, about 20% of patients with gastric cancer have stage IV disease involving the liver, lung, and bone. Brain metastasis from gastric cancer is exceedingly rare, with an incidence of <1% of clinical cases. A 59-year-old man was admitted with hearing loss in the left ear and left facial palsy for 1 month. A magnetic resonance imaging scan revealed a tumor in the cerebellopontine angle that extended to the inner auditory canal and that was clinically diagnosed as acoustic neuroma. After complete resection, histological examination showed metastatic poorly differentiated carcinoma. Further investigation revealed advanced gastric cancer involving the antrum with no evidence of the involvement of other sites except the brain parenchyma. Palliative total gastrectomy was performed and the surgical specimen revealed a poorly cohesive carcinoma that was histopathologically identical to that of the resected brain tumor. Here we report this rare case of gastric cancer that initially presented as a solitary brain metastasis mimicking acoustic neuroma.


High throughput screening in duchenne muscular dystrophy: from drug discovery to functional genomics.
Centers for the screening of biologically active compounds and genomic libraries are becoming common in the academic setting and have enabled researchers devoted to developing strategies for the treatment of diseases or interested in studying a biological phenomenon to have unprecedented access to libraries that, until few years ago, were accessible only by pharmaceutical companies. As a result, new drugs and genetic targets have now been identified for the treatment of Duchenne muscular dystrophy (DMD), the most prominent of the neuromuscular disorders affecting children. Although the work is still at an early stage, the results obtained to date are encouraging and demonstrate the importance that these centers may have in advancing therapeutic strategies for DMD as well as other diseases. This review will provide a summary of the status and progress made toward the development of a cure for this disorder and implementing high-throughput screening (HTS) technologies as the main source of discovery. As more academic institutions are gaining access to HTS as a valuable discovery tool, the identification of new biologically active molecules is likely to grow larger. In addition, the presence in the academic setting of experts in different aspects of the disease will offer the opportunity to develop novel assays capable of identifying new targets to be pursued as potential therapeutic options. These assays will represent an excellent source to be used by pharmaceutical companies for the screening of larger libraries providing the opportunity to establish strong collaborations between the private and academic sectors and maximizing the chances of bringing into the clinic new drugs for the treatment of DMD.


Central nervous system effects of the second-generation antihistamines marketed in Japan--review of inter-drug differences using the proportional impairment ratio (PIR)-.
Second-generation antihistamines (AHs) have, in general, fewer sedative effects than the first-generation. However, important inter-drug differences remain in the degree of cognitive and/or psychomotor impairment. The extent to which a particular compound causes disruption can be conveniently compared, to all other AHs, using the Proportional Impairment Ratio (PIR). Although the PIR can differentiate the relative impairment caused by individual drugs, there is no indication of the reliability of the ratios obtained. To calculate the PIRs -together with 95% confidence intervals (CIs), as an index of reliability- and compare AHs currently, or soon to be, available in Japan, with respect to their intrinsic capacity to cause impairment. Results from studies of cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine, loratadine, mequitazine, and olopatadine were included in the PIR calculations. All data utilised came from crossover studies in healthy volunteers which were randomised and placebo and positive-internal controlled. Existing databases from studies reporting the sedative effects of AHs on objective (speed, accuracy, memory) and subjective (feeling) psychometrics were augmented, via results from suitable studies published after the previous reviews. The null value for a PIR was one. A total of 45 studies were finally included for this review. Of the AHs assessed, fexofenadine, ebastine, and levocetirizine showed a PIR for objective tests of 0. However, only fexofenadine (PIR = 0.49) had an upper limit of the 95% CI of less than 1. Fexofenadine, levocetirizine, desloratadine, olopatadine, loratadine, and mequitazine all had a PIR for subjective ratings of 0, but the upper limits of the 95% CIs were all in excess of 1, although fexofenadine (PIR = 2.57) was the lowest. The results show that there are differences between second-generation AHs in the extent of sedation produced. However, subjective ratings indicate that patients may not necessarily be aware of this.


Controlling corporate influence in health policy making? An assessment of the implementation of article 5.3 of the World Health Organization framework convention on tobacco control.
The World Health Organization (WHO) Framework Convention on Tobacco Control (FCTC) stands to significantly reduce tobacco-related mortality by accelerating the introduction of evidence-based tobacco control measures. However, the extent to which States Parties have implemented the Convention varies considerably. Article 5.3 of the FCTC, is intended to insulate policy-making from the tobacco industry's political influence, and aims to address barriers to strong implementation of the Convention associated with tobacco industry political activity. This paper quantitatively assesses implementation of Article 5.3's Guidelines for Implementation, evaluates the strength of Parties' efforts to implement specific recommendations, and explores how different approaches to implementation expose the policy process to continuing industry influence. We cross-referenced a broad range of documentary data (including FCTC Party reports and World Bank data on the governance of conflicts of interest in public administration) against Article 5.3 implementation guidelines (n = 24) for 155 Parties, and performed an in-depth thematic analysis to examine the strength of implementation for specific recommendations. Across all Parties, 16% of guideline recommendations reviewed have been implemented. Eighty-three percent of Parties that have taken some action under Article 5.3 have introduced less than a third of the guidelines. Most compliance with the guidelines is achieved through pre-existing policy instruments introduced independently of the FCTC, which rarely cover all relevant policy actors and fall short of the guideline recommendations. Measures introduced in response to the FCTC are typically restricted to health ministries and not explicit about third parties acting on behalf of the industry. Parties systematically overlook recommendations that facilitate industry monitoring. Highly selective and incomplete implementation of specific guideline recommendations facilitates extensive ongoing opportunities for industry policy influence. Stronger commitment to implementation is required to ensure consistently strong compliance with the FCTC internationally.


Looking down: a model for visual route following in flying insects.
Insect visual navigation is often assumed to depend on panoramic views of the horizon, and how these change as the animal moves. However, it is known that honey bees can visually navigate in flat, open meadows where visual information at the horizon is minimal, or would remain relatively constant across a wide range of positions. In this paper we hypothesise that these animals can navigate using view memories of the ground. We find that in natural scenes, low resolution views from an aerial perspective of ostensibly self-similar terrain (e.g. within a field of grass) provide surprisingly robust descriptors of precise spatial locations. We propose a new visual route following approach that makes use of transverse oscillations to centre a flight path along a sequence of learned views of the ground. We deploy this model on an autonomous quadcopter and demonstrate that it provides robust performance in the real world on journeys of up to 30 m. The success of our method is contingent on a robust view matching process which can evaluate the familiarity of a view with a degree of translational invariance. We show that a previously developed wavelet based bandpass orientated filter approach fits these requirements well, exhibiting double the catchment area of standard approaches. Using a realistic simulation package, we evaluate the robustness of our approach to variations in heading direction and aircraft height between inbound and outbound journeys. We also demonstrate that our approach can operate using a vision system with a biologically relevant visual acuity and viewing direction.


Angiography of the regenerating liver after lobar resection.
Angiography was performed in 18 patients before and after resection of parts of the liver. The regenerative process was a rule complete within few months and had a characteristic appearance with mainly stretching and displacement of arteries.


Effect of Three-wall Bony Defect along Various Root Surfaces on Position of Center of Resistance: A 3D Finite Element Analysis.
Increase in adult orthodontic patients has increased the challenges faced by orthodontists, as they often present themselves with a varying degree of dental and peri-odontal compromise, in which the entire orthodontic treatment planning will revolve around maintenance and augmentation of supporting apparatus. One of the many factors to be considered during treating an adult patient is the height of alveolar bone and its effect on center of resistance (CRes). Eight 3D analytical models of upper central incisor were designed using 'Solid Works Office Premium'. The models were subjected to 3 and 6 mm bone loss along all four surfaces, i.e. labial, lingual, mesial and distal. One Newton of retraction force was applied on labial surface of tooth on model number 1, 2, 5 and 6 and 1N of distalization force was applied to model number 3, 4, 7 and 8. The relative location of the CRes to the total root length was taken as 41.8% of total root length from the root apex. The ANSYS software was used to evaluate the change in CRes on all the models. It was observed that CRes shifted apically from its relative location (41.8% from apex); however, this shift was clinically insignificant. Minimum deflection of CRes, 0.0122 mm, was seen when a distalization force was applied on model with 6 mm bone loss on distal surface, while maximum deflection of 0.0245 mm was seen when retraction force was applied on model with 6 mm bone loss on labial surface. The resultant displacement in position of center of resistance is negligible; hence, there is no need of changing biomechanics during orthodontic treatment for a tooth with three wall infrabony defects. However, it is necessary to further study other infrabony defects like two wall or one wall defect, and their effect on position of CRes.


[Toxic effect of immunosuppression agent Everolimus on insuloma cells and pancreatic islets of SD rat].
To investigate the effect of immunosuppression agent Everolimus on the viability and function of insuloma cells (INS-1) and pancreatic islet cells cultured in vitro. INS-1 cells and islets were treated with a series of concentrations of immunosuppression agents (Everolimus, Cyclosporin A, Sirolimus and Mycophenolate Mofetil). The viability of INS-1 cells and rat pancreatic islets were determined with MTT and the function of INS-1 cells and rat pancreatic islets was evaluated with Glucose-stimulated insulin secretion assay. Above the clinical blood concentration, the inhibition rate of islet cell proliferation in the high concentration group of Everolimus and Sirolimus was significantly lower than that of Cyclosporin A and Mycophenolate Mofetil group (P < 0.05); Everolimus in the blood drug level, like other immunosuppressive agents, can inhibit the function of insulin secretion, and the stimulation index of each group was no significant difference. Compared to Mycophenolate Mofetil and Cyclosporin A, Everilimus and Sirolimus demonstrate lower toxicity effect on INS-1 cells and rat pancreatic islets in vitro and Everolimus is expected as a new type of immunosuppressive agent used in clinical islet transplantation.


MK-1 expression in gastric carcinoma with liver metastasis.
The prognosis for gastric carcinoma patients with liver metastasis is very poor. This retrospective study investigated the prognostic significance of MK-1 expression in gastric carcinoma patients with liver metastasis. Immunohistochemical staining using monoclonal antibody FU-MK-1 against MK-1 antigen was performed on paraffin-embedded tissues from 64 gastric carcinoma patients with liver metastasis. We attempted to determine the presence of any relationship between pathological prognostic factors and the expression of MK-1 in 64 gastric carcinoma patients with liver metastasis. MK-1 expression was found in 43 (67%) of 64 tumor samples. MK-1 expression was significantly higher in the intestinal type (73%) than in the diffuse type carcinoma (33%, P = 0.049). Multivariate analysis showed that MK-1 expression and lymph node metastasis were significant factors for overall survival. The difference between overall survival rates with positive or negative MK-1 expression was statistically significant as shown by Kaplan-Meier survival analysis (P < 0.0001; log-rank). In addition, the difference between cumulative disease-free survival rates with positive or negative MK-1 expression in gastric carcinoma patients with metachronous liver metastasis was statistically significant as well, as shown by Kaplan-Meier survival analysis (P = 0.0006; log-rank). The prognostic significance of MK-1 expression as a biological tumor marker was demonstrated in a series of gastric carcinoma patients with liver metastasis. MK-1 positivity may be a reliable marker for predicting and taking measures to control liver metastasis after curative gastrectomy for gastric carcinoma.


Indacyclopentadienes and Aromatic Indacyclopentadienyl Dianions: Synthesis and Characterization.
A series of unprecedented metallacycles of indium, including indacyclopentadienes (2), spiro indacyclopentadienes (3), aromatic indacyclopentadienyl dianions with an In-Li bond (4), and aromatic indacyclopentadienyl dianions with an In-In bond (5), were synthesized and structurally characterized by single-crystal X-ray structural analysis for the first time. Both indacyclopentadienes 2 and 3 were synthesized by reaction of 1,4-dilithio-1,3-butadienes with InCl3 . Structural transformations between 2 and 3 were observed. Reduction of indacyclopentadienes 2 with an excess amount of lithium afforded aromatic indacyclopentadienyl dianions 4 with an In-Li bond or 5 with an In-In bond, respectively, depending on the substituents on the ring. The aromatic character of 4 and 5 was confirmed by both experimental measurements and theoretical analysis.


Clinicopathological Characteristics of Lung Adenocarcinoma with Unexpected Lymph Node Metastasis.
The objective is to demonstrate the clinicopathological characteristics of patients with unexpected node-positive lung adenocarcinoma and to analyze predictive factors of unexpected disease. We reviewed 225 patients with lung adenocarcinoma who underwent curative-intent operation between January 2008 and December 2014. Unexpected node-positive diseases were defined as cases with hilar or mediastinal lymph nodes metastasis in spite of both negative significant enlargement of lymph nodes on preoperative chest computed tomography (CT) and negative fluorodeoxyglucose (FDG) uptake in lymph nodes on preoperative positron emission tomography (PET)/CT. We retrospectively analyzed clinical features of these patients and evaluated associated factors for unexpected diseases. There were 41 patients (18%) with unexpected node-positive disease, consisting of 16 (39%) unexpected pN1 and 25 (61%) unexpected pN2 diseases. The most common predominant subtype was papillary (22 patients; 54%), and 17 patients (41%) had micropapillary component in the tumors. Younger age (p <0.01), left side (p <0.01), larger tumor size (p <0.01), and having a micropapillary component (p <0.01) were significant associated factors of unexpected diseases in multivariate analysis. Histological findings of the primary tumor are often important because they can provide predictive information for lymph nodes status. Having a micropapillary component was one of the significant predictors of unexpected node-positive diseases.


Suture technique for implanting the superior notched loop of a posterior chamber intraocular lens.
A suture technique for compressing the superior notched loop of a posterior chamber intraocular lens is presented, which will provide controllability, less trauma, and no zonular pressure.


Risk mapping of clonorchiasis in the People's Republic of China: A systematic review and Bayesian geostatistical analysis.
Clonorchiasis, one of the most important food-borne trematodiases, affects more than 12 million people in the People's Republic of China (P.R. China). Spatially explicit risk estimates of Clonorchis sinensis infection are needed in order to target control interventions. Georeferenced survey data pertaining to infection prevalence of C. sinensis in P.R. China from 2000 onwards were obtained via a systematic review in PubMed, ISI Web of Science, Chinese National Knowledge Internet, and Wanfang Data from January 1, 2000 until January 10, 2016, with no restriction of language or study design. Additional disease data were provided by the National Institute of Parasitic Diseases, Chinese Center for Diseases Control and Prevention in Shanghai. Environmental and socioeconomic proxies were extracted from remote-sensing and other data sources. Bayesian variable selection was carried out to identify the most important predictors of C. sinensis risk. Geostatistical models were applied to quantify the association between infection risk and the predictors of the disease, and to predict the risk of infection across P.R. China at high spatial resolution (over a grid with grid cell size of 5×5 km). We obtained clonorchiasis survey data at 633 unique locations in P.R. China. We observed that the risk of C. sinensis infection increased over time, particularly from 2005 onwards. We estimate that around 14.8 million (95% Bayesian credible interval 13.8-15.8 million) people in P.R. China were infected with C. sinensis in 2010. Highly endemic areas (≥ 20%) were concentrated in southern and northeastern parts of the country. The provinces with the highest risk of infection and the largest number of infected people were Guangdong, Guangxi, and Heilongjiang. Our results provide spatially relevant information for guiding clonorchiasis control interventions in P.R. China. The trend toward higher risk of C. sinensis infection in the recent past urges the Chinese government to pay more attention to the public health importance of clonorchiasis and to target interventions to high-risk areas.


Immunological aspects of scorpion toxins: current status and perspectives.
Significant progress has been made in immunological studies of scorpion toxins and several formats of antibodies directed against scorpion toxins have been reported. Some of these are commonly used in a specific treatment against envenoming; others are primarily used for immuno-biochemical characterizations. The preparation protocol of the antibody or its fragments can be substantially different from one laboratory to another, which complicates a direct comparison of the potency of the antivenom. The use of immune sera, the total immunoglobulin fraction or Fab and Fab'2 fragments as the therapeutic agent is widespread. A number of monoclonal antibodies have also been reported and used for engineering of Fv, ScFv or Fab fragments. Recently, a novel antibody format - known as nanobodies - derived from HCAbs of camelids and selected after phage display shows great potential to provide a more efficient therapy against scorpion envenoming. Subsequent bispecific derivatives have been designed and their pharmacokinetics have been studied. Distinct advantages and disadvantages have been attributed to these equine, murine or camelid antibodies and their derived fragments. Some fragments are easily amenable into next generation therapeutics after proper manufacturing and provide an ensured availability of the product to the medical community. Through examples, we will show how the comparison of the serotherapeutic effectiveness is compromised due to the absence of standardization, on the preparation of immunogens, production processes and / or nature of the products. We will report on recent advances in the field.


Lipid interactions with human alpha-fetoprotein (AFP). A study of the role of such interactions in the ability of human AFP to suppress lymphocyte transformation.
The ability of human alpha-fetoprotein (HAFP) isolates to inhibit human lymphocyte transformation varies over 2-3 orders of magnitude. Since HAFP is known to bind fatty acids, we have examined the possible role of lipid binding in producing this variability. While certain oxygenated sterols are potent inhibitors of lymphocyte transformation, and while the kinetics of such inhibition precisely mimic those of HAFP, HAFP is, by contrast, a weak inhibitor of sterol synthesis in mitogen-stimulated human lymphocytes. Fatty acids (18:0, 18:1, 18:2, 18:3, 20:4, 22:6) and 10(-4) M have little or no effect upon lymphocyte transformation. The fatty acid content of seen HAFP isolates ranged from 2.3 to 8.0 mol fatty acid/mol HAFP and included 12:0, 14:0, 16:0 (the most abundant), 18:0, 20:4, and 22:0; no 22:6 was found. There was no correlation between the total or individual fatty acid contents of HAFPs and their ability to inhibit lymphocyte transformation. Lysooleoyl-, lysostearoyl-, and lysopalmitoyl-lecithin at 5 X 10(-5) M all inhibited lymphocyte transformation (30.1%, 52.1%, and 58.1%, respectively) and the latter was active at 6.3 X 10(-6) M. Exposure of HAFP to a 5-fold molar excess of [14C]-lysopalmitoyl lecithin resulted in significant (10%) binding to HAFP, while no significant binding of dipalmitoyl lecithin occurred under similar conditions. Analysis of lipid extracts of potent HAFP isolates by thin-layer chromatography failed to reveal the presence of phospholipids. Although HAFP can bind certain lipids, and although certain lipids inhibit lymphocyte transformation, we conclude that HAFP suppression of lymphocyte transformation cannot be attributed to the binding of hydrocortisone, prostaglandins, fatty acids, lysolecithins, or oxygenated sterol compounds.


A prospective comparative study of clinical and histological characteristics in Icelandic and Danish patients with gastric ulcer, duodenal ulcer, and X-ray negative dyspepsia. I. Design and clinical features.
Iceland (IS) and Denmark (DK) are ethnically, culturally, and economically closely related Nordic countries, but gastric cancer is much more frequent in Iceland, and other differences in the occurrence rates of gastric diseases are also suspected. Therefore a cooperative study was initiated comparing Icelandic and Danish patients with gastric ulcer (GU), duodenal ulcer (DU), and X-ray negative dyspepsia (XND) as regards clinical features, external factors of possible importance for gastritis and cancer, gastroscopic appearance, and histological gastric mucosal changes. The project lasted one year and comprised 93 Icelandic and 88 Danish patients. A large number of comparisons showed a high degree of similarity between Icelandic and Danish patients. Significant differences were found in tobacco consumption (DK greater than IS), duration of symptoms in XND (IS greater than DK), whereas the positon ratio of GU (IS less than DK) and acetylsalicylic acid consumption (DK greater than IS) showed non-significant trends. Significant difference was found between the occurrence of diffuse macroscopic changes of the gastric mucosa (IS greater than DK), which corresponds to the histological differences to be described in a subsequent article.


Changes in interfacial potentials induced by carbonylcyanide phenylhydrazone uncouplers: possible role in inhibition of mitochondrial oxygen consumption and other transport processes.
The charged and uncharged forms of carbonylcyanide phenylhydrazone uncouplers bind to phosphatidylcholine monolayers in a dose-dependent fashion, inducing changes in the interfacial potential of these model membranes. The interfacial potential change produced by the charged uncoupler is composed of a double-layer potential and an internal electrostatic potential (boundary and/or dipole). Changes in double-layer potential induced by the uncouplers in mitochondrial membranes can explain both the inhibition of oxygen consumption (QO2) caused by the uncouplers and the competition shown by succinate when mitochondria are respiring in the presence of rotenone. From these results and from dose-response curves of QO2 versus uncoupler concentrations, we conclude that 1 microM is an upper limit for free uncoupler concentration in the medium to avoid unwanted side effects during cell physiology studies that require total mitochondrial uncoupling.


Peptide synthesis catalyzed by papain at alkaline pH values.
The synthesis of peptides in the presence of papain at pH 8-9.5 is described. Starting substances are acylamino acid alkyl esters (the carboxyl component) and amides or tert.-butylesters of amino acids, as well as peptide (the amino component). Under such conditions secondary hydrolysis is not essential, making the synthesis of peptides soluble in aqueous medium. The yield of peptides is 50-94%. The effect of different factors (temperature, solvents, reagent concentrations) on the result of the reaction has been studied. It has been found that an excess of the carboxyl component is expedient to increase the yield of peptides.


CHANGES IN MYOPIC MACULOPATHY BASED ON ATN CLASSIFICATION SYSTEM: An Optical Coherence Tomography Angiography Study.
To assess changes in myopic maculopathy based on the ATN classification system with optical coherence tomography angiography. This was a cross-sectional study. The macular choroidal thickness (MCT) and the choriocapillaris flow (CC) were measured with optical coherence tomography angiography. The relationship of MCT and CC with different chorioretinal atrophy (A), myopic foveoschisis (T), and myopic neovascularization (N) grades was investigated. One hundred and fifty-three participates (219 eyes) were included. MCT and CC had no significant correlation with different T grades (P > 0.05). Choriocapillaris flow had a significant decrease in eyes with lacquer cracks compared with those with no neovascular maculopathy (P < 0.05) and showed a significant increase in active choroidal neovascularization compared with those with lacquer cracks (P < 0.05). Macular choroidal thickness and CC had negative correlations with different A grades (P < 0.001). MCT showed the greatest decrease in the early stage of myopic atrophic maculopathy (P < 0.001), and CC showed the most significant reduction in the late stage (P < 0.001). Choroidal changes in the highly myopic patients were detected by optical coherence tomography angiography. Progressive ischemia in the macula may play an important role in the development of myopic atrophic maculopathy. Active choroidal neovascularization may have manifested as compensation for the decrease in MCT and CC. On the contrary, myopic traction maculopathy had little correlation with choroidal changes.


Desferrioxamine attenuates minor lung injury following surgical acute liver failure.
Acute liver failure (ALF) can be complicated by lung dysfunction. The aim of this study was to test the hypothesis that inhibition of oxidative stress through iron chelation with desferrioxamine (DFX) attenuates pulmonary injury caused by ALF. 14 adult female domestic pigs were subjected to surgical devascularisation of the liver and were randomised to a study group (DFX group, n = 7), which received post-operative intravenous infusion of DFX (14.5 mg x kg(-1) x h(-1) for the first 6 h post-operatively and 2.4 mg x kg(-1) x h(-1) until completion of 24 h), and a control group (n = 7). Post-operative lung damage was evaluated by histological and bronchoalveolar lavage fluid (BALF) analysis. DFX resulted in reduced BALF protein levels and tissue phospholipase (PL)A(2) activity. Plasma malondialdehyde and BALF nitrate and nitrite concentrations were lower, while catalase activity in the lung was higher after DFX treatment. PLA(2), platelet-activating factor acetylhydrolase and total cell counts in BALF did not differ between groups. Histological examination revealed reduced alveolar collapse, pneumonocyte necrosis and total lung injury in the DFX-treated animals. DFX reduced systemic and pulmonary oxidative stress during ALF. The limited activity of PLA(2) and the attenuation of pneumonocyte necrosis could represent beneficial mechanisms by which DFX improves alveolar-capillary membrane permeability and prevents alveolar space collapse.


Primary total hip arthroplasty with an uncemented femoral component: two- to seven-year results.
This prospective study reports the midterm outcome of total hip arthroplasty performed in a consecutive series of patients using a tapered uncemented femoral component. The cohort consists of 631 patients (700 hips). The clinical records and the routine serial radiographs of these patients were monitored closely over a 5-year period. Follow-up averaged 4.35 years. There was a significant improvement in functional outcome of these patients as measured by Harris hip score and short-form 36.There were 4 revisions for aseptic loosening of the femoral component in this series, accounting for an overall survivorship of 99.4%. The study confirms that the midterm outcome of this stem is excellent, with a low revision rate.


A heteroleptic ferrous complex with mesoionic bis(1,2,3-triazol-5-ylidene) ligands: taming the MLCT excited state of iron(II).
Strongly σ-donating N-heterocyclic carbenes (NHCs) have revived research interest in the catalytic chemistry of iron, and are now also starting to bring the photochemistry and photophysics of this abundant element into a new era. In this work, a heteroleptic Fe(II) complex (1) was synthesized based on sequentially furnishing the Fe(II) center with the benchmark 2,2'-bipyridine (bpy) ligand and the more strongly σ-donating mesoionic ligand, 4,4'-bis(1,2,3-triazol-5-ylidene) (btz). Complex 1 was comprehensively characterized by electrochemistry, static and ultrafast spectroscopy, and quantum chemical calculations and compared to [Fe(bpy)3](PF6)2 and (TBA)2[Fe(bpy)(CN)4]. Heteroleptic complex 1 extends the absorption spectrum towards longer wavelengths compared to a previously synthesized homoleptic Fe(II) NHC complex. The combination of the mesoionic nature of btz and the heteroleptic structure effectively destabilizes the metal-centered (MC) states relative to the triplet metal-to-ligand charge transfer ((3)MLCT) state in 1, rendering it a lifetime of 13 ps, the longest to date of a photochemically stable Fe(II) complex. Deactivation of the (3)MLCT state is proposed to proceed via the (3)MC state that strongly couples with the singlet ground state.


[A case of segmental colitis associated with diverticular disease].
Segmental colitis associated with diverticular disease (SCAD) is a colonic inflammatory disorder with localized non-granulomatous inflammation at sigmoid colon, and associated with colonic diverticulosis. SCAD is an apparently uncommon disorder in Western. We experienced a rare case of SCAD in a 46-year-old woman who visited the hospital due to abdominal discomfort. Colonoscopic examination showed multiple sigmoid diverticula in association with a segment length colitis. Colonoscopic biopsies of the sigmoid colon demonstrated cryptitis and crypt abscess along with chronic inflammatory cells infiltration. The biopsies of the rectum was histologically normal. The patient was given the diagnosis of SCAD and treated with oral mesalamine. This is the first case of SCAD reported in Korea.


Role of Text Message Reminder on Oral Hygiene Maintenance of Orthodontic Patients.
Fixed orthodontic treatment is frequently associated with increased plaque accumulation leading to gingivitis and white spot lesions (WSLs). This study evaluated the role of text message reminder on oral hygiene of orthodontic patients. A total of 60 patients under fixed orthodontic treatment were randomly divided into two equal groups as control group and study (text message) group. Text message group received reminders about oral hygiene, while the control group did not receive any messages. Oral hygiene of both the groups was evaluated at baseline, 2, and 3 months using plaque indices (PIs) along with WSL status. Data were statistically analyzed using Statistical Package for the Social Sciences (SPSS) statistical software, version 19, with chi-square test and t-test. At the baseline, plaque score was higher in the study group over control group (p > 0.038), whereas it was decreased after 3 months in the test group (p > 0.001). For WSL, there was no significant difference at baseline, but it was significantly lower in study group (p > 0.003). Oral hygiene status improved with text message reminder.


Generative Mechanisms in Early Childhood Interventions: A Confirmatory Research Framework for Prevention.
This article reviews methodological and analytic approaches and impact evidence for understanding the mechanisms of effects of early childhood interventions, including delinquency and violence prevention. Illustrations from longitudinal studies of preschool preventive interventions are provided. We restrict our attention to preventive interventions for children from birth to age 5, including evidence from the Chicago Longitudinal Study (CLS), which investigates the impact of an established school-based early childhood intervention. Frameworks and evidence will be organized according to the Five-Hypothesis Model (5HM), which postulates that a variety of early childhood interventions impact later well-being through the promotion of cognitive and scholastic advantages, motivational advantages, social adjustment, family support behaviors, and school supports. Recommendations are made for advancing confirmatory approaches for identifying the most effective prevention programs using identification of generative mechanisms as a major methodological criterion.


Main Reasons for Registration Application Refusal of Generic and Similar Pharmaceutical Drug Products by the Brazilian Health Regulatory Agency (ANVISA).
Objective. The marketing authorization of generic and similar pharmaceutical drug products involves the analysis of proposing company's administrative aspects as well as drug product technical description and scientific evaluations. This study evaluated the main reasons for registration refusal of generic and similar pharmaceutical drug products in Brazil. The aim is to help future applicants to better organize the proposal. Methods. A retrospective search of drug products registration processes was performed on the Brazilian Government Official Gazette from January 1, 2015, and December 31, 2015. Results. Drug product quality control, drug product stability study, deadline accomplishment, API quality control made by drug manufacturer, active pharmaceutical ingredient (API), and production report were the main reasons for marketing authorization application refusal of generic and similar pharmaceutical drug products in 2015. Conclusion. Disclosure of the reasons behind failed applications is a step forward on regulatory transparency. Sharing of experiences is essential to international regulatory authorities and organizations to improve legislation requirements for the marketing authorization of generic and similar pharmaceutical drug products.


Efficacy of Palonosetron vs. Ramosetron for the Prevention of Postoperative Nausea and Vomiting: A Meta-Analysis of Randomized Controlled Trials.
This study was designed as a meta-analysis of randomized controlled trials (RCTs) that included the comparison of palonosetron and ramosetron for postoperative nausea and vomiting (PONV) prophylaxis. A systematic search was conducted for the PubMed, EMBASE, Web of Science, CENTRAL, KoreaMed, and Google Scholar databases (PROSPERO protocol number CRD42015026009). Primary outcomes were the incidences of postoperative nausea (PON) and postoperative vomiting (POV) during the first 48 hrs after surgery. The total 48-hr period was further analyzed in time epochs of 0-6 hrs (early), 6-24 hrs (late), and 24-48 hrs (delayed). Subgroup analyses according to number of risk factors, sex, and type of surgery were also performed. Eleven studies including 1373 patients were analyzed. There was no difference in PON or POV between the two drugs for the total 48-hr period after surgery. However, palonosetron was more effective in preventing POV during the delayed period overall [relative risk (RR), 0.59; 95% confidence interval (CI), 0.39 to 0.89; p=0.013], as well as after subgroup analyses for females and laparoscopies (RR, 0.56; 95% CI, 0.36 to 0.86; p=0.009 and RR, 0.46; 95% CI, 0.23 to 0.94; p=0.033). Subgroup analysis for spine surgery showed that ramosetron was more effective in reducing POV during the total 48-hr (RR, 3.34; 95% CI, 1.46 to 7.63; p=0.004) and early periods (RR, 8.47; 95% CI, 1.57 to 45.72; p=0.013). This meta-analysis discovered no definite difference in PONV prevention between the two drugs. The significant findings that were seen in different time epochs and subgroup analyses should be confirmed in future RCTs.


Gender differences in physical aggression: A prospective population-based survey of children before and after 2 years of age.
There has been much controversy over the past decades on the origins of gender differences in children's aggressive behavior. A widely held view is that gender differences emerge sometime after 2 years of age and increase in magnitude thereafter because of gender-differentiated socialization practices. The objective of this study was to test for (a) gender differences in the prevalence of physical aggression in the general population of 17-month-old children and (b) change in the magnitude of these differences between 17 and 29 months of age. Contrary to the differential socialization hypothesis, the results showed substantial gender differences in the prevalence of physical aggression at 17 months of age, with 5% of boys but only 1% of girls manifesting physically aggressive behaviors on a frequent basis. The results suggest that there is no change in the magnitude of these differences between 17 and 29 months of age.


Management of common bile duct stones: selective endoscopic retrograde cholangiography and endoscopic sphincterotomy: short- and long-term results.
Common bile duct stones are still a frequent problem. Although new diagnostic and therapeutic techniques are continually being development, they remain poorly defined. Therefore, we decided to evaluate our standard method of diagnosing and treating common bile duct stones. The aim of the study was to determine the short- and long-term results of this method. Between 1985 and 1995, 552 consecutive patients (200 men and 352 women; median age, 69 years) underwent endoscopic retrograde cholangiography (ERC) because of suspected common bile duct stones. If stones were detected, they were treated endoscopically, if possible. The results and complications of this policy were recorded. Patients were followed 1-13 years after undergoing ERC and endoscopic sphincterotomy (ES). Long-term results and complications during this period were also recorded. ERC was attempted in 552 patients and succeeded in 510 patients (92%): ES was attempted in 315 patients and failed in five (98%). Duct clearance was done in 271 patients; in 26 of these patients, symptoms disappeared spontaneously. Ten patients underwent common bile duct exploration. Complications occurred in 46 patients (8.3%). Mortality was 0.4%, hemorrhage occurred in 3.6%, pancreatitis in 1.4%, sepsis and cholangitis also in 1.4%, and the lithotripter basket became impacted in four patients (0.8%), necessitating to common bile duct exploration. During follow-up, 45 patients (8%) returned, 35 with recurrent stones, five with cholangitis, two with stenosis of the papilla of Vater, and one with biliary pancreatitis. In 35 cases, complications were treated endoscopically, common bile duct exploration was performed in five cases, and symptoms disappeared spontaneously in five cases. ERC is a safe and reliable way of diagnosing common bile duct stones, and ES is a very efficient way of treating them. Morbidity and mortality are low, and the long-term results are very good.


In vitro amplification of H-type atypical bovine spongiform encephalopathy by protein misfolding cyclic amplification.
The in vitro amplification of prions by serial protein misfolding cyclic amplification has been shown to detect PrPSc to levels at least as sensitive as rodent bioassay but in a fraction of the time. Bovine spongiform encephalopathy is a zoonotic prion disease in cattle and has been shown to occur in 3 distinct forms, classical BSE (C-BSE) and 2 atypical BSE forms (L-BSE and H-BSE). Atypical forms are usually detected in asymptomatic, older cattle and are suggested to be spontaneous forms of the disease. Here, we show the development of a serial protein misfolding cyclic amplification method for the detection of H-BSE. The assay could detect PrPSc from 3 distinct experimental isolates of H-BSE, could detect PrPSc in as little as 1×10-12 g of brain material and was highly specific. Additionally, the product of serial protein misfolding cyclic amplification at all dilutions of seed analyzed could be readily distinguished from L-BSE, which did not amplify, and C-BSE, which had PrPSc with distinct protease K-resistance and protease K-resistant PrPSc molecular weights.


Silver Diamine Fluoride in Children Using Physiologically Based PK Modeling.
Silver diamine fluoride (SDF) is used topically to prevent or arrest dental caries and has been tested clinically in toddlers to elderly adults. Following SDF application, small quantities of silver can be swallowed and absorbed. To monitor silver concentrations, pharmacokinetic studies can be performed. However, pharmacokinetic studies are time-consuming, resource intensive, and challenging to perform in young children. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict silver disposition in children. The PBPK model for silver was developed using Simcyp software (version 17.0) based on information obtained from literature sources. The predictive performance of the model was assessed by comparing the predicted PK profiles and parameters with the observed data from published rat and human data following intravenous or oral silver administration. The predicted silver concentrations were within 2-fold of observed blood and tissue silver concentrations in rats and within the 95% confidence interval of observed plasma silver concentrations in healthy human adults. The PBPK model was applied to the pediatric population by accounting for developmental physiological changes. For a given SDF dose, the simulated peak silver concentrations were 5.2-, 4.3-, 2.7-, and 1.3-fold higher in children aged 1 to 2, 2 to 4, 5 to 10, and 12 to 17 y, respectively, compared to adults. As silver is reportedly excreted in the bile, the half-life of silver was comparable in all ages and plasma and tissue silver concentrations were predicted to return to baseline levels within 2 wk after SDF application. The simulation in children suggests that conventional SDF application to teeth to prevent or arrest dental caries results in plasma and tissue silver concentrations lower than toxic concentrations. PBPK modeling offers a novel approach to studying dental exposures in younger children, where pharmacokinetic studies would be difficult to conduct.


Surface Alloying in Silver-Cobalt through a Second Wave Solution Combustion Synthesis Technique.
Herein, we report the synthesis of silver-cobalt nanopowders using three different modes of solution combustion synthesis, and we present the effects of the synthesis conditions on particle morphology. The synthesized nanoparticles were characterized using X-ray diffraction (XRD), Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), UV-Visible spectrophotometer (UV-vis), Transmission electron microscopy (TEM), and X-Ray Photoelectron Spectroscopy (XPS) to understand the structural and elemental properties. When Co is synthesized over Ag in a second wave of combustion, peak shifts observed in XRD and XPS show a change in the cell parameters and prove the existence of a strong electronic interaction between Ag and Co. Better control of mixing and alloying through the second wave combustion synthesis mode (SWCS) was evident. The sequence of combustion affects the structure and composition of the material. SWCS reduces the amount of carbon content, as compared to single-stage combustion, and the combustion of carbon is followed by a rearrangement of atoms.


Death dwells in spaces: Bodies in the hospital mortuary.
This paper explores the idea of death spaces, in particular the ways that diverse, at times disruptive, meanings about the dead are inscribed in mortuary spaces. The author draws upon data from an ethnographic study based in a hospital's Department of Anatomical Pathology to introduce the concept of three co-constructed spaces: that of sentiment, science and spirit. The author explores the daily interactions between the living and the materially dead through description of perceptions and practices that form the discursive space of the mortuary.


Outcome of surgical treatment for recurrent thymic epithelial tumors with reference to world health organization histologic classification system.
The aim of this study was to clarify the significance of surgical treatment for recurrent thymic epithelial tumors with reference to the World Health Organization (WHO) histological classification system. Among 67 patients with tumor recurrence, 22 underwent a re-resection. There were 1 patient with a type AB tumor, 5 with type B1 tumors, 10 with type B2 tumors, 5 with type B3 tumors, and 1 with a carcinoma. The 10-year survival rate following the initial resection was 70% in patients who underwent a re-resection and 35% in those who did not. The average intervals from the initial resection to re-resection were 10.3, 7.8, 6.0, 2.4, and 2.6 years for patients with type AB, B1, B2, B3 tumors, and carcinoma, respectively. The patient with a type AB tumor was alive at 2.4 years after re-resection, 12.7 years after the initial resection. The 5-year survival rates following re-resection in the patients with type B1, B2, and B3 tumors were 100, 56, and 60, respectively. The patient with a carcinoma died as a result of the tumor 2 years after re-resection. WHO histological classification indicates the outcome of surgical treatment for recurrent thymic epithelial tumors.


Experimental enhancement of corticosterone levels positively affects subsequent male survival.
Corticosterone is an important hormone of the stress response that regulates physiological processes and modifies animal behavior. While it positively acts on locomotor activity, it may negatively affect reproduction and social activity. This suggests that corticosterone may promote behaviors that increase survival at the cost of reproduction. In this study, we experimentally investigate the link between corticosterone levels and survival in adult common lizards (Lacerta vivipara) by comparing corticosterone-treated with placebo-treated lizards. We experimentally show that corticosterone enhances energy expenditure, daily activity, food intake, and it modifies the behavioral time budget. Enhanced appetite of corticosterone-treated individuals compensated for increased energy expenditure and corticosterone-treated males showed increased survival. This suggests that corticosterone may promote behaviors that reduce stress and it shows that corticosterone per se does not reduce but directly or indirectly increases longer-term survival. This suggests that the production of corticosterone as a response to a stressor may be an adaptive mechanism that even controls survival.


Feasibility of intraoperative water testing in aortic valve repair: Direct visualization from left ventricle with a videoscope.
We describe a simple method to assess the aortic valve using a videoscope inserted in the left ventricle (LV-VS) during valve-sparing root replacement. The aim of this study was to evaluate the feasibility of this technique by comparing it with the findings of postoperative transesophageal echocardiography (TEE). Thirty-six patients (29 male, mean age 45.4 ± 20.1 years) undergoing aortic root reimplantation were assessed intraoperatively with LV-VS. The LV-VS was inserted from the right upper pulmonary vein into the left ventricle and set toward the aortic valve. After completion of graft implantation, inspection was performed with LV-VS by pressurizing the neo-sinus before attachment of coronary arteries. Valve competency evaluated by LV-VS was compared with postoperative TEE findings, according to the group of cusp morphologies. Group 1 included 26 patients with tricuspid aortic valve, and group 2 included 9 patients with bicuspid aortic valve and 1 quadricuspid aortic valve. The grade of aortic regurgitation (AR) improved from 2.9 ± 1.6 preoperatively to 0.33 ± 0.6 postoperatively (P < .001 vs preoperatively). In 4 patients, LV-VS was used only before repair. In group 1, intraoperative LV-VS showed a competent valve in 20 and an incompetent valve in 3 patients, and postoperative TEE showed non/trivial AR in 15, mild AR in 5, and mild-to-moderate AR in 3 patients. In group 2, 9 patients achieved a competent valve on intraoperative LV-VS and non/trivial AR on postoperative TEE. Intraoperative direct inspection with LV-VS is a feasible method for confirming the completion of cusp repair.


Regulation of the interferon-inducible PKR kinase gene: the KCS element is a constitutive promoter element that functions in concert with the interferon-stimulated response element.
The RNA-dependent protein kinase PKR plays important roles in the antiviral and antiproliferative actions of IFN. The IFN-inducible promoter of the human PKR gene contains a 15-bp DNA element designated KCS. The KCS element is located 4 bp upstream of the interferon-stimulated response element (ISRE) and is required for both basal and IFN-inducible transcription. We have examined the effect of insertion mutations between the KCS and the ISRE elements, as well as altered orientation of the KCS element relative to the ISRE element, to assess a possible functional interaction between them. Large insertions (>or=93 bp) between the KCS and ISRE elements significantly reduced both basal and IFN-inducible promoter activity. The function of the KCS element was dependent on the orientation of KCS relative to the ISRE element. Multimerization of the KCS element increased both basal and IFN-inducible transcription. Electrophoretic mobility shift analyses (EMSA) identified IFN-inducible protein complex formation that required both the KCS and the ISRE DNA element sequences. The novel IFN-inducible protein complexes contained the transcription factor STAT1, as shown by supershift analyses and by their presence in extracts prepared from STAT1 wild-type but not from STAT1-/- null cells. These results, taken together, strongly suggest that the KCS and ISRE elements of the human PKR promoter represent a functional unit.


[Quinidine-induced rheumatic toxicity].
2 women with quinidine-induced lupus are presented. This condition is rare; only about 30 cases have been reported in the English literature. Both our patients had arthritis of the wrist, antinuclear antibodies with homogenous pattern and elevated ESR. Anti-double stranded DNA antibodies were present in 1 patient, and a petechial rash in the other. Complete resolution of arthritis occurred within a few days after quinidine withdrawal, but antinuclear antibodies persisted for several months.


Risk of contamination of the wound in a hydrotherapeutic tank.
Over a 4-week period, samples for culture were taken from active hydrotherapeutic tanks (whirlpools) from two institutions in a university medical center. Samples were obtained in the morning before treatments began, and in the evening after, the final patient had been treated. Specific attention was directed toward recovery of S. aureus, P. aeruginosa, and E. coli, organisms felt to be especially dangerous for the diabetic dysvascular patients utilizing the hydrotherapeutic tanks involved in this study. Only eleven of 96 cultures (11.5%) were positive for these prospective pathogens. Of the positive cultures, nine (9.4%) were taken from near the agitator-jet, and only two (2.1%) from the floor of the hydrotherapeutic tanks, where the extremity is likely to be placed. Our results reveal that hydrotherapeutic immersion is not likely to expose patients with open wounds to potential iatrogenic contamination of the wound.


Ampelozyziphus amazonicus Ducke (Rhamnaceae), a medicinal plant used to prevent malaria in the Amazon Region, hampers the development of Plasmodium berghei sporozoites.
Most medicinal plants used against malaria in endemic areas aim to treat the acute symptoms of the disease such as high temperature fevers with periodicity and chills. In some endemic areas of the Brazilian Amazon region one medicinal plant seems to be an exception: Ampelozyziphus amazonicus, locally named "Indian beer" or "Saracura-mira", used to prevent the disease when taken daily as a cold suspension of powdered dried roots. In previous work we found no activity of the plant extracts against malaria blood parasites in experimentally infected animals (mice and chickens) or in cultures of Plasmodium falciparum. However, in infections induced by sporozoites, chickens treated with plant extracts were partially protected against Plasmodium gallinaceum and showed reduced numbers of exoerythrocytic forms in the brain. We now present stronger evidence that the ethanolic extract of "Indian beer" roots hampers in vitro and in vivo development of Plasmodium berghei sporozoites, a rodent malaria parasite. Some mice treated with high doses of the plant extract did not become infected after sporozoite inoculation, whereas others had a delayed prepatent period and lower parasitemia. Our data validates the use of "Indian beer" as a remedy for malaria prophylaxis in the Amazon, where the plant exists and the disease represents an important problem which is difficult to control. Studies aiming to identify the active compounds responsible for the herein described causal prophylactic activity are needed and may lead to a new antimalarial prophylactic.


Effects of cecal oxytetracycline infusion, and dietary avidin and biotin supplementation on the biotin status of nongravid gilts.
The objective of this 49-d experiment was to test effects of cecal oxytetracycline (OTC) infusion, and dietary avidin and biotin supplementation on the biotin status of nongravid gilts. Twenty-eight crossbred gilts with an initial age of 160 d and BW of 120 kg were surgically fitted with a T-cannula in the terminal ileum, a cecal fistula, and an indwelling catheter in the anterior vena cava, and allotted to 7 dietary treatments. Treatments with the basal semipurified (SP) diet fed at 1.86 kg/d were: SP-1, negative control; SP-2, positive control with 270 μg of biotin/kg; SP-3, with spray-dried egg albumen (EA, 100 g/d) and OTC (2.56 g/d by cecal infusion); and SP-4, with EA, OTC, and 700 μg of biotin/kg. Treatments with the basal corn-soybean meal (CS) diet fed at 1.80 kg/d were: CS-1, negative control; CS-2, with EA and OTC; and CS-3, with EA, OTC, and 700 μg of biotin/kg. Response criteria were: fecal bacteria counts; plasma concentrations of biotin, glucose, and urea N (PUN); liver pyruvate carboxylase (PC) activity; kidney and epithelial tissue histology; ileal and fecal biotin concentrations; ileal and total tract N and energy utilization; daily gilt observation; and BW gain. Blood samples were collected every 7 d with serial samples collected on d 49. Total urine collections and fecal grab samples were made twice daily from d 44 to 49. Gilts were killed on d 50 and liver, kidney, and skin samples were collected. No gilts had symptoms of biotin deficiency. There were no treatment differences in BW gain, plasma glucose concentrations, liver PC activity, kidney and epithelial tissue histology, or fecal bacteria counts. Ileal and total tract N and energy digestibilities (%) did not differ among treatments within the same protein source, with greater (P ≤ 0.05) values for gilts on the SP treatments than the CS treatments. However, N retained/N absorbed and N retained/N intake (%) were less (P ≤ 0.05) and PUN concentrations were greater (P ≤ 0.05) for SP treatments with cecal OTC infusion. The overall fecal biotin concentration mean was 2.6-fold greater than the overall ileal biotin concentration mean. In conclusion, no gilts in the current experiment became biotin deficient because the biotin requirements were met primarily by microbial synthesis and absorption of biotin from the distal small intestine and large intestine, with corn and soybean meal contributing endogenous biotin. Therefore, supplementation of diets for gilts entering the breeding herd with 100% of the current NRC biotin requirement for sows is adequate.


Arsenic exposure is associated with pediatric pneumonia in rural Bangladesh: a case control study.
Pneumonia is the leading cause of death for children under 5 years of age globally, making research on modifiable risk factors for childhood pneumonia important for reducing this disease burden. Millions of children globally are exposed to elevated levels of arsenic in drinking water. However, there is limited data on the association between arsenic exposure and respiratory infections, particularly among pediatric populations. This case control study of 153 pneumonia cases and 296 controls 28 days to 59 months of age in rural Bangladesh is the first to assess whether arsenic exposure is a risk factor for pneumonia in a pediatric population. Cases had physician diagnosed World Health Organization defined severe or very severe pneumonia. Urine collected during hospitalization (hospital admission time point) and 30 days later (convalescent time point) from cases and a single specimen from community controls was tested for urinary arsenic by graphite furnace atomic absorption. The odds for pneumonia was nearly double for children with urinary arsenic concentrations higher than the first quartile (≥6 μg/L) at the hospital admission time point (Odd Ratio (OR):1.88 (95% Confidence Interval (CI): 1.01, 3.53)), after adjustment for urinary creatinine, weight for height, breastfeeding, paternal education, age, and number of people in the household. This was consistent with findings at the convalescent time point where the adjusted OR for children with urinary arsenic concentrations greater than the first quartile (≥6 μg/L) was 2.32 (95% CI: 1.33, 4.02). We observed a nearly two times higher odds of pneumonia for children with creatinine adjusted urinary arsenic concentrations greater than the first quartile (≥6 μg/L) at the hospital admission time point. This novel finding suggests that low to moderate arsenic exposure may be a risk factor for pneumonia in children under 5 years of age.


Added soft tissue contrast using signal attenuation and the fractal dimension for optical coherence tomography images of porcine arterial tissue.
Optical coherence tomography (OCT) images of left-descending coronary tissues harvested from three porcine specimens were acquired with a home-build swept-source OCT setup. Despite the fact that OCT is capable of acquiring high resolution circumferential images of vessels, many distinct histological features of a vessel have comparable optical properties leading to poor contrast in OCT images. Two classification methods were tested in this report for the purpose of enhancing contrast between soft-tissue components of porcine coronary vessels. One method involved analyzing the attenuation of the OCT signal as a function of light penetration into the tissue. We demonstrated that by analyzing the signal attenuation in this manner we were able to differentiate two media sub-layers with different orientations of the smooth muscle cells. The other classification method used in our study was fractal analysis. Fractal analysis was implemented in a box-counting (fractal dimension) image-processing code and was used as a tool to differentiate and quantify variations in tissue texture at various locations in the OCT images. The calculated average fractal dimensions had different values in distinct regions of interest (ROI) within the imaged coronary samples. When compared to the results obtained by using the attenuation of the OCT signal, the method of fractal analysis demonstrated better classification potential for distinguishing amongst the tissue ROI.


Nephrin TRAP mice lack slit diaphragms and show fibrotic glomeruli and cystic tubular lesions.
The molecular mechanisms maintaining glomerular filtration barrier are under intensive study. This study describes a mutant Nphs1 mouse line generated by gene-trapping. Nephrin, encoded by Nphs1, is a structural protein of interpodocyte filtration slits crucial for formation of primary urine. Nephrin(trap/trap) mutants show characteristic features of proteinuric disease and die soon after birth. Morphologically, fibrotic glomeruli with distorted structures and cystic tubular lesions were observed, but no prominent changes in the branching morphogenesis of the developing collecting ducts could be found. Western blotting and immunohistochemical analyses confirmed the absence of nephrin in nephrin(trap/trap) glomeruli. The immunohistochemical staining showed also that the interaction partner of nephrin, CD2-associated protein (CD2AP), and the slit-diaphragm-associated protein, ZO-1alpha (-), appeared unchanged, whereas the major anionic apical membrane protein of podocytes, podocalyxin, somewhat punctate as compared with the wild-type (wt) and nephrin(wt/trap) stainings. Electron microscopy revealed that >90% of the podocyte foot processes were fused. The remaining interpodocyte junctions lacked slit diaphragms and, instead, showed tight adhering areas. In the heterozygote glomeruli, approximately one third of the foot processes were fused and real-time RT-PCR showed >60% decrease of nephrin-specific transcripts. These results show an effective nephrin gene elimination, resulting in a phenotype that resembles human congenital nephrotic syndrome. Although the nephrin(trap/trap) mice can be used to study the pathophysiology of the disease, the heterozygous mice may provide a useful model to study the gene dose effect of this crucial protein of the glomerular filtration barrier.


Insights into pathogenesis of fatal COVID-19 pneumonia from histopathology with immunohistochemical and viral RNA studies.
We describe post-mortem pulmonary histopathologic findings of COVID-19 pneumonia in patients with a spectrum of disease course, from rapid demise to prolonged hospitalisation. Histopathologic findings in post-mortem lung tissue from eight patients who died from COVID-19 pneumonia were reviewed. Immunohistochemistry (IHC) and next-generation sequencing (NGS) were performed to detect virus. Diffuse alveolar damage (DAD) was seen in all cases with a spectrum of acute phase and/or organising phase. IHC with monoclonal antibodies against SARS-CoV-2 viral nucleoprotein and spike protein detected virus in areas of acute but not organising DAD, with intracellular viral antigen and RNA expression seen predominantly in patients with duration of illness less than 10 days. Major vascular findings included thrombi in medium- and large-calibre vessels, platelet microthrombi detected by CD61 IHC and fibrin microthrombi. Presence of SARS-CoV-2 viral RNA by NGS early in the disease course and expression of viral antigen by IHC exclusively in the acute, but not in the organising phase of DAD, suggests that the virus may play a major role in initiating the acute lung injury of DAD, but when DAD progresses to the organising phase the virus may have been cleared from the lung by the patient's immune response. These findings suggest the possibility of a major change during the disease course of COVID-19 pneumonia that may have therapeutic implications. Frequent thrombi and microthrombi may also present potential targets for therapeutic intervention.


Comparison of Efficiency of Video Endoscopy and Open Inguinal Lymph Node Dissection.
To compare the efficiency and complications of video endoscopy, inguinal lymphadenectomy and open inguinal lymph node dissection. Nineteen video endoscopy inguinal lymphadenectomies were performed on 16 patients from September 2014 to December 2015, and 21 open inguinal lymph node dissections were performed on 18 patients from September 2013 to September 2014. Surgical time, operative blood loss, incidence of complications, length of stay, lymph node harvest and suture removal time were compared between the two groups. Operative time (135.5±45.52 vs. 169.8±55.19 min), lymph node harvest (10.78±5.22 vs. 12.60±5.53), and hospital stay (10.43±2.53 vs. 12.50±4.98 days) did not statistically differ between the two groups (p>0.05). However, operative blood loss (22.50±14.24 vs. 68.44±42.19 ml), drainage tube removal time (7.23±1.79 vs. 11.44±2.69 days), incidence of complications (21.05% vs. 61.9%), and suture removal time (7.52±1.24 vs. 12.81±2.04 min) were significantly reduced in the video endoscopy surgery group compared with the open surgery group (p<0.05). Compared with open surgery, video endoscopy surgery achieved the same efficiency, and had the advantage of reduction of complications, suture removal time and in-surgery blood loss.


Synthesis and polymerization of bicyclic ketals: a practical route to high-molecular weight polyketals.
Polyketals are an important class of materials for drug delivery to sensitive tissues as they degrade in vivo to nonacidic species. We report the synthesis of high-molecular weight cyclic polyketals by the cationic ring-opening polymerization of bicyclic ketal monomers, which were prepared by the metal-catalyzed rearrangement of epoxy ketones. Three different cyclic polyketals with high molecular weights were synthesized using this protocol.


Multi-target pharmacology: possibilities and limitations of the "skeleton key approach" from a medicinal chemist perspective.
Multi-target drugs have raised considerable interest in the last decade owing to their advantages in the treatment of complex diseases and health conditions linked to drug resistance issues. Prospective drug repositioning to treat comorbid conditions is an additional, overlooked application of multi-target ligands. While medicinal chemists usually rely on some version of the lock and key paradigm to design novel therapeutics, modern pharmacology recognizes that the mid- and long-term effects of a given drug on a biological system may depend not only on the specific ligand-target recognition events but also on the influence of the repeated administration of a drug on the cell gene signature. The design of multi-target agents usually imposes challenging restrictions on the topology or flexibility of the candidate drugs, which are briefly discussed in the present article. Finally, computational strategies to approach the identification of novel multi-target agents are overviewed.


CXCL13-producing PD-1hiCXCR5- helper T cells in chronic inflammation.
CXCL13-producing PD-1hiCXCR5-CD4+ T cells were discovered in synovial tissues of rheumatoid arthritis (RA). Further intensive analysis of RA samples led to the proposal of PD-1hiCXCR5-CD4+ T cells as a pathogenic CD4 subset, peripheral helper T (Tph) cells. Tph cells are upregulated also in the peripheral blood of seropositive RA patient and exert B-cell helper activities. Furthermore, Tph cells are associated with other inflammatory conditions including systemic lupus erythematosus, IgG4-related diseases, type 1 diabetes, inflammatory bowel diseases, and malignant tumors. In this review, molecular feature and pathogenic and beneficial functions of Tph cells in inflammatory conditions are discussed.


Providing a Population Based Registry Model of Drug Poisoning in Iran.
The prevalence of drug poisoning is on the rise in Iran due to the increased public access to drugs. A national drug poisoning registry system is a suitable tool for better management, control, and prevention of drug poisoning. This study aimed to propose a national drug poisoning registry model for Iran. This was an applied research conducted in two major phases. In the first phase, all sources pertaining to drug poisoning registries were reviewed, and a national drug poisoning registry model was proposed. In the second phase, this model was validated and finalized using a researcher-made questionnaire and through a two-stage Delphi technique. The focus of national drug poisoning activities and registry management reached the 100% consensus of experts at the Drug and Poison Information Center of the Food and Drug Organization (Ministry of Health and Medical Education). Goals, data sources, registry system structure, data set, standards, data exchange, registry features, and processes of the proposed model also achieved unanimous expert consensus. Given the importance of a national drug poisoning registry in gathering, storing, analyzing, and reporting the data of patients, it is essential to provide a framework for evaluating and controlling drug poisoning and for generating valuable data for decision-making. The model proposed herein can offer the information infrastructure for designing and implementing such a system.


In vitro and in vivo evaluation of puerarin-loaded PEGylated mesoporous silica nanoparticles.
Puerarin, which is extracted from Chinese medicine, is widely used in China and mainly used as a therapeutic agent for the treatment of cardiovascular diseases. Owing to its short elimination half-life in human beings, frequently intravenous administration of high doses of puerarin may be needed, which possibly leads to severe and acute side effects. The development of an effective sustained-release drug delivery system is urgently needed. In this study, PEGylated mesoporous silica nanoparticles (PEG-MSNs) had become a preferred way to prolong the half-life and improve the bioavailability of drugs. The release of puerarin from PEG-MSNs was pH dependent, and the release rate was much faster at lower pH than that at higher pH. Moreover, the PEG-MSNs exhibited improved blood compatibility over the MSNs in terms of low hemolysis, and it could also reduce the side effect of hemolysis induced by PUE. Compared with puerarin, PUE-loaded PEG-MSNs showed a 2.3-fold increase in half-life of puerarin and a 1.47-fold increase in bioavailability. Thus, the PEG-MSNs hold the substantial potential to be further developed as an effective sustained-release drug delivery system.


Sequential electrochemical oxidation and site-selective growth of nanoparticles onto AFM probes.
In this work, we reported an approach for the site-selective growth of nanoparticle onto the tip apex of an atomic force microscopy (AFM) probe. The silicon AFM probe was first coated with a self-assembled monolayer (SAM) of octadecyltrichlorosilane (OTS) through a chemical vapor deposition (CVD) method. Subsequently, COOH groups were selectively generated at the tip apex of silicon AFM probes by applying an appropriate bias voltage between the tip and a flat gold electrode. The transformation of methyl to carboxylic groups at the tip apex of the AFM probe was investigated through measuring the capillary force before and after electrochemical oxidation. To prepare the nanoparticle terminated AFM probe, the oxidized AFM probe was then immersed in an aqueous solution containing positive metal ions, for example, Ag+, to bind positive metal ions to the oxidized area (COOH terminated area), followed by chemical reduction with aqueous NaBH 4 and further development (if desired) to give a metal nanoparticle-modified AFM probe. The formation of a metal nanoparticle at the tip apex of the AFM probe was confirmed by scanning electron microscopy (SEM) and energy dispersive X-ray analysis (EDXA).


Co-infusion of autologous adipose tissue derived insulin-secreting mesenchymal stem cells and bone marrow derived hematopoietic stem cells: viable therapy for type III.C. a diabetes mellitus.
Transition from acute pancreatitis to insulin-dependent diabetes mellitus (IDDM) is a rare manifestation of primary hyperparathyroidism caused by parathyroid adenoma because of impaired glucose tolerance and suppresses insulin secretion. We report the case of a 26-year-old male with pancreatic diabetes caused by parathyroid adenoma induced chronic pancreatitis. He had serum C-peptide 0.12 ng/ml, glutamic acid decarboxylase antibody 5.0 IU/ml, and glycosylated hemoglobin (HbA1C) 8.9%, and required 72 IU/day of biphasic-isophane insulin injection for uncontrolled hyperglycemia. We treated him with his own adipose tissue derived insulin-secreting mesenchymal stem-cells (IS-ADMSC) along with his bone marrow derived hematopoietic stem cells (BM-HSC). Autologous IS-ADMSC + BM-HSC were infused into subcutaneous tissue, portal and thymic circulation without any conditioning. Over a follow-up of 27 months, the patient is maintaining fasting and postprandial blood sugar levels of 132 and 165 mg/dl, respectively, with HbA1C 6.8% and requiring 36 IU/day of biphasic-isophane insulin. Co-infusion of IS-ADMSC + BM-HSC offers a safe and viable therapy for type III.C.a Diabetes Mellitus.


Antibiotic suppression of intestinal microbiota reduces heme-induced lipoperoxidation associated with colon carcinogenesis in rats.
Epidemiological studies show that heme iron from red meat is associated with increased colorectal cancer risk. In carcinogen-induced-rats, a heme iron-rich diet increases the number of precancerous lesions and raises associated fecal biomarkers. Heme-induced lipoperoxidation measured by fecal thiobarbituric acid reagents (TBARs) could explain the promotion of colon carcinogenesis by heme. Using a factorial design we studied if microbiota could be involved in heme-induced carcinogenesis, by modulating peroxidation. Rats treated or not with an antibiotic cocktail were given a control or a hemoglobin-diet. Fecal bacteria were counted on agar and TBARs concentration assayed in fecal water. The suppression of microbiota by antibiotics was associated with a reduction of crypt height and proliferation and with a cecum enlargement, which are characteristics of germ-free rats. Rats given hemoglobin diets had increased fecal TBARs, which were suppressed by the antibiotic treatment. A duplicate experiment in rats given dietary hemin yielded similar results. These data show that the intestinal microbiota is involved in enhancement of lipoperoxidation by heme iron. We thus suggest that microbiota could play a role in the heme-induced promotion of colorectal carcinogenesis.


Learning to reflect and to attribute constructively as basic components of self-regulated learning.
Higher education is facing a number of problems: adjusting to larger and more heterogeneous student populations, increasing the number of graduating students, and preparing for lifelong learning. Improving learning competence can make a substantial contribution to solving each of these major concerns. The growing knowledge base on self-regulated learning was taken as one of the main starting points for our study. In this article we report on reflection and attribution as basic components of self-regulated learning. We examine their trainability and their effect on academic performance. This study is part of a wider research project aimed at improving meta-cognitive knowledge as well as affective, conative and regulation skills. The experimental treatment consisted of an integrated set of instructional conditions, which were operationalized in a series of training sessions, as well as practice and transfer tasks. The participants in this study were 141 first year students of business economics. The experimental group and both control groups each consisted of 47 students. The effects of the learning environment were investigated using a quasiexperimental design. To control for unintended effects of the design the experimental and the first control group had the same number of teaching hours (time-on-task) and both teachers and students were not informed about the experimental design. Attribution and reflection behaviour was measured through specific assignments; study results during and after the intervention period were taken as indicators of academic performance. To test the hypotheses, t tests and effect-sizes were calculated. After the intervention the experimental students showed a higher degree of reflective behaviour than the control students. Moreover, their attribution skills had also measurably improved. The experimental students obtained better study results than their peers in the control groups. This intervention study, focused on the combined training of learning to reflect and to attribute constructively, provides evidence of the successful fostering both of meta-cognitive and of conative learning activities resulting in a positive impact on academic achievement.


Transperineal versus transvaginal color Doppler imaging of the uterine circulation.
Transperineal sonography has been described as being useful in assessing patients in special clinical situations such as posterior placenta previa, preterm labor, stress incontinence, and vaginal atresia. We explored the feasibility of this approach in assessing the uterine circulation in 54 subjects, of whom 36 were postmenopausal. We found that visualization of the uterine artery by the transperineal approach was satisfactory in most patients. The uterine arterial Doppler indices obtained from this approach were compared with those obtained by the transvaginal route. Highly significant correlations were found (correlation coefficient tau for pulsatility index = 0.74, p < 0.0001). No significant differences in results between the two approaches were detected using the Wilcoxon Matched-Pairs Signed-Rank test. We conclude that transperineal Doppler studies of the uterine circulation are possible and may be useful in certain patient groups.


Treatment of aged wound healing models with FGF2 and ABT-737 reduces the senescent cell population and increases wound closure rate.
Delayed tissue repair in the aged presents a major socio-economic and clinical problem. Age-associated delay in wound healing can be attributed to multiple factors, including an increased presence of senescent cells persisting in the wound. Although the transient presence of senescent cells is physiologic during the resolution phase of normal healing, increased senescent cell accumulation with age can negatively impact tissue repair. The objective of the study was to test interventional strategies that could mitigate the negative effect of senescent cell accumulation and possibly improve the age-associated delay in wound healing. We utilised a 3D in vitro senescent fibroblast populated collagen matrix (FPCM) to study cellular events associated with senescence and delayed healing. Senescent fibroblasts showed an increase in anti-apoptotic B-cell lymphoma 2 (BCL-2) family proteins. We hypothesized that reducing the senescent cell population and promoting non-senescent cell functionality would mitigate the negative effect of senescence and improve healing kinetics. BCL-2 inhibition and mitogen stimulation (FGF2) improved healing in the in vitro senescent models. These results were confirmed with an ex vivo human skin biopsy model. These data suggested that modulation of the senescent cell population with soluble factors improved the healing outcome in our in vitro and ex vivo healing models.


A complement-dependent model of thrombotic thrombocytopenic purpura induced by antibodies reactive with endothelial cells.
Thrombotic thrombocytopenic purpura (TTP) is an immunologically mediated disease characterized by thrombocytopenia, hemolytic anemia, and pathologic changes in various organs, including the kidney, which are secondary to widespread thromboses. Central to TTP is platelet activation, which may occur from a variety of mechanisms, including endothelial cell activation or injury. In this study, injection of K6/1, a monoclonal antibody with widespread reactivity toward endothelia, led to dose-dependent thrombocytopenia in rats. This was magnified if animals were preimmunized with mouse IgG, thereby resulting in an accelerated autologous phase of injury. In this setting, significant anemia also resulted. Rats injected with K6/1 developed renal injury, consisting of tubular damage and glomerular thrombi. Thrombocytopenia and renal morphological abnormalities were eliminated if animals were complement depleted with cobra venom factor prior to K6/1 injection and worsened when the activity of the ubiquitous complement regulator Crry was inhibited with function-neutralizing antibodies. Therefore, we have developed a complement-dependent model of TTP in rats by injecting monoclonal antibodies reactive with endothelial cells. Antibody-directed complement activation leads to stimulation of platelets, through direct interactions with complement fragments and/or indirectly through endothelial cell activation or injury, with the subsequent development of TTP.