Design and development of EMR supporting medical process management.
Current EMR system benefits physicians by facilitating order entry and reducing errors. It can improve the safety and effectiveness of medical services, but cannot manage the whole medical process and the quality of medical services. In addition to physicians, EMR should be designed for all medical professionals because medical services cannot be accomplished by physicians alone, but also requires the involvement of other medical professionals. Therefore, we applied PDCA, the famous quality management cycle to design a comprehensive and coherent EMR system which can be used throughout the entire treatment process. EMR with the PDCA Cycle can record every order state and every treatment procedure in order to monitor the whole medical process. This extends the safety from planning the treatment to fulfilling it. By analyzing the records, doctors and hospital managers can perfect the medical process and improve healthcare quality. The EMR we designed with the PDCA Cycle provides a record entry interface for physicians and a worksheet interface for nurses and other professionals. Every treatment procedure and every change of orders or tasks will be fed back to medical professionals. So information generated from the beginning to the end of treatment will link with each other to avoid any information islands. Furthermore, the EMR can display the additional information intuitively and real-timely without increasing the burden of medical professionals' work.


Noncytotoxic artificial bacterial flagella fabricated from biocompatible ORMOCOMP and iron coating.
Magnetic microrobots have potential use in biomedical applications such as minimally invasive surgery, targeted diagnosis and therapy. Inspired by nature, artificial bacterial flagella (ABFs) are a form of microrobot powered by magnetic helical propulsion. For the promise of ABFs to be realized, issues of biocompatibility must be addressed and the materials used in their fabrication should be carefully considered. In this work, we fabricate the helical bodies of ABFs from a commercially available biocompatible photoresist, ORMOCOMP, by subsequently coating them with Fe for magnetic actuation. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays show that Fe-coated ORMOCOMP layers do not undermine the cell viability during 72 hours of incubation compared to control substrates. Cells exhibit normal morphology on ABF arrays and show good lamellipodial and filopodial interactions with the ABF surfaces. The swimming performance of Fe-coated ABFs is characterized using a three-pair Helmholtz coil arrangement. ABFs exhibit a maximum forward speed of 48.9 μm s-1 under a field of 9 mT at a frequency of 72 Hz. In summary, our Fe-coated ABFs exhibit little cytotoxicity and have potential for in vivo applications, especially those involving difficult to access regions within the human body.


Antidepressant-like deliverables from the sea: evidence on the efficacy of three different brown seaweeds via involvement of monoaminergic system.
Brown seaweeds exhibit several health benefits in treating and managing wide array of ailments. In this study, the antidepressant-like effect of methaolic extracts from Sargassum swartzii (SS), Stoechospermum marginatum (SM), and Nizamuddinia zanardinii (NZ) was examined in forced swimming test (FST), in rats. Oral administration of SS, SM, and NZ extract (30-60 mg/kg) exhibited antidepressant-like activity in FST by reducing immobility time as compared to control group, without inducing significant change in ambulatory behavior in open field test. In order to evaluate the involvement of monoaminergic system, rats were pretreated with the inhibitor of brain serotonin stores p-chlorophenylalanin (PCPA), dopamine (SCH23390 and sulpiride), and adrenoceptor (prazosin and propranolol) antagonists. Rats receiving treatment for 28 days were decapitated and brains were analyzed for monoamine levels. It may be concluded that the extracts of SS, SM, and NZ produces antidepressant-like activity via modulation of brain monoaminergic system in a rat model.


Orthostatic Hypotension in Middle-Age and Risk of Falls.
One-third of older adults fall each year. Orthostatic hypotension (OH) has been hypothesized as an important risk factor for falls, but findings from prior studies have been inconsistent. We conducted a prospective study of the association between baseline OH (1987-1989) and risk of falls in the Atherosclerosis Risk in Communities (ARIC) Study. Falls were ascertained during follow-up via ICD-9 hospital discharge codes or Centers for Medicare & Medicaid Services claims data. OH was defined as a drop in systolic blood pressure (SBP) ≥20mm Hg or diastolic blood pressure (DBP) ≥10mm Hg within 2 minutes of moving from the supine to standing position. Changes in SBP or DBP during OH assessments were also examined as continuous variables. During a median follow-up of 23 years, there were 2,384 falls among 12,661 participants (mean age 54 years, 55% women, 26% black). OH was associated with risk of falls even after adjustment for demographic characteristics and other risk factors (hazard ratio (HR): 1.30; 95% confidence interval (CI): 1.10, 1.54; P = 0.002). Postural change in DBP was more significantly associated with risk of falls (HR 1.09 per -5mm Hg change in DBP; 95% CI: 1.05, 1.13; P < 0.001) than postural change in SBP (HR 1.03 per -5mm Hg change in SBP; 95% CI: 1.01, 1.05; P = 0.002). In a community-based, middle-aged population, OH, and in particular, postural change in DBP, were independent risk factors for falls over 2 decades of follow-up. Future studies are needed to examine OH thresholds associated with increased risk of falls.


The central adaptor molecule TRIF influences L. sigmodontis worm development.
Worldwide approximately 68 million people are infected with lymphatic filariasis (Lf), provoked by Wuchereria bancrofti, Brugia malayi and Brugia timori. This disease can lead to massive swelling of the limbs (elephantiasis) and disfigurement of the male genitalia (hydrocele). Filarial induced immune regulation is characterised by dominant type 2 helper T cell and regulatory immune responses. In vitro studies have provided evidence that signalling via Toll-like receptor-mediated pathways is triggered by filarial associated factors. Nevertheless, until now, less is known about the role of the adapter molecule TRIF during in vivo infections. Here, we used the rodent-specific nematode Litomosoides sigmodontis to investigate the role of TLR signalling and the corresponding downstream adapter and regulatory molecules TRIF, MyD88, IRF1 and IRF3 during an ongoing infection in semi-susceptible C57BL/6 mice. Interestingly, lack of the central adapter molecule TRIF led to higher worm burden and reduced overall absolute cell numbers in the thoracic cavity (the site of infection) 30 days post-infection. In addition, frequencies of macrophages and lymphocytes in the TC were increased in infected TRIF-/- C57BL/6 mice, whereas frequencies of eosinophils, CD4+ and CD8+ T cells were reduced. Nevertheless, cytokine levels and regulatory T cell populations remained comparable between TRIF-deficient and wildtype C57BL/6 mice upon 30 days of L. sigmodontis infection. In summary, this study revealed a crucial role of the adapter molecule TRIF on worm recovery and immune cell recruitment into the site of infection 30 days upon L. sigmodontis infection in C57BL/6 mice.


Opportunistic mobility support for resource constrained sensor devices in smart cities.
A multitude of wireless sensor devices and technologies are being developed and deployed in cities all over the world. Sensor applications in city environments may include highly mobile installations that span large areas which necessitates sensor mobility support. This paper presents and validates two mechanisms for supporting sensor mobility between different administrative domains. Firstly, EAP-Swift, an Extensible Authentication Protocol (EAP)-based sensor authentication protocol is proposed that enables light-weight sensor authentication and key generation. Secondly, a mechanism for handoffs between wireless sensor gateways is proposed. We validate both mechanisms in a real-life study that was conducted in a smart city environment with several fixed sensors and moving gateways. We conduct similar experiments in an industry-based anechoic Long Term Evolution (LTE) chamber with an ideal radio environment. Further, we validate our results collected from the smart city environment against the results produced under ideal conditions to establish best and real-life case scenarios. Our results clearly validate that our proposed mechanisms can facilitate efficient sensor authentication and handoffs while sensors are roaming in a smart city environment.


Human Immunodeficiency Virus Infection Promotes Human Papillomavirus-Mediated Anal Squamous Carcinogenesis: An Immunologic and Pathobiologic Review.
Anal squamous cell carcinoma (SCC) is a rare gastrointestinal malignancy with rising incidence, both in the United States and internationally. The primary risk factor for anal SCC is human papillomavirus (HPV) infection. However, there is a growing burden of disease in patients with human immunodeficiency virus (HIV) and HPV coinfection, with the incidence of anal SCC significantly increasing in this population. This is particularly true in HIV-infected men. The epidemiologic correlation between HIV-HPV coinfection and anal SCC is established; however, the immunologic mechanisms underlying this relationship are not well understood. HIV-related immunosuppression due to low circulating CD4+ T cells is one component of increased risk, but other mechanisms, such as the effect of HIV on CD8+ T lymphocyte tumor infiltration and the PD-1/PD-L1 axis in antitumor and antiviral response, is emerging as significant contributors. The goal of this article is to review existing research on HIV-HPV coinfected anal SCC and precancerous lesions, propose explanations for the detrimental synergy of HIV and HPV on the pathogenesis and immunologic response to HPV-associated cancers, and discuss implications for future treatments and immunotherapies in HIV-positive patients with HPV-mediated anal SCC. Key Messages: The incidence of anal squamous cell carcinoma is increased in human immunodeficiency virus (HIV)-infected patients, even in patients on highly active antiretroviral therapy. Locoregional HIV infection may enhance human papillomavirus oncogenicity. Chronic inflammation due to HIV infection may contribute to CD8+ T lymphocyte exhaustion by upregulating PD-1 expression, thereby blunting cytotoxic antitumor response.


Update on Mpox: a brief narrative review.
Mpox (formerly Monkeypox), a neglected tropical disease once confined to Central and West Africa, emerged as a global epidemic outbreak in May, 2022 with 87,529 cases reported as of May, 23, 2023. It predominantly affected men (96.2%) who have sex with men (84-100%), although other transmission routes have been reported, including occupational exposure and vertical transmission. Concomitant HIV infection has been recorded in 21-46.9% and pre-exposure prophylaxis against HIV infection has been reported in 11-57% of published cases. The current outbreak clinical presentation differs from endemic cases with prodromal symptoms that could be absent: the number of lesions is generally low, with skin lesions predominantly localised in the ano-genital areas and frequent lesions present in different stages of progression (i.e., asynchronous). Asymptomatic Mpox infection can occur in 1.8-6.5% of at-risk subjects. People living with HIV with severe immunodeficiency (less than 100 CD4+ lymphocytes per microliter) are at risk of more severe clinical manifestations and death. According to a systematic review and meta-analysis, the hospitalisation rate is around 6% and the observed case-fatality rate is less than 0.1%. Tecovirimat is the drug of choice for treating severe cases although there is no evidence of efficacy from randomised controlled trials. Immunization with a live non-replicating vaccine (JYNNEOS) effectively reduces the disease's incidence.


Regional planning of maternity services.
Analysis of utilization data from maternity units in a ten-county region in New York indicates that more small rural maternity units exist in that region than are needed. A mathematical model is used to ascertain optimal unit sizes, and criteria are developed by which units could be combined for more efficient use of facilities.


Gender differences in the effect of urge-to-cough and dyspnea on perception of pain in healthy adults.
Previous studies have reported that respiratory sensations, such as urge-to-cough and dyspnea, have an inhibitory effect on pain. Considering the existence of gender differences in both urge-to-cough and pain, it is conceivable that a gender difference also exists in the analgesia induced by urge-to-cough. In this study, we evaluated gender differences in the pain perception response to urge-to-cough, as well as to dyspnea. Twenty-seven male and 26 female healthy nonsmokers were originally enrolled. Citric acid challenge was used to induce the urge-to-cough sensation, and dyspnea was elicited by inspiratory loaded breathing. Before and during inductions of these two respiratory sensations, perception of pain was assessed by the thermal pain threshold, and differences between men and women were compared. The thermal pain threshold in women (43.83 ± 0.17°C) was significantly lower than that in men (44.75 ± 0.28°C; P < 0.05) during the baseline period. Accompanying increases in both citric acid concentration and inspiratory resistive load, thermal pain threshold values significantly increased in both men and women. The average thermal pain threshold changes for comparable increases in the urge-to-cough Borg score were parallel between men and women. Furthermore, the mean value of the thermal pain threshold plotted against the dyspnea Borg score also showed no significant gender difference. These results demonstrate that although gender differences exist in respiratory sensations, that is, urge-to-cough and dyspnea, the inhibitory effects of these respiratory sensations on the perception of pain are not significantly different between the sexes.


Long-term use of pegylated liposomal doxorubicin to a cumulative dose of 4600 mg/m2 in recurrent ovarian cancer.
Pegylated liposomal doxorubicin (PLD) is used widely in gynecologic oncology and other oncology disciplines. Native doxorubicin use is associated with the potential for significant toxicity. Cardiac toxicity in particular limits lifetime dose. PLD has not been shown to be associated with clinical cardiac toxicity. We report on the long-term use of PLD in a patient with recurrent high-grade serous ovarian cancer to a lifetime dose of 4600 mg/m. This therapy was associated with long-term stable disease, good performance status, and minimal adverse effects.


Valve-sparing root replacement-reimplantation technique.
The first valve sparing root replacement (VSRR) was first described over thirty years ago. Reimplantation is favored at our institution to provide maximum annular support in the setting of annuloaortic ectasia. Multiple iterations for this operation have been reported. Surgical intervention varies in terms of graft sizing, the number and method of inflow suture placement, strategy for annular plication and stabilization, and finally choice of graft type. Our specific technique has evolved over the last eighteen years and the current approach is to use a larger straight graft loosely based on the original Feindel-David formula, six inflow sutures to anchor the graft, and some degree of annular plication with annular stabilization. The long-term results for both trileaflet and bicuspid valves are associated with a low reintervention rate. Herein we provide a clear outline for our specific approach to the reimplantation technique.


[Monopolization of honeydew sources by Crematogaster macaoensis and its effects on lac production].
From October 2008 to May 2010, an investigation was made in a lac plantation in Yayi region of Mojiang County, Yunnan Province, China, aimed to understand the behavior of the monopolization of honeydew sources by ant Crematogaster macaoensis, and its effects on the sex ratio, mortality, fecundity, and lac production of Yunnan lac insect Kerria yunnanensis. The results showed that C. macaoensis fed and monopolized the honeydews around the clock during the whole life cycle of K. yunnanensis on the stick-lac, and the average number of visiting C. macaoensis ranged from 16.8 +/- 2.3 to 39.3 +/- 10.0 per 10 cm length of the stick-lac. C. macaoensis constructed shelters to prevent other animals from visiting the lac insect. C. macaoensis monopolization reduced the lac production of individual K. yunnanensi significantly, but had no significant effects on the lac production of whole lac insect colony. In addition, C. macaoensis monopolization reduced the mortality of K. yunnanensis significantly, and increased the percentage of K. yunnanensis females and the adult female fecundity. It was concluded that ant monopolization of the lac insect honeydew seemed to be beneficial to the lac production by the Yunnan lac insect.


Concept Maps for Teaching, Training, Testing and Thinking.
This article was migrated. The article was marked as recommended. Concept maps are evidence based pedagogical tools to fathom how meaningfully students have accomplished their learning objectives. They also give intuitive insights to improvise instruction to enable better and deeper understanding the foundations of learning. In this paper we provide an overview of concept maps and share our experiences of using concept maps for the 4 t's of education - teaching, training, testing and thinking.


4-Component relativistic magnetically induced current density using London atomic orbitals.
We present the implementation and application of 4-component relativistic magnetically induced current density using London atomic orbitals for self-consistent field models. We obtain a magnetically balanced basis by a simple scheme where orbitals obtained by imposing restricted kinetic balance are extended by their unrestricted kinetic balance complement. The presented methodology makes it possible to analyze the concept of aromaticity based on the ring current criterion for closed-shell molecules across the periodic table and is independent of the choice of gauge origin. As a first illustration of the methodology we study plots of the magnetically induced current density and its divergence in the series C(5)H(5)E (E = CH, N, P, As, Sb, Bi) at the Kohn-Sham level, as well as integrated ring current susceptibilities, which we compare to previous results (R. Bast et al., Chem. Phys., 2009, 356, 187) obtained using a common gauge origin approach. We find that the current strength decreases monotonically along the series, but that all molecules qualify as aromatic according to the ring current criterion.


Analysis of the bond-valence method for calculating (29) Si and (31) P magnetic shielding in covalent network solids.
(29) Si and (31) P magnetic-shielding tensors in covalent network solids have been evaluated using periodic and cluster-based calculations. The cluster-based computational methodology employs pseudoatoms to reduce the net charge (resulting from missing co-ordination on the terminal atoms) through valence modification of terminal atoms using bond-valence theory (VMTA/BV). The magnetic-shielding tensors computed with the VMTA/BV method are compared to magnetic-shielding tensors determined with the periodic GIPAW approach. The cluster-based all-electron calculations agree with experiment better than the GIPAW calculations, particularly for predicting absolute magnetic shielding and for predicting chemical shifts. The performance of the DFT functionals CA-PZ, PW91, PBE, rPBE, PBEsol, WC, and PBE0 are assessed for the prediction of (29) Si and (31) P magnetic-shielding constants. Calculations using the hybrid functional PBE0, in combination with the VMTA/BV approach, result in excellent agreement with experiment. © 2016 Wiley Periodicals, Inc.


Associativity of One-Loop Corrections to the Celestial Operator Product Expansion.
There has been recent interest in the question of whether QCD collinear singularities can be viewed as the operator product expansion of a two-dimensional conformal field theory. We analyze a version of this question for the self-dual limit of pure gauge theory (incorporating states of both helicities). We show that the known one-loop collinear singularities do not form an associative chiral algebra. The failure of associativity can be traced to a novel gauge anomaly on twistor space. We find that associativity can be restored for certain gauge groups if we introduce an unusual axion, which cancels the twistor space anomaly by a Green-Schwarz mechanism. Alternatively, associativity can be restored for some gauge groups with carefully chosen matter.


Seasonal Variations in the Diagnosis of Testicular Germ Cell Tumors: A National Cancer Registry Study in Austria.
We conducted a retrospective National Cancer Registry study in Austria to assess a possible seasonal variation in the clinical diagnosis of testicular germ cell tumors (TGCT). In total, 3615 testicular cancer diagnoses were identified during an 11-year period from 2008 to 2018. Rate ratios for the monthly number of TGCT diagnoses, as well as of seasons and half-years, were assessed using a quasi-Poisson model. We identified, for the first time, a statistically significant seasonal trend (p < 0.001) in the frequency of monthly newly diagnosed cases of TGCT. In detail, clear seasonal variations with a reduction in the tumor incidence during the summer months (Apr-Sep) and an increase during the winter months (Oct-Mar) were observed (p < 0.001). Focusing on seasonality, the incidence during the months of Oct-Dec (p = 0.008) and Jan-Mar (p < 0.001) was significantly higher compared to the months of Jul-Sep, respectively. Regarding histopathological features, there is a predominating incidence in the winter months compared to summer months, mainly concerning pure seminomas (p < 0.001), but not the non-seminoma or mixed TGCT groups. In conclusion, the incidence of TGCT diagnoses in Austria has a strong seasonal pattern, with the highest rate during the winter months. These findings may be explained by a delay of self-referral during the summer months. However, the hypothetical influence of vitamin D3 in testicular carcinogenesis underlying seasonal changes in TGCT diagnosis should be the focus of further research.


Challenges in Anaesthetic management of a child for thoracoscopic assisted oesophageal replacement.
The loss of oesophageal length or obliteration of oesophageal lumen due to stricture acquired by accidental caustic ingestion is more common in children that may require major operative reconstruction. A number of procedures have been developed for anatomic replacement of oesophagus of which thoracoscopic assisted gastric transposition has shown the best outcome in children. This demands an extensive pre-operative evaluation, preparation and anaesthetic management since this is challenging and prolonged procedure done under one lung ventilation (OLV). Though it is a minimally invasive procedure, providing OLV and management of complications associated with it are the anaesthetic challenges among these children. We report anaesthetic management of an 8-year-old boy with oesophageal stricture following corrosive injury posted for thoracoscopic assisted gastric transposition.


n-6 Linoleic Acid Induces Epigenetics Alterations Associated with Colonic Inflammation and Cancer.
The farnesoid-X-receptor (FXR) protects against inflammation and cancer of the colon through maintenance of intestinal bile acid (BA) homeostasis. Conversely, higher levels of BA and cyclooxygenase-2 (COX-2) are risk factors for inflammation and cancer of the colon. In the United States, n-6 linoleic acid (LA) is the most commonly used dietary vegetable fat. Metabolism of n-6 fatty acids has been linked to a higher risk of intestinal cancer. The objectives of this study were to investigate in colonic mucosa the effects of a high-fat diet rich in LA (n-6HFD) on CpG methylation of Fxr and prostaglandin-endoperoxide synthase-2 (Ptsg-2) genes, and the impact on the expression of tumor suppressor adenomatous polyposis Coli (Apc) and proliferative cyclin D1 (Ccnd1) genes. Weaned C57BL/6J male mice were fed for 6 weeks either an n-6HFD containing 44% energy (44%E) from 22% safflower oil (SO, 76% LA by weight) or a 13% energy (13%E) control diet (Control) from SO (5% by weight). Mice fed the n-6HFD had reduced (60%) Fxr promoter CpG methylation and increased (~50%) Fxr mRNA. The expression of FXR-target ileal bile acid-binding protein (Ibabp), small heterodimer protein (Shp), and anti-inflammatory peroxisome proliferator-activated-γ1 genes was increased. The n-6HFD reduced Ptgs-2 CpG methylation, increased the expression of Cox-2, and increased Apc CpG methylation in colonic mucosa. Accordingly, reduced expression of Apc was coupled to accumulation of c-JUN and Ccnd1, respectively cofactor and gene targets for the β-catenin/Wnt signaling pathway. Finally, the n-6HFD reduced the expression of histone deacetylase-1 while favoring the accumulation of acetylated histone 3. We conclude that an n-6HFD epigenetically modifies Fxr, leading to the activation of downstream factors that participate in BA homeostasis. However, epigenetic activation of Ptsg-2 coupled with silencing of Apc and accumulation of C-JUN and Ccnd1 may increase the risk of inflammation and cancer of the colon.


Distal femoral torsion is correlated with higher-grade trochlear dysplasia and shorter anterior condyles in patients with patellar dislocation and increased femoral torsion.
To describe the characteristics of femoral torsion in patients with different segmental torsion types and to evaluate the correlations between segmental torsion and the morphology of the femoral condyles and trochlea in patients with patellar dislocation and increased femoral torsion. Between January 2021 and March 2023, 69 patients were included and classified into two groups according to the femoral segment contributing the most to total torsion: 32 patients in Group A (femoral neck and shaft torsion) and 37 patients in Group B (distal torsion). Trochlear dysplasia was evaluated using Dejour's classification and sulcus angle. The morphology of the femoral condyles was evaluated using the lengths and ratios of the medial and lateral condyles. Correlations between femoral torsion and morphology were evaluated. Total torsion was significantly correlated with femoral neck and shaft torsion (r = 0.882, P < 0.001) and distal torsion (r = 0.262, P = 0.030). Femoral neck and shaft torsion was significantly increased with increasing total torsion. The trochlear sulcus was flatter and more dysplastic, and the anterior condyles were shorter in Group B. Distal torsion was significantly correlated with the lengths of the medial and lateral anterior condyles (r = - 0.567, P < 0.001; r = -0.701, P < 0.001), sulcus angle (r = 0.611, P < 0.001) and Dejour trochlea type (r = 0.512, P = 0.001), while femoral neck and shaft torsion showed no correlations. Femoral torsion is a complex of femoral neck and shaft torsion and distal torsion, especially femoral neck and shaft torsion. Distal torsion was significantly correlated with a flatter trochlear sulcus, higher-grade trochlear dysplasia, and shorter anterior condyles. The new findings highlighted the importance of the segmental evaluation of femoral torsion, which would facilitate understanding of the anatomical characteristics of femoral torsion in patients with patellar dislocation and increased femoral torsion and may lead to improvement in the surgical options regarding femoral torsion. Level III.


Reversible, strokelike migraine attacks in patients with previous radiation therapy.
We report 2 adults with a past history of radiation therapy to the head for malignancy (one with primary B-cell lymphoma confined to the skull and the other with multiple hemangioendotheliomas) who developed episodes consistent with migraine with and without aura. In addition to more typical migraine attacks and beginning many years after their radiation therapy, both patients have experienced infrequent, stereotyped, prolonged, reversible neurologic deficits associated with headache, occasional seizures, and striking, transient, cortical gadolinium enhancement of the posterior cerebral gyri on MRI. Interictal MRI brain scans show stable abnormalities consistent with the patients' previous radiation therapy. The neurologic deficits often progressed over a few days, sometimes lasted weeks, and completely resolved. Electroencephalograms did not show epileptiform activity. Thorough investigation showed no residual or recurrent tumor and no recognized cause for the patients' attacks. We postulate a causal relationship between the patients' remote radiation therapy and their prolonged, strokelike migraine attacks. Radiation-induced vascular changes could provoke the episodes, with or without an underlying migraine diathesis. Recognition of this syndrome can help avoid invasive testing.


Quantitative Assessment of Mass Flow Boundaries in Continuous Twin-screw Granulation.
In pharmaceutical manufacturing, there is an increasing interest in continuous manufacturing. As an example for fast continuous processes in general of considerable complexity, this study was focussed on improving the understanding of twin-screw wet granulation. The impact of the liquid-to-solid (L/S) mass flow ratio on product quality (granules) as well as on downstream process operations (tableting) was investigated in detail. Initially two methods were used to define L/S ratio boundaries for the granulation regime in twin-screw wet granulation. It was shown that the first method, which is based on measuring the wet granule mass flow variation, can be used to define the upper L/S ratio boundary of the granulation regime. The second method, based on measuring the granule size distribution, can be used to define the lower L/S ratio boundary of the regime. Using these methods, the granulation regime for different formulations could be established. This information was then used to show that the formulation could be optimised such that the process is more robust (i.e. wider L/S ratio boundaries for the granulation regime). Also it could be used to optimise the formulation considering further downstream processing such as drying (using as little water as possible to reduce drying efforts) or tableting (obtain granules with optimised tableting properties). Preferably, the process should be performed close to the lower L/S ratio boundary of the granulation regime. In summary, these tools enabled the quantitative establishment of granulation regime boundaries in a twin-screw wet granulation process and can be used to optimise formulation and to create a robust process. Analogies to other continuous processes in completely different applications can be conceived.


Evaluation of Quality of Life in Adult Individuals With Cleft Lip and/or Palate.
The purpose of the present study was to systematically review literature relating to the quality of life (QoL) in adult individuals with cleft lip and/or palate (CLP) and identify which aspect of QoL adults with CLP find to be the most problematic, in comparison to a general non-cleft population. Different databases were searched for this review including the Cochrane Central Register of Controlled Trials, Ovid MEDLINE and Embase. Five domains of QoL were identified to evaluate the overall results of these QoL measures. These domains were; physical function, physical pain, psychological implications and self-esteem, self-perception in relation to facial aesthetics, and social function. The studies included underwent critical appraisal and different types of bias were assessed based on the Cochrane handbook for systematic reviews of interventions. Ten studies were included in this review. The total number of participants was 541. The most common QoL measure for adults with CLP was Short-Form (SF-36). Seven studies out of 10 reported statistically significantly worse scores (P < 0.05) in the psychological implications and self-esteem domains of QoL in adults with CLP, indicating lower QoL in terms of these domains. The least affected QoL domain was physical function. A high heterogeneity was found among the studies, including variation in the QoL measures, types of orofacial clefts, types of treatment and comparison groups. The presence of CLP did seem to negatively affect the QoL for adults with CLP, mainly in terms of psychological implications and self-esteem.


Nitrososphaera viennensis, an ammonia oxidizing archaeon from soil.
Genes of archaea encoding homologues of ammonia monooxygenases have been found on a widespread basis and in large amounts in almost all terrestrial and marine environments, indicating that ammonia oxidizing archaea (AOA) might play a major role in nitrification on Earth. However, only one pure isolate of this group from a marine environment has so far been obtained, demonstrating archaeal ammonia oxidation coupled with autotrophic growth similar to the bacterial counterparts. Here we describe the cultivation and isolation of an AOA from soil. It grows on ammonia or urea as an energy source and is capable of using higher ammonia concentrations than the marine isolate, Nitrosopumilus maritimus. Surprisingly, although it is able to grow chemolithoautotrophically, considerable growth rates of this strain are obtained only upon addition of low amounts of pyruvate or when grown in coculture with bacteria. Our findings expand the recognized metabolic spectrum of AOA and help explain controversial results obtained in the past on the activity and carbon assimilation of these globally distributed organisms.


Efficacy and toxicity of pentostam against Panamanian mucosal leishmaniasis.
We tested the World Health Organization (WHO) recommended treatment for mucosal leishmaniasis in 16 Panamanians with disease due to Leishmania braziliensis panamensis. Disease was mild in this population because it was limited to the nasal mucosa and only one patient had septal perforation. The patients were administered 20 mg antimony (in the form of Pentostam) per kg intravenously each day for 28 days. Ten patients completed therapy and were cured at 12 month follow-up. Three patients completed therapy, healed their lesions, but relapsed at the six or 12 month follow-up. Three patients terminated therapy prematurely because of liver enzyme elevations in conjunction with either EKG abnormalities or musculoskeletal complaints; none of these patients were healed. This study indicates that in patients with mild mucosal leishmaniasis, the WHO regimen is curative in 77% patients who complete treatment and in 63% of all patients.


Radiological concepts of cholecystokinin cholecystography.
Cholecystokinin-cholecystography originated in Stockholm in 1955. At the present time the radiological procedure is conducted under supervision of medical research teams in the United States. The cholecystokininpancreozymin preparation is imported for clinical investigation under "Investigational Drug" regulations. Dr. Donald Hanscom, gastroenterologist, who is conducting clinical investigations in the Midwest, submitted radiographs, publications and evaluations from his files for this manuscript. This gastrointestinal hormone "squeezes out a diagnosis" as it is observed fluoroscopically. Dr. LeRoy B. Garbe, radiologist, evaluates these findings in the cases presented. The effects of cholecystokinin on the contrast-filled gall bladder give enhanced diagnostic information for the patient suffering with chronic cholecystitis and cystic ductitis.


Nitric Oxide Synthase Inhibition Prevents Cell Proliferation in Glioblastoma.
Glioblastoma multiforme (GBM) is a prevalent and aggressive primary brain tumor, presenting substantial treatment challenges and high relapse rates. GBM is characterized by alterations in molecular signaling and enzyme expression within malignant cells. This tumor exhibits elevated nitric oxide (NO.) levels. NO. is a crucial signaling molecule involved in the regulation of neuronal functions, synaptic transmission, and cell proliferation. It is primarily synthesized from L-arginine by nitric oxide synthase (NOS) enzymes. The increased levels of NO. in GBM stem from dysregulated activity and expression of clinically relevant NOS isoforms, particularly inducible NOS (iNOS) and neuronal NOS (nNOS). Based on this knowledge, we hypothesize that targeted pharmacological intervention with N6-(1-iminoethyl)-L-lysine (L-NIL), an iNOS inhibitor, and 7-Nitroindazole (7-NI), an nNOS inhibitor, may suggest a promising therapeutic strategy for the treatment of GBM. To test our hypothesis, we utilized the U87-MG cell line as an in vitro model of GBM. Our results showed that treatment with L-NIL and 7-NI led to a reduction in NO. levels, NOS activity, and clonogenic proliferation in U87-MG cells. These findings suggest that NO. and NOS enzymes might be prospective therapeutic targets for GBM.


Low pass filtering mechanism enhancing dynamical robustness in coupled oscillatory networks.
A network that consists of a set of active and inactive nodes is called a damaged network and this type of network shows an aging effect (degradation of dynamical activity). This dynamical deterioration affects the normal functioning of the network and also its performance. Therefore, it is necessary to design a proper mechanism to avoid undesired dynamical activity like degradation. In this work, an efficient mechanism, called the low pass filtering technique, is proposed to enhance the dynamical activity of damaged networks of coupled oscillators. Using this mechanism, the dynamic behavior of the damaged network of coupled active and inactive dynamical units is improved and the network survivability is ensured. Because a minor deviation of the controlling parameter is sufficient to restore the oscillatory behavior when the entire network undergoes an aging transition. Even when the whole network degrades due to the deterioration of each node, the larger values of the interaction strength and the controlling parameter play a key role in favor of the revival of dynamic activity in the entire network. Our proposed mechanism is very simple and effective to recover the dynamic features of a damaged network. The effectiveness of this technique has been testified in globally coupled and Erdős Rényi random networks of Stuart-Landau oscillators.


Effective inspired oxygen concentration measured via transtracheal and oral gas analysis.
The fraction of inspired oxygen (F(IO(2))) is quoted for different oxygen delivery systems, but variations in inspiratory flow and tidal volume make precise measurement difficult. We developed a reliable method of measuring the effective F(IO(2)) in patients receiving supplemental oxygen. Ten subjects with chronic hypoxemia breathed through a mouthpiece with a sampling probe connected to a mass spectrometer. Four of the 10 subjects had transtracheal catheters that allowed direct sampling of tracheal gas. We used oxygen concentrations of 47% and 97%, and flow rates between 1 L/min and 8 L/min. We also compared oxygen delivery via nasal cannula and transtracheal catheter. Effective F(IO(2)) was derived from plots of the fractional concentrations of carbon dioxide versus oxygen. We found excellent correlation between the effective F(IO(2)) values from tracheal and oral sampling (r = 0.960, P < .001). With 97% oxygen via nasal cannula, effective F(IO(2)) increased by 2.5% per liter of increased flow (P < .001); effective F(IO(2)) reached 32.7% at 5 L/min while P(aO(2)) increased by 12 mm Hg per liter of increased flow. In 4 subjects with a transtracheal catheter, effective F(IO(2)) increased 5.0% (P < .001) per liter of increased flow, and P(aO(2)) increased by 13 mm Hg per liter of increased flow, whereas in the same 4 subjects using nasal cannula for oxygen delivery, P(aO(2)) increased by only 6 mm Hg per liter of increased flow. Exhaled gas sampled at the mouth accurately reflected the effective F(IO(2)) in the trachea. In relation to inspired oxygen flow, the effective F(IO(2)) was lower than is conventionally thought. Compared to nasal cannula, transtracheal catheter approximately doubled the effective F(IO(2)) at a given flow rate. Accurate knowledge of F(IO(2)) should aid clinicians in managing patients with acute and chronic lung diseases.


Multilevel dynamic systems affecting introduction of HIV/STI prevention innovations among Chinese women in sex work establishments.
Social and public health scientists are increasingly interested in applying system dynamics theory to improve understanding and to harness the forces of change within complex, multilevel systems that affect community intervention implementation, effects, and sustainability. Building a system dynamics model based on ethnographic case study has the advantage of using empirically documented contextual factors and processes of change in a real-world and real-time setting that can then be tested in the same and other settings. System dynamics modeling offers great promise for addressing persistent problems like HIV and other sexually transmitted epidemics, particularly in complex rapidly developing countries such as China. We generated a system dynamics model of a multilevel intervention we conducted to promote female condoms for HIV/sexually transmitted infection (STI) prevention among Chinese women in sex work establishments. The model reflects factors and forces affecting the study's intervention, implementation, and effects. To build this conceptual model, we drew on our experiences and findings from this intensive, longitudinal mixed-ethnographic and quantitative four-town comparative case study (2007-2012) of the sex work establishments, the intervention conducted in them, and factors likely to explain variation in process and outcomes in the four towns. Multiple feedback loops in the sex work establishments, women's social networks, and the health organization responsible for implementing HIV/STI interventions in each town and at the town level directly or indirectly influenced the female condom intervention. We present the conceptual system dynamics model and discuss how further testing in this and other settings can inform future community interventions to reduce HIV and STIs.


Abnormalities in auditory efferent activities in children with selective mutism.
Two efferent feedback pathways to the auditory periphery may play a role in monitoring self-vocalization: the middle-ear acoustic reflex (MEAR) and the medial olivocochlear bundle (MOCB) reflex. Since most studies regarding the role of auditory efferent activity during self-vocalization were conducted in animals, human data are scarce. The working premise of the current study was that selective mutism (SM), a rare psychiatric disorder characterized by consistent failure to speak in specific social situations despite the ability to speak normally in other situations, may serve as a human model for studying the potential involvement of auditory efferent activity during self-vocalization. For this purpose, auditory efferent function was assessed in a group of 31 children with SM and compared to that of a group of 31 normally developing control children (mean age 8.9 and 8.8 years, respectively). All children exhibited normal hearing thresholds and type A tympanograms. MEAR and MOCB functions were evaluated by means of acoustic reflex thresholds and decay functions and the suppression of transient-evoked otoacoustic emissions, respectively. Auditory afferent function was tested by means of auditory brainstem responses (ABR). Results indicated a significantly higher proportion of children with abnormal MEAR and MOCB function in the SM group (58.6 and 38%, respectively) compared to controls (9.7 and 8%, respectively). The prevalence of abnormal MEAR and/or MOCB function was significantly higher in the SM group (71%) compared to controls (16%). Intact afferent function manifested in normal absolute and interpeak latencies of ABR components in all children. The finding of aberrant efferent auditory function in a large proportion of children with SM provides further support for the notion that MEAR and MOCB may play a significant role in the process of self-vocalization.


Treatment of latent infection with Mycobacterium tuberculosis: update 2010.
Much remains unknown about latent infection with Mycobacterium tuberculosis. Existing immunodiagnostic tools for this condition have various limitations, most importantly in their ability to predict disease. Randomised controlled trials have established protective efficacy of isoniazid therapy for 6-12 months among non-HIV-infected and HIV-infected subjects. While efficacy may reach 90%, acceptance and adherence to prolonged therapy are less than desired. Rifampicin plus pyrazinamide for 2 months, though efficacious, has been associated with excess hepatotoxicity in non-HIV-infected persons. Isoniazid plus rifampicin for 3 months has proven efficacy, but adverse effects may be more frequent than isoniazid or rifampicin monotherapy. Rifampicin monotherapy for 3-4 months is well tolerated, but efficacy data are currently limited, and concerns remain over possible selection of rifampicin-resistant mutants. For contacts of patients with multidrug-resistant tuberculosis, expert opinions differ on whether to treat with at least two drugs or just a fluoroquinolone, and for how long. With the existing diagnostic and treatment tools, efficacy of preventive therapy does not necessarily translate into field effectiveness. A targeted approach is required to maximise cost-effectiveness. Each geographic region needs to set its own priority after taking into account available scientific data and local circumstances.


Influence of caecectomy and source of dietary fibre or starch on excretion of endogenous amino acids by laying hens.
Two experiments were conducted to evaluate the effects of caecectomy and source of dietary fibre and starch on excretion of amino acids by laying hens. In Expt 1, caecectomized hens excreted significantly higher levels of several amino acids than intact hens during a 24 h fasting period. These differences were greatest for threonine, proline and leucine. In Expt 2, caecectomized and intact hens were given either a nitrogen-free diet containing 500 g cellulose/kg or one containing 400 g uncooked potato starch/kg and 100 g citrus pectin/kg. The potato starch-pectin (PSP) diet increased excretion of most amino acids by both caecectomized and intact hens compared with the cellulose diet, with this response being larger for intact hens. When compared across diets, caecectomized hens excreted more threonine and serine than intact hens. Excreta voided by hens given PSP contained higher levels of alanine and valine and lower levels of aspartic acid, glutamic acid and methionine than excreta from the cellulose diet. When compared across diets, excreta from caecectomized hens contained more threonine, serine and isoleucine and less aspartic acid and alanine than excreta from intact hens. Multiple regression analyses of excreta amino acid profiles on profiles of endogenous and microbial protein suggested that the intestinal microflora had greater influence on amino acids excreted by caecectomized hens than on those excreted by intact hens.


The perinatal bereavement project: development and evaluation of supportive guidelines for families experiencing stillbirth and neonatal death in Southeast Brazil-a quasi-experimental before-and-after study.
For most parents, getting pregnant means having a child. Generally, the couple outlines plans and has expectations regarding the baby. When these plans are interrupted because of a perinatal loss, it turns out to be a traumatic experience for the family. Validating the grief of these losses has been a challenge to Brazilian society, which is evident considering the childbirth care offered to bereaved families in maternity wards. Positively assessed care that brings physical and emotional memories about the baby has a positive impact on the bereavement process that family undergoes. Therefore, this study aims to assess the effects supportive guidelines have on mental health. They were designed to assist grieving parents and their families while undergoing perinatal loss in public maternities in Ribeirão Preto, São Paulo state, Brazil. A mixed-methods (qualitative/quantitative), quasi-experimental (before/after) study. The intervention is the implementation of bereavement supportive guidelines for women who experienced a stillbirth or a neonatal death. A total of forty women will be included. Twenty participants will be assessed before and twenty will be assessed after the implementation of the guidelines. A semi-structured questionnaire and three scales will be used to assess the effects of the guidelines. Health care professionals and managers of all childbirth facilities will be invited to participate in focus group. Data will be analyzed using statistical tests, as well as thematic analysis approach. The Perinatal Bereavement guidelines are a local adaptation of the Canadian and British corresponding guidelines. These guidelines have been developed based on the families' needs of baby memories during the bereavement process and include the following aspects: (1) Organization of care into periods, considering their respective needs along the process; (2) Creation of the Bereavement Professional figure in maternity wards; (3) Adequacy of the institutional environment; (4) Communication of the guidance; (5) Creation of baby memories. We expect that the current project generates additional evidence for improving the mental health of women and families that experience a perinatal loss. Trial registration RBR-3cpthr For many couples, getting pregnant does not only mean carrying a baby, but also having a child. Most of the time, the couple has already made many plans and has expectations towards the child. When these plans are interrupted because of a perinatal loss, it turns out to be a traumatic experience for the family. In Brazilian culture, validating this traumatic grief is very difficult, especially when it happens too soon. The barriers can be noticed not only by the way society deals with the parents' grief, but also when we see the care the grieving families receive from the health care establishment. Creating physical and emotional memories might bring the parents satisfaction regarding the care they receive when a baby dies. These memories can be built when there is good communication throughout the care received; shared decisions; the chance to see and hold the baby, as well as collect memories; privacy and continuous care during the whole process, including when there is a new pregnancy, childbirth and postnatal period. With this in mind, among the most important factors are the training of health staff and other professionals, the preparation of the maternity ward to support bereaved families and the continuous support to the professionals involved in the bereavement. This article proposes guidelines to support the families who are experiencing stillbirth and neonatal death. It may be followed by childbirth professionals (nurses, midwives, obstetricians and employees of a maternity ward), managers, researchers, policymakers or those interested in developing specific protocols for their maternity wards.


Small whole heart volume predicts cardiovascular events in patients with stable chest pain: insights from the PROMISE trial.
The size of the heart may predict major cardiovascular events (MACE) in patients with stable chest pain. We aimed to evaluate the prognostic value of 3D whole heart volume (WHV) derived from non-contrast cardiac computed tomography (CT). Among participants randomized to the CT arm of the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE), we used deep learning to extract WHV, defined as the volume of the pericardial sac. We compared the WHV across categories of cardiovascular risk factors and coronary artery disease (CAD) characteristics and determined the association of WHV with MACE (all-cause death, myocardial infarction, unstable angina; median follow-up: 26 months). In the 3798 included patients (60.5 ± 8.2 years; 51.5% women), the WHV was 351.9 ± 57.6 cm3/m2. We found smaller WHV in no- or non-obstructive CAD, women, people with diabetes, sedentary lifestyle, and metabolic syndrome. Larger WHV was found in obstructive CAD, men, and increased atherosclerosis cardiovascular disease (ASCVD) risk score (p < 0.05). In a time-to-event analysis, small WHV was associated with over 4.4-fold risk of MACE (HR (per one standard deviation) = 0.221; 95% CI: 0.068-0.721; p = 0.012) independent of ASCVD risk score and CT-derived CAD characteristics. In patients with non-obstructive CAD, but not in those with no- or obstructive CAD, WHV increased the discriminatory capacity of ASCVD and CT-derived CAD characteristics significantly. Small WHV may represent a novel imaging marker of MACE in stable chest pain. In particular, WHV may improve risk stratification in patients with non-obstructive CAD, a cohort with an unmet need for better risk stratification. • Heart volume is easily assessable from non-contrast cardiac computed tomography. • Small heart volume may be an imaging marker of major adverse cardiac events independent and incremental to traditional cardiovascular risk factors and established CT measures of CAD. • Heart volume may improve cardiovascular risk stratification in patients with non-obstructive CAD.


Causal effects of informal care and health on falls and other accidents among the elderly population in China.
This article analyzes the causal effects of informal care, mental health, and physical health on falls and other accidents (e.g., traffic accidents) among elderly people. We also examine if there are heterogeneous impacts on elderly of different gender, urban status, and past accident history. To purge potential reversal causal effects, e.g., past accidents induce more future informal care, we use two-stage least squares to identify the impacts. We use longitudinal data from a representative national China Health and Retirement Longitudinal Study of people aged 45 and older in China. A total of 3935 respondents with two-wave data are included in our study. Each respondent is interviewed to measure health status and report their accident history. Mental health is assessed using CES-D questions. Our findings indicate that while informal care decreased the occurrence of accidents, poor health conditions increase the occurrence of accidents. We also find heterogeneous impacts on the occurrence of accidents, varying by gender, urban status, and past accident history. Our findings suggest the following three policy implications. First, policy makers who aim to decrease accidents should take informal care of elders into account. Second, ease of birth policy and postponed retirement policy are urgently needed to meet the demands of informal care. Third, medical policies should attach great importance not only to physical health but also mental health of elderly parents especially for older people with accident history.


Point-of-Care Testing in Liver Disease and Liver Surgery.
The alterations in coagulation and hemostasis that accompany liver disease are complex, and while patients with this disease have traditionally been perceived as having a bleeding diathesis, it is now understood that in stable patients hemostasis is "re-balanced." Hepatic surgery, and particularly liver transplantation, can be associated with large fluid shifts, massive bleeding, and coagulopathy, as well as postoperative thrombosis. Point-of-care tests (POCTs) of coagulation facilitate goal-directed treatments and hemostatic monitoring in dynamic environments where the coagulation status can alter rapidly and often unpredictably. POCTs reflect more accurately the re-balanced hemostatic system than do conventional coagulation tests (CCTs). Viscoelastic POCT-guided transfusion algorithms permit a reduction in blood product administration and are a key component of patient blood management programs. Moreover, viscoelastic POCTs are better able to identify patients with hypercoagulability than CCTs. With thrombosis increasingly recognized to be a problem in patients with liver disease, POCTs hold promise for both individualized bleeding and thrombosis management.


A systematic review of effect of prenatal zinc supplementation on birthweight: meta-analysis of 17 randomized controlled trials.
The effect of prenatal zinc supplementation on birthweight is controversial as randomized controlled trials (RCTs) report conflicting conclusions. A systematic review which includes meta-analysis was done on 17 RCTs conducted worldwide since 1984 to assess the effect of prenatal zinc supplementation on birthweight. The studies were identified through web-based search. Heterogeneity among studies was assessed using Cochrane Q test statistic. Effect-size was measured based on standardized mean difference. Pooled effect-size was computed using a variant of random effect model. Thirteen of the 17 RCTs found no association, three reported positive association, and one reported negative association. Based on fixed and random effect models, the pooled effect-sizes were 0.0268 [95% confidence interval (CI) 0.0764, -0.0229) and 0.0712 (95% CI 0.1619, -0.0194) respectively. The effect-size estimate remains insignificant after stratification was made based on the dose of supplementation (optimal vs high dose), type of study (community vs institution-based), and type of source country (developed vs developing). The meta-analysis did not witness any association between birthweight and prenatal zinc supplementation.


A reactive metabolite of furan, cis-2-butene-1,4-dial, is mutagenic in the Ames assay.
Furan is classified as a nongenotoxic hepatocarcinogen. It is thought to be activated to a toxic metabolite, cis-2-butene-1,4-dial, which is acutely toxic to liver cells. The resulting cytotoxicity is followed by compensatory cell proliferation, increasing the likelihood of tumor production. We examined the genotoxic activity of cis-2-butene-1,4-dial in several strains of Salmonella typhimurium commonly used in the Ames assay. This reactive compound tested positive in TA104, a strain that is sensitive to aldehydes. Mutagenic activity was concentration-dependent (1000 +/- 180 revertants/micromol). Incubation of cis-2-butene-1,4-dial with glutathione prior to addition of bacteria inhibited both the acute toxic and genotoxic activity of this compound. No evidence of mutagenic activity was seen at nontoxic concentrations in TA97, TA98, TA100, and TA102. Our findings are consistent with the hypothesis that cis-2-butene-1,4-dial reacts with DNA to form mutagenic adducts. Our data suggest that cis-2-butene-1,4-dial may be an important genotoxic as well as toxic intermediate in furan-induced tumorigenesis.


Day-surgery versus overnight stay surgery for laparoscopic cholecystectomy.
Laparoscopic cholecystectomy is used to manage symptomatic gallstones. There is considerable controversy regarding whether it should be done as day-surgery or as an overnight stay surgery with regards to patient safety. To assess the impact of day-surgery versus overnight stay laparoscopic cholecystectomy on patient-oriented outcomes such as mortality, severe adverse events, and quality of life. We searched the Cochrane Hepato-Biliary Group Controlled Trials Register and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and mRCT until September 2012. We included randomised clinical trials comparing day-surgery versus overnight stay surgery for laparoscopic cholecystectomy, irrespective of language or publication status. Two authors independently assessed trials for inclusion and independently extracted the data. We analysed the data with both the fixed-effect and the random-effects models using Review Manager 5 analysis. We calculated the risk ratio (RR), mean difference (MD), or standardised mean difference (SMD) with 95% confidence intervals (CI) based on intention-to-treat or available case analysis. We identified a total of six trials at high risk of bias involving 492 participants undergoing day-case laparoscopic cholecystectomy (n = 239) versus overnight stay laparoscopic cholecystectomy (n = 253) for symptomatic gallstones. The number of participants in each trial ranged from 28 to 150. The proportion of women in the trials varied between 74% and 84%. The mean or median age in the trials varied between 40 and 47 years.With regards to primary outcomes, only one trial reported short-term mortality. However, the trial stated that there were no deaths in either of the groups. We inferred from the other outcomes that there was no short-term mortality in the remaining trials. Long-term mortality was not reported in any of the trials. There was no significant difference in the rate of serious adverse events between the two groups (4 trials; 391 participants; 7/191 (weighted rate 1.6%) in the day-surgery group versus 1/200 (0.5%) in the overnight stay surgery group; rate ratio 3.24; 95% CI 0.74 to 14.09). There was no significant difference in quality of life between the two groups (4 trials; 333 participants; SMD -0.11; 95% CI -0.33 to 0.10).There was no significant difference between the two groups regarding the secondary outcomes of our review: pain (3 trials; 175 participants; MD 0.02 cm visual analogue scale score; 95% CI -0.69 to 0.73); time to return to activity (2 trials, 217 participants; MD -0.55 days; 95% CI -2.18 to 1.08); and return to work (1 trial, 74 participants; MD -2.00 days; 95% CI -10.34 to 6.34). No significant difference was seen in hospital readmission rate (5 trials; 464 participants; 6/225 (weighted rate 0.5%) in the day-surgery group versus 5/239 (2.1%) in the overnight stay surgery group (rate ratio 1.25; 95% CI 0.43 to 3.63) or in the proportion of people requiring hospital readmissions (3 trials; 290 participants; 5/136 (weighted proportion 3.5%) in the day-surgery group versus 5/154 (3.2%) in the overnight stay surgery group; RR 1.09; 95% CI 0.33 to 3.60). No significant difference was seen in the proportion of failed discharge (failure to be discharged as planned) between the two groups (5 trials; 419 participants; 42/205 (weighted proportion 19.3%) in the day-surgery group versus 43/214 (20.1%) in the overnight stay surgery group; RR 0.96; 95% CI 0.65 to 1.41). For all outcomes except pain, the accrued information was far less than the diversity-adjusted required information size to exclude random errors. Day-surgery appears just as safe as overnight stay surgery in laparoscopic cholecystectomy. Day-surgery does not seem to result in improvement in any patient-oriented outcomes such as return to normal activity or earlier return to work. The randomised clinical trials backing these statements are weakened by risks of systematic errors (bias) and risks of random errors (play of chance). More randomised clinical trials are needed to assess the impact of day-surgery laparoscopic cholecystectomy on the quality of life as well as other outcomes of patients.


Maternal influence in learning by observation in kittens.
Kittens who observed their mothers perform a stimulus-controlled response (lever pressing to a visual stimulus for food) acquired and discriminated that response sooner than kittens who observed a strange female cat's performance. Kittens exposed to a trial and error condition never acquired the response. Initial differences in attentiveness to demonstrator performances disappeared by the second day. "Altruism" (food sharing) and other forms of social behavior were exhibited by both mother and stranger demonstrators.


Racial differences in surgeons and hospitals for endometrial cancer treatment.
To determine whether (1) black and white women with endometrial cancer were treated by different surgical specialties and in different types of hospitals and (2) differences in specialty and hospital type contributed to racial differences in survival. Retrospective cohort study of 12,307 women aged 65 years and older who underwent surgical treatment of endometrial cancer between 1991 and 1999 in the 11 Surveillance Epidemiology and End Results registries. Black women were more likely to have a gynecologic oncologist to perform their surgery and to be treated at hospitals that were higher volume, larger, teaching, National Cancer Institute centers, urban, and where a greater proportion of the surgeries were performed by a gynecologic oncologist. In unadjusted models, black women were over twice as likely as white women who died because of cancer (hazards ratio [HR]: 2.33), but nearly all of the initial racial difference in survival was explained by differences in cancer stage, and grade as well as age and comorbidities at presentation (adjusted HR: 1.10). Surgical specialty was not associated with survival and, of the hospital characteristics studied, only surgical volume was associated with survival (P < 0.005). Adjusting for hospital characteristics did not change the racial difference in survival (HR: 1.10). Adjustment for the specific hospital where the woman was treated eliminated the association between race and surgeon specialty and slightly widened the residual racial difference in survival (HR: 1.23 vs. 1.10). In contrast to several studies suggesting that blacks with breast cancer, colon cancer, or cardiovascular disease are treated in hospitals with lower quality indicators, black women diagnosed with endometrial cancer in Surveillance Epidemiology and End Results regions between 1991 and 1999 were more likely to be treated by physicians with advanced training and in high volume, large, urban, teaching hospitals. However, except for a modest association with hospital surgical volume, these provider and hospital characteristics were largely unrelated to survival for women with endometrial cancer. The great majority of the difference in survival was explained by differences in tumor and clinical characteristics at presentation.


Fluorometric optical sensor arrays for the detection of urinary bladder cancer specific volatile organic compounds in the urine of patients with frank hematuria: a prospective case-control study.
This study outlines a simple fluorometric optical sensor system for the sensitive, real time measurement of volatile organic compounds (VOCs) as biomarkers of urinary bladder cancer in patients presenting with frank hematuria and confirmed to have the disease on histopathology. Arrays of 24 sensor points based on fluorescence VOC sensitive materials were made. Urine samples of 38 consecutive patients with pathologically confirmed bladder tumours and 41 age and gender matched healthy controls were recruited and analysed using this sensor array. This system correctly classified 68 out of 79 urine samples with 84.21% sensitivity and 87.80% specificity; the system also achieved 66.67% sensitivity and 75.00% specificity for classification of high-grade and low-grade bladder cancer patients. This study showed promising results in the detection of urinary bladder cancer as well as to classify high grade versus low grade bladder cancers.


Novel device to conduct flash-heat treatment in efforts to reduce mother-to-child HIV transmission in low-resource areas.
The objective of this design project was to create a device to prevent mother-to-child transmission (MTCT) of HIV through breast milk in preterm infants. Our team created a robust and intuitive device which utilizes Flash Heat Treatment (FHT), an established method to inactivate HIV. The FHT method heats jarred breast milk in boiling water for a short amount of time, enough to denature HIV reverse transcriptase while preserving the nutritional value of breast milk. Thorough observation of users and available resources in Cape Town, South Africa enabled establishment of a design that can be used in urban/peri-urban areas. User research conveyed that low cost and effortless household adaptability were the most important elements of the design. As a result, a modified electric kettle was designed to function as a breast milk pasteurization device. Published data illustrating temperature curves during FHT with corresponding virology tests on the pasteurized milk were used to verify whether the device is likely to function effectively. Experimental results indicate that the device matches the required temperature profile. After virology experimentation is complete, the new device may be incorporated into hospitals as well as households in the Cape Town area, and may be expanded to other low resource periurban/urban areas as well.


"Internal Waves" Advancing along Submarine Canyons.
Patterns of alternating up- and downcanyon currents have been traced along the axes of submarine canyons off California. The patterns arrive later at stations nearer the heads of coastal canyons. Where a canyon heads between two islands, the patterns advance down the axis. The propagation speeds of these patterns were estimated as 25 to 88 centimeters per second. Internal waves are the probable explanation.


The chicken polydactyly (Po) locus causes allelic imbalance and ectopic expression of Shh during limb development.
Point mutations in the intronic ZRS region of Lmbr1, a limb specific cis-regulatory element of Sonic hedgehog (Shh), are associated with polydactyly in humans, cats, and mice. We and others have recently mapped the dominant preaxial polydactyly (Po) locus in Silkie chickens to a single nucleotide polymorphism (SNP) in the ZRS region. Using polymorphisms in the chicken Shh sequence, we confirm that the ZRS region directly regulates Shh expression in the developing limb causing ectopic Shh expression in the anterior leg, prolonged Shh expression in the posterior limb, and allelic imbalance between wt and Slk Shh alleles in heterozygote limbs. Using Silkie legs, we have explored the consequences of increased Shh expression in the posterior leg on the patterning of the toes, and the induction of preaxial polydactyly.


A single-site mutant and revertants arising in vivo define early steps in the pathogenesis of Venezuelan equine encephalitis virus.
The early stages of Venezuelan equine encephalitis virus (VEE) pathogenesis in the mouse model have been examined using a genetic approach. Disease progression of a molecularly cloned single-site mutant was compared with that of the parental virus to determine the step in the VEE pathogenetic sequence at which the mutant was blocked. Assuming that such a block constitutes a genetic screen, isolates from different tissues thought to be distal to the block in the VEE pathogenetic sequence were analyzed to determine the pathogenetic step at which revertants of the mutant were selected. Directed mutation and analysis of reversion in vivo provide two powerful genetic tools for the dissection of the wild-type VEE pathogenetic sequence. Virus from the parental virulent clone, V3000, first replicated in the draining lymph node after subcutaneous inoculation in the left rear footpad. Movement of a cloned avirulent mutant, V3010 (E2 76 Glu to Lys), to the draining lymph node was impaired, replication in the node was delayed, and spread beyond the draining lymph node was sporadic. Serum, contralateral lymph node, spleen, and brain isolates from V3010 inoculated animals were invariably revertant with respect to sequence at E2 76 and/or virulence in mice. Revertants isolated from serum and contralateral lymph node retained the V3010 E2 Lys 76 mutation but also contained a second-site mutation, Glu to Lys at E2 116. Modification of the V3010 clone by addition of the second-site mutation at E2 116 produced a virus that bypassed the V3010 block at the draining lymph node but that did not possess full wild-type capacity for replication in the central nervous system or for induction of mortality. A control construct containing only the E2 116 reverting mutation on the V3000 background was identical to V3000 in terms of early pathogenetic steps and virulence. Therefore, analysis of mutant replication and reversion in vivo suggested (1) that the earliest steps in VEE pathogenesis are transit to the draining lymph node and replication at that site, (2) that the mutation in V3010 impairs transit to the draining lymph node and blocks dissemination to other tissues, and (3) that reversion can overcome the block without restoring full virulence.


Laboratory-based surveillance of pertussis using multitarget real-time PCR in Japan: evidence for Bordetella pertussis infection in preteens and teens.
Between January 2013 and December 2014, we conducted laboratory-based surveillance of pertussis using multitarget real-time PCR, which discriminates among Bordetella pertussis, Bordetella parapertussis, Bordetella holmesii and Mycoplasma pneumoniae. Of 355 patients clinically diagnosed with pertussis in Japan, B. pertussis, B. parapertussis and M. pneumoniae were detected in 26% (n = 94), 1.1% (n = 4) and 0.6% (n = 2), respectively, whereas B. holmesii was not detected. It was confirmed that B. parapertussis and M. pneumoniae are also responsible for causing pertussis-like illness. The positive rates for B. pertussis ranged from 16% to 49%, depending on age. Infants aged ≤ 3 months had the highest rate (49%), and children aged 1 to 4 years had the lowest rate (16%, p < 0.01 vs. infants aged ≤ 3 months). Persons aged 10 to 14 and 15 to 19 years also showed high positive rates (29% each); the positive rates were not statistically significant compared with that of infants aged ≤ 3 months (p ≥ 0.06). Our observations indicate that similar to infants, preteens and teens are at high risk of B. pertussis infection.


Ejaculate evolution in external fertilizers: Influenced by sperm competition or sperm limitation?
The evolution of sperm quality and quantity is shaped by various selective processes, with sperm competition generally considered the primary selective agent. Particularly in external fertilizers, however, sperm limitation through gamete dispersal can also influence gamete investments, but empirical data examining this effect are limited. Here, we studied the relative importance of sperm competition and the spawning conditions in explaining the macroevolutionary patterns of sperm size and number within two taxa with external fertilization but differences in their reproductive biology. In frogs, sperm swim slowly but for up to hours as they penetrate the gelatinous egg coating, whereas fish sperm typically swim fast, are very short-lived (seconds to minutes), and often face a relatively higher risk of being moved away from the ova by currents. Our phylogenetic models and path analyses revealed different trajectories of ejaculate evolution in these two taxa. Sperm size and number responded primarily to variation in sperm competition in the anurans, but more strongly to egg number and water turbulence in the fishes. Whereas the results across anurans align with the general expectation that sexual selection is the main driver of ejaculate evolution, our findings across the fishes suggest that sperm limitation has been underappreciated.


Implication of dipeptidylpeptidase IV activity in human bronchial inflammation and in bronchoconstriction evaluated in anesthetized rabbits.
Decreased dipeptidylpeptidase IV (DPPIV) activity within the human nasal mucosa has previously been shown to contribute to the severity of chronic inflammatory rhinosinusitis. To investigate and correlate the role of DPPIV activity with regard to bronchial inflammation. DPPIV/CD26 activity/concentration was investigated in the bronchial tissue of human subjects suffering from chronic bronchial inflammation. In addition, the effect of a recombinant Aspergillus fumigatus DPPIV (fuDPPIV) was investigated on histamine-induced bronchoconstriction in anesthetized rabbits. DPPIV/CD26 was present in submucosal seromucous glands, in leukocytes and to a very low degree in endothelial cells of human bronchi. DPPIV activity was correlated with tissue CD26 content measured by immunoassay. As previously reported for the nasal mucosa, DPPIV/CD26 activity was inversely correlated with the degree of airway inflammation. Systemic pretreatment with recombinant fuDPPIV markedly reduced the increase in histamine-induced airway resistance in rabbits. In conclusion, DPPIV activity modulates lower airway tone by degrading unknown peptidic substrates released by histamine in response to an allergen. Contrasting with our observations in the nose, this modulation is apparently not mediated via a neurokinin (NK1) receptor.


Effect of Applying Molasses and Propionic Acid on Fermentation Quality and Aerobic Stability of Total Mixed Ration Silage Prepared with Whole-plant Corn in Tibet.
The objective of this study was to evaluate the effects of molasses and propionic acid on the fermentation quality and aerobic stability of total mixed ration (TMR) silages prepared with whole-plant corn in Tibet. TMR (354 g/kg DM) was ensiled with four different treatments: no additive (control), molasses (M), propionic acid (P), and molasses+propionic acid (PM), in laboratory silos (250 mL) and fermented for 45 d. Silos were opened and silages were subjected to an aerobic stability test for 12 days, in which chemical and microbiological parameters of TMR silages were measured to determined the aerobic deterioration. After 45 d of ensiling, the four TMR silages were of good quality with low pH value and ammonia/total N (AN), and high lactic acid (LA) content and V-scores. M silage showed the highest (p<0.05) LA content and higher dry matter (DM) recovery than the control and P silages. P silage had lower (p<0.05) LA content than the control silage. During aerobic exposure, lactic acid contents decreased gradually in the control and M silages, while that of P and PM silages increased, and the peak values were observed after 9 d. M silage had similar yeast counts with the control silage (>10(5) cfu/g FM), however, it appeared to be more stable as indicated by a delayed pH value increase. P and PM silages showed fewer yeasts (<10(5) cfu/g FM) (p<0.05) and were more stable than the control and M silages during aerobic exposure. It was concluded that M application increased LA content and improved aerobic stability of TMR silage prepared with whole-plant corn in Tibet. P application inhibited lactic acid production during ensiling, and apparently preserved available sugars which stimulated large increases in lactic acid during aerobic exposure stage, which resulted in greater aerobic stability of TMR silage.


Increased expression of CD23 in rheumatoid synovitis.
Soluble (s)CD23 is a potent macrophage stimulator. High levels of this molecule have been reported in rheumatoid arthritis (RA) serum. We investigated the expression of CD23 and its ligands in rheumatoid synovial fluid and cells. Levels of sCD23, and cellular expression of CD23 and its ligands CD21, CD11b, and CD11c were measured in synovial fluid (SF) of RA patients and in blood of RA patients and controls. SF contained higher levels of sCD23 than either rheumatoid or normal sera (median 4.8, 3.16,and 1.13 ng/ml respectively, p <0.01). Synovial CD23 was found to be expressed principally on macrophages. While little CD21 expression was detected, CD11b and CD11c were both expressed at high levels, particularly on macrophages. Soluble CD23 is present in high levels in RA synovial fluid. Macrophages appear to be the principal source. Macrophages also express ligands for sCD23, and may therefore also be the targets of this potent pro-inflammatory molecule.


Facile folding of insulin variants bearing a prosthetic C-peptide prepared by α-ketoacid-hydroxylamine (KAHA) ligation.
The chemical synthesis of insulin is an enduring challenge due to the hydrophobic peptide chains and construction of the correct intermolecular disulfide pattern. We report a new approach to the chemical synthesis of insulin using a short, traceless, prosthetic C-peptide that facilitates the formation of the correct disulfide pattern during folding and its removal by basic treatment. The linear precursor is assembled by an ester forming α-ketoacid-hydroxylamine (KAHA) ligation that provides access to the linear insulin precursors in good yield from two readily prepared segments. This convergent and flexible route provides access to various human, mouse, and guinea pig insulins containing a single homoserine mutation that shows no detrimental effect on the biological activities.


[Multidisciplinary management of patients with acute coronary syndrome and diabetes mellitus: from antithrombotic therapy to treatment of hyperglycemia].
Patients with diabetes mellitus (DM) and acute coronary syndromes (ACS) present a significantly higher risk of developing ischemic complications as compared to nondiabetic patients. Multiple mechanisms contribute to DM patients' enhanced prothrombotic status, including impaired fibrinolysis and coagulation, as well as endothelial and platelet dysfunction. Therefore, antithrombotic agents generally, and antiplatelet agents in particular, represent a logical secondary preventive strategy to reduce the risk of recurrent ischemic events in DM patients with ACS. However, DM patients often show attenuated responses to antiplatelet therapies for ACS patients. DM patients benefit from early coronary angiography and revascularization. Although randomized clinical trials have demonstrated that surgical revascularization is associated with an improved prognosis compared to percutaneous coronary intervention, a tailored revascularization strategy should be provided for each patient. The type of revascularization should be decided on the basis of SYNTAX score, surgical risk profile, and feasibility of total arterial revascularization in case of surgery. An accurate diagnosis and prompt treatment of hyperglycemia should also be provided for all patients. The present multidisciplinary document provides practical recommendations regarding diagnosis of DM and the management of hyperglycemia, from the acute phase to discharge. It is aimed at favoring early detection of hyperglycemia and identification of diabetic patients so as to provide adequate glucose control.


copepodTCR: Identification of Antigen-Specific T Cell Receptors with combinatorial peptide pooling.
T cell receptor (TCR) repertoire diversity enables the orchestration of antigen-specific immune responses against the vast space of possible pathogens. Identifying TCR/antigen binding pairs from the large TCR repertoire and antigen space is crucial for biomedical research. Here, we introduce copepodTCR , an open-access tool for the design and interpretation of high-throughput experimental assays to determine TCR specificity. copepodTCR implements a combinatorial peptide pooling scheme for efficient experimental testing of T cell responses against large overlapping peptide libraries, useful for "deorphaning" TCRs of unknown specificity. The scheme detects experimental errors and, coupled with a hierarchical Bayesian model for unbiased results interpretation, identifies the response-eliciting peptide for a TCR of interest out of hundreds of peptides tested using a simple experimental set-up. We experimentally validated our approach on a library of 253 overlapping peptides covering the SARS-CoV-2 spike protein. We provide experimental guides for efficient design of larger screens covering thousands of peptides which will be crucial for the identification of antigen-specific T cells and their targets from limited clinical material.


Ultrasensitive detection of SARS-CoV-2 spike protein by graphene field-effect transistors.
COVID-19, caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), originated a global health crisis, causing over 2 million casualties and altering human daily life all over the world. This pandemic emergency revealed the limitations of current diagnostic tests, highlighting the urgency to develop faster, more precise and sensitive sensors. Graphene field effect transistors (GFET) are analytical platforms that enclose all these requirements. However, the design of a sensitive and robust GFET is not a straightforward objective. In this work, we report a GFET array biosensor for the detection of SARS-CoV-2 spike protein using the human membrane protein involved in the virus internalisation: angiotensin-converting enzyme 2 (ACE2). By finely controlling the graphene functionalisation, by tuning the Debye length, and by deeply characterising the ACE2-spike protein interactions, we have been able to detect the target protein with an extremely low limit of detection (2.94 aM). This work set the basis for a new class of analytical platforms, based on human membrane proteins, with the potential to detect a broad variety of pathogens, even before their isolation, being a powerful tool in the fight against future pandemics.


Synergistic Evaluation of Ginger and Licorice Extracts in a Mouse Model of Colorectal Cancer.
Herbal medicine can be used to overcome the side effects of conventional treatments. This study aimed to evaluate the anticancer activities of ginger and licorice extracts, as well as the synergistic effects of their combination. Ginger ethanolic extract (GEE) and licorice methanolic extract (LME) were isolated by a Soxhlet extractor. Next, the anti-proliferative activity of the extracts, apoptosis induction, tumor growth inhibition, and tumor-infiltrating T lymphocytes were investigated. The MTT (3-[4, 5-dimethylthiazol-2-yl]-2, five diphenyl tetrazolium bromide) assay showed that GEE and LME decreased the CT26 cell viability in a dose-dependent manner; however, the GEE + LME combination was more effective (P < 0.05). The CT26 cells treated with each extract showed a significant increase in Bax/Bcl-2 ratio and caspase-3 gene expression, especially in the GEE + LME group (P < 0.001). Tumor volume significantly reduced in the GEE + LME group, compared to the negative controls. Finally, mice treated with GEE + LME showed a significant increase in the CTL/Treg cell ratio (P < 0.001) and Bax/Bcl2 ratio (P < 0.05). The study results revealed that GEE + LME can suppress cancer cell growth, increase apoptosis, and improve CTL infiltrating to the tumor site in a synergetic manner in-vivo and in-vitro. Therefore, the prepared mixture can be used in future clinical trials.


3D Facial Analysis in Acromegaly: Gender-Specific Features and Clinical Correlations.
Objective: Quantitative investigations of facial changes in acromegaly are rare. A new imaging technique, three-dimensional (3D) stereophotography, can accurately quantify whole facial changes. We aimed to measure facial characteristics in acromegaly patients using 3D stereophotography, analyze gender-specific features, and explore clinical influencing factors. Design: Single-center case-control study. Methods: Thirty-nine acromegaly patients and 39 age- and gender-matched healthy subjects were prospectively enrolled. 3D stereophotography was performed, and facial lines and angles were quantified for each subject. Clinical information for each acromegaly patient was acquired. Results: The nose width, length, height and depth were longer; the upper and lower lips were thicker; the face length, face width and gonion-gnathion distances were longer; and the nasofrontal and columella-labial angles were smaller in the acromegaly patients, especially in males, than in the healthy controls, with statistical significance (p < 0.05). No differences were found in the face breadth, columella-labial angle, or nose length, height or depth between the female patient and healthy control groups. The insulin-like growth factor 1 (IGF-1) levels in the acromegaly patients were linearly and positively correlated with the nose width (p = 0.006) and gonion-gnathion distance (p = 0.029) and linearly and negatively correlated with the nasofrontal angle (p = 0.026). Conclusions: The acromegaly patients' facial changes exhibit a unique trend, and the characteristics are not identical between genders. 3D stereophotography is an accurate and reliable tool for investigating facial characteristics. Recognizing the above facial features might be potential to assist in the early diagnosis and timely treatment of acromegaly and aid in predicting the severity of systemic complications.


Enhanced Killing of Triple-Negative Breast Cancer Cells by Reassortant Reovirus and Topoisomerase Inhibitors.
Breast cancer is the second leading cause of cancer-related deaths in women in the United States. Triple-negative breast cancer constitutes a subset of breast cancer that is associated with higher rates of relapse, decreased survival, and limited therapeutic options for patients afflicted with this type of breast cancer. Mammalian orthoreovirus (reovirus) selectively infects and kills transformed cells, and a serotype 3 reovirus is in clinical trials to assess its efficacy as an oncolytic agent against several cancers. It is unclear if reovirus serotypes differentially infect and kill triple-negative breast cancer cells and if reovirus-induced cytotoxicity of breast cancer cells can be enhanced by modulating the activity of host molecules and pathways. Here, we generated reassortant reoviruses by forward genetics with enhanced infective and cytotoxic properties in triple-negative breast cancer cells. From a high-throughput screen of small-molecule inhibitors, we identified topoisomerase inhibitors as a class of drugs that enhance reovirus infectivity and cytotoxicity of triple-negative breast cancer cells. Treatment of triple-negative breast cancer cells with topoisomerase inhibitors activates DNA damage response pathways, and reovirus infection induces robust production of type III, but not type I, interferon (IFN). Although type I and type III IFNs can activate STAT1 and STAT2, triple-negative breast cancer cellular proliferation is only negatively affected by type I IFN. Together, these data show that reassortant viruses with a novel genetic composition generated by forward genetics in combination with topoisomerase inhibitors more efficiently infect and kill triple-negative breast cancer cells.IMPORTANCE Patients afflicted by triple-negative breast cancer have decreased survival and limited therapeutic options. Reovirus infection results in cell death of a variety of cancers, but it is unknown if different reovirus types lead to triple-negative breast cancer cell death. In this study, we generated two novel reoviruses that more efficiently infect and kill triple-negative breast cancer cells. We show that infection in the presence of DNA-damaging agents enhances infection and triple-negative breast cancer cell killing by reovirus. These data suggest that a combination of a genetically engineered oncolytic reovirus and topoisomerase inhibitors may provide a potent therapeutic option for patients afflicted with triple-negative breast cancer.


Tomosyn associates with secretory vesicles in neurons through its N- and C-terminal domains.
The secretory pathway in neurons requires efficient targeting of cargos and regulatory proteins to their release sites. Tomosyn contributes to synapse function by regulating synaptic vesicle (SV) and dense-core vesicle (DCV) secretion. While there is large support for the presynaptic accumulation of tomosyn in fixed preparations, alternative subcellular locations have been suggested. Here we studied the dynamic distribution of tomosyn-1 (Stxbp5) and tomosyn-2 (Stxbp5l) in mouse hippocampal neurons and observed a mixed diffuse and punctate localization pattern of both isoforms. Tomosyn-1 accumulations were present in axons and dendrites. As expected, tomosyn-1 was expressed in about 75% of the presynaptic terminals. Interestingly, also bidirectional moving tomosyn-1 and -2 puncta were observed. Despite the lack of a membrane anchor these puncta co-migrated with synapsin and neuropeptide Y, markers for respectively SVs and DCVs. Genetic blockade of two known tomosyn interactions with synaptotagmin-1 and its cognate SNAREs did not abolish its vesicular co-migration, suggesting an interplay of protein interactions mediated by the WD40 and SNARE domains. We hypothesize that the vesicle-binding properties of tomosyns may control the delivery, pan-synaptic sharing and secretion of neuronal signaling molecules, exceeding its canonical role at the plasma membrane.


Transplantation of human adipose tissue-derived multilineage progenitor cells reduces serum cholesterol in hyperlipidemic Watanabe rabbits.
Familial hypercholesterolemia (FH) is an autosomal codominant disease characterized by high concentrations of proatherogenic lipoproteins and premature atherosclerosis secondary to low-density lipoprotein (LDL) receptor deficiency. We examined a novel cell therapy strategy for the treatment of FH in the Watanabe heritable hyperlipidemic (WHHL) rabbit, an animal model for homozygous FH. We delivered human adipose tissue-derived multilineage progenitor cells (hADMPCs) via portal vein and followed by immunosuppressive regimen to avoid xenogenic rejection. Transplantation of hADMPCs resulted in significant reductions in total cholesterol, and the reductions were observed within 4 weeks and maintained for 12 weeks. (125)I-LDL turnover study showed that the rate of LDL clearance was significantly higher in the WHHL rabbits with transplanted hADMPCs than those without transplanted. After transplantation hADMPCs were localized in the portal triad, subsequently integrated into the hepatic parenchyma. The integrated cells expressed human albumin, human alpha-1-antitrypsin, human Factor IX, human LDL receptors, and human bile salt export pump, indicating that the transplanted hADMPCs resided, survived, and showed hepatocytic differentiation in vivo and lowered serum cholesterol in the WHHL rabbits. These results suggested that hADMPC transplantation could correct the metabolic defects and be a novel therapy for inherited liver diseases.


Dropped head syndrome associated with cervical spondylotic myelopathy.
We report a case of an 80-year-old woman with dropped head syndrome associated with cervical spondylotic myelopathy. She could not keep her cervical spine in a neutral position for >1 minute. She had a disturbed gait and severe kyphotic deformity in her thoracic spine. Magnetic resonance imaging revealed severe compression of the spinal cord due to cervical spondylotic change. Laminoplasty from C2 through C6 levels was performed. One year after operation, she could keep her cervical spine in a neutral position easily. Her gait was also improved. The symptoms did not recur during 4 years of follow-up. We surmise that to maintain daily activities, she had to extend her cervical spine owing to the thoracic kyphotic deformity, resulting in compression of the spinal cord. The compression led to weakening of the cervical extensor muscles. Cervical laminoplasty was effective.


[Aspects of psychologic disorders in Japanese students].
The present study discusses the reasons which moved 88 students during one year from April 1987 till March 1988 to make their first spontaneous visit to the Department of Psychiatry in the Health Service Center of Tokyo University. The number of patients amounted to 0.60% of the total student enrollment during the period mentioned. The sufferings which motivated their visits could be phenomenally divided into two sectors. The first sector was related to the individual problems of the students and could be sub-divided into somatic and psychic spheres. To the other sector belonged the social or intersubjective relationships with either a general or a special point of reference. The majority of cases (ca. 70% of all patients) fell into the individual sector. Some reasons for this distribution are discussed. Among the patients there was a large percentage of freshmen. This seems to be due to the internal and external milieu changes caused by entering the university life. The ICD-9 diagnosis showed that ca. 80% of the patients exhibited Neurotic disorder and Adjustment reactions. This raises the question of applicability of ICD-9 to minor ailments, frequent among the clients of a Student Health Center. The dominant source of troubles motivating students to seek psychiatric help appeared to be problems connected with the academic life, like entrance into the university, examinations, choice of field of study, and graduation.


[Comparative lipid composition of mare's milk and a koumiss mixture prepared with cow's milk].
Fractional and fatty acid lipid composition of mare's milk and a kumiss mixture prepared on the basis of cow's milk components were studied and compared. Lipids contained by the products indicated were found to substantially differ. This is mainly accounted for by specific features of milk synthesized by different animals.