SRSF1-Regulated Alternative Splicing in Breast Cancer.
Splicing factor SRSF1 is upregulated in human breast tumors, and its overexpression promotes transformation of mammary cells. Using RNA-seq, we identified SRSF1-regulated alternative splicing (AS) targets in organotypic three-dimensional MCF-10A cell cultures that mimic a context relevant to breast cancer. We identified and validated hundreds of endogenous SRSF1-regulated AS events. De novo discovery of the SRSF1 binding motif reconciled discrepancies in previous motif analyses. Using a Bayesian model, we determined positional effects of SRSF1 binding on cassette exons: binding close to the 5' splice site generally promoted exon inclusion, whereas binding near the 3' splice site promoted either exon skipping or inclusion. Finally, we identified SRSF1-regulated AS events deregulated in human tumors; overexpressing one such isoform, exon-9-included CASC4, increased acinar size and proliferation, and decreased apoptosis, partially recapitulating SRSF1's oncogenic effects. Thus, we uncovered SRSF1 positive and negative regulatory mechanisms, and oncogenic AS events that represent potential targets for therapeutics development.


Low Molecular Weight Oligosaccharide from Panax ginseng C.A. Meyer against UV-Mediated Apoptosis and Inhibits Tyrosinase Activity In Vitro and In Vivo.
To find new anti-UV and whitening agents, 21 fractions isolated from three preparations of ginseng (white, red, and black ginseng) were screened, and their antioxidant effects on AAPH- or H2O2-induced damage were investigated. Furthermore, the protective effect against UV-mediated apoptosis and the tyrosinase inhibitory activity of the targeted fractions were evaluated in vitro and in a zebrafish model. Among all fractions, F10 from white ginseng was selected as having the strongest anti-UV and antimelanogenesis activities. This fraction exhibited excellent inhibitory effects on the pigmentation of zebrafish, which may be due to its potential tyrosinase inhibitory activity. Additionally, the chemical composition of F10 was evaluated by UPLC-MS and NMR instruments. The results indicated that F10 had a carbohydrate content of more than 76%, and the weight-average molecular weight was approximately 239 Da. Disaccharide sucrose was the main active compound in F10. These results suggest that F10 could be used as an ingredient for whitening cosmetics and regarded as an anti-UV filter in the future.


Comparative study of two methods for RNA extraction prior to detection of resistance to human immunodeficiency virus type 1 with the line probe assay.
We evaluated two methods from Roche and Promega for RNA extraction prior to the genotypic detection of human immunodeficiency virus type 1 resistance by line probe assay (LiPA). Fifty plasma RNA extracts were processed in parallel by LiPA. Results obtained by the Roche method were superior in the proportion of amplified samples, the percentage of mutated samples, and band intensity.


[Paroxystic abdominal pain in children].
Acute abdominal pain in children is a frequent symptom of a wide spectrum of abdominal and extra-abdominal pathologies. Some of them are more common in specific age groups. Prompt diagnosis and treatment are facilitated by a good knowledge of the etiologies. Although surgery is mandatory in most of the cases of perforation, torsion, ischemia or necrosis, a medical treatment will prevent an unnecessary laparotomy in some circumtances.


Intestinal Epithelial-Specific mTORC1 Activation Enhances Intestinal Adaptation After Small Bowel Resection.
Intestinal adaptation is a compensatory response to the massive loss of small intestine after surgical resection. We investigated the role of intestinal epithelial cell-specific mammalian target of rapamycin complex 1 (i-mTORC1) in intestinal adaptation after massive small bowel resection (SBR). We performed 50% proximal SBR on mice to study adaptation. To manipulate i-mTORC1 activity, Villin-CreER transgenic mice were crossed with tuberous sclerosis complex (TSC)1flox/flox or Raptorflox/flox mice to inducibly activate or inactivate i-mTORC1 activity with tamoxifen. Western blot was used to confirm the activity of mTORC1. Crypt depth and villus height were measured to score adaptation. Immunohistochemistry was used to investigate differentiation and rates of crypt proliferation. After SBR, mice treated with systemic rapamycin showed diminished structural adaptation, blunted crypt cell proliferation, and significant body weight loss. Activating i-mTORC1 via TSC1 deletion induced larger hyperproliferative crypts and disorganized Paneth cells without a significant change in villus height. After SBR, ablating TSC1 in intestinal epithelium induced a robust villus growth with much stronger crypt cell proliferation, but similar body weight recovery. Acute inactivation of i-mTORC1 through deletion of Raptor did not change crypt cell proliferation or mucosa structure, but significantly reduced lysozyme/matrix metalloproteinase-7-positive Paneth cell and goblet cell numbers, with increased enteroendocrine cells. Surprisingly, ablation of intestinal epithelial cell-specific Raptor after SBR did not affect adaptation or crypt proliferation, but dramatically reduced body weight recovery after surgery. Systemic, but not intestinal-specific, mTORC1 is important for normal adaptation responses to SBR. Although not required, forced enterocyte mTORC1 signaling after resection causes an enhanced adaptive response.


Vitamin D reduces the expression of collagen and key profibrotic factors by inducing an antifibrotic phenotype in mesenchymal multipotent cells.
Hypovitaminosis D is an important public health problem. Serum 25-hydroxyvitamin D (25-OHD) is now recognized as an independent predictor for cardiovascular and related diseases (CVD) as well as other chronic medical conditions. However, the biologic pathways through which these effects are mediated remain poorly understood. We hypothesized that exposing mesenchymal multipotent cells (MMCs) to the active form of vitamin D would increase the expression of selected antifibrotic factors that in turn would ameliorate the progression of chronic diseases. MMCs were primed with 5'-azacytidine to induce a fibrotic phenotype and then treated with active vitamin D (1,25D) or ethanol <0.1% as vehicle in a time course manner (30 min, 1, 5, and 24 h, and for 4 and 7 days). The addition of 1,25D to MMCs promotes: a) increased expression and nuclear translocation of the vitamin D receptor; b) decreased expression of TGFB1 and plasminogen activator inhibitor (SERPINE1), two well-known profibrotic factors; c) decreased expression of collagen I, III and other collagens isoforms; and d) increased expression of several antifibrotic factors such as BMP7 a TGFB1 antagonist, MMP8 a collagen breakdown inducer and follistatin, an inhibitor of the profibrotic factor myostatin. In conclusion, the addition of 1,25D to differentiated MMCs displays a decreased profibrotic signaling pathway and gene expression, leading to decrease in collagen deposition. This study highlights key mechanistic pathways through which vitamin D decreases fibrosis, and provides a rationale for studies to test vitamin D supplementation as a preventive and/or early treatment strategy for CVD and related fibrotic disorders.


Selective FGFR inhibitor BGJ398 inhibits phosphorylation of AKT and STAT3 and induces cytotoxicity in sphere-cultured ovarian cancer cells.
Epithelial ovarian cancer is the most aggressive and lethal among the gynecological malignancies, which is often found disseminated to peritoneal cavity at the time of diagnosis. There is accumulating evidence on the existence of genetic alteration and amplification of fibroblast growth factor receptor (FGFR) in various cancers. Also the aberrated FGFR/FGF signaling has been implicated in cancer development and tumor microenvironment. However, the antitumor activity of BGJ398, a selective inhibitor of FGFR 1/2/3 against ovarian cancer still remains unknown. The aim of the present study is to evaluate the antitumoral activity of BGJ398 on ovarian cancer cell line SKOV3ip1 using 3-dimensional (3D) sphere culture system which has been accepted as a better mimic in vivo microenvironment than conventional 2-dimensional (2D) monolayer culture system. We examined the differential expression features of key signaling molecules which have a role in cell survival and proliferation between sphere-cultured SKOV3ip1 cells and monolayer-cultured SKOV3ip1 cells. The phosphorylation of AKT and signal transducer and activator of transcription 3 (STAT3) known as survival signaling molecules were upregulated in sphere-cultured SKOV3ip1 cells compared to in monolayer-cultured SKOV3ip1 cells. Next, we evaluated the antitumor activity of BGJ398 in monolayer-cultured SKOV3ip1 cells or sphere-cultured SKOV3ip1 cells. Treatment of BGJ398 did not affect the SKOV3ip1 cell viability in monolayer culture system, but, the cell viability of sphere-cultured SKOV3ip1 cells was markedly reduced by BGJ398. The phosphorylation of AKT and STAT3 was downregulated by BGJ398 in sphere-cultured SKOV3ip1 cells, but not in monolayer cultured-SKOV3ip1 cells. Moreover, combination treatment with BGJ398 and paclitaxel in sphere-cultured SKOV3ip1 showed synergistic inhibitory effect on cell viability. Collectively, our report reveals the BGJ398 is a potent antitumor agent against ovarian cancer and FGFR is a promising therapeutic target to anticancer therapy considering ovarian cancer metastatic microenvironment.


Influence of Deposition Pressure on the Properties of Round Pyramid Textured a-Si:H Solar Cells for Maglev.
HIT (Heterojunction with Intrinsic Thin-layer) photovoltaic cells is one of the highest efficiencies in the commercial solar cells. The pyramid texturization for reducing surface reflectance of HIT solar cells silicon wafers is widely used. For the low leakage current and high shunt of solar cells, the intrinsic amorphous silicon (a-Si:H) on substrate must be uniformly thick of pyramid structure. However, it is difficult to control the thickness in the traditional pyramid texturing process. Thus, we textured the intrinsic a-Si:H thin films with the round pyramidal structure by using HNO3, HF, and CH3COOH solution. The characteristics of round pyramid a-Si:H solar cells deposited at pressure of 500, 1000, 1500, and 2000 mTorr by PECVD (Plasma Enhanced Chemical Vapor Deposition) was investigated. The lifetime, open circuit voltage, fill factor and efficiency of a-Si:H solar cells were investigated with respect to various deposition pressure.


Evaluation of methylene blue and squamous epithelial cells as oropharyngeal markers: a means of identifying oropharyngeal contamination during transtracheal aspiration.
The usefulness of 1% methylene blue (MB) and squamous epithelial cells as oropharyngeal markers in transtracheal aspiration was prospectively evaluated. In vitro studies showed that failure to detect MB by spectrophotometry ruled out contamination by greater than 0.05 microliters of oropharyngeal secretions and that visual inspection was almost as sensitive as spectrophotometry. Even minute contamination could be ruled out if greater than 5 x 10(4) organisms were found by culture of Gram-stained smear in a specimen that was MB-negative by spectrophotometry. In specimens of transtracheal aspirate obtained from 10 bronchitic patients, quantitative bacteriology ruled out even minute contamination in nine. Cytologic-morphometric examination revealed that 70% of both sterile and colonized specimens of transtracheal aspirate contained squamous epithelial cells that were indistinguishable, except by electron microscopy, from buccal mucosal cells. MB is a useful marker for identification of oropharyngeal contamination during transtracheal aspiration, and traditional cytologic screening is misleading in conditions associated with tracheobronchial squamous metaplasia.


Trends in primary and secondary syphilis and HIV infections in men who have sex with men--San Francisco and Los Angeles, California, 1998-2002.
Because syphilis infection facilitates acquisition and transmission of human immunodeficiency virus (HIV), recent outbreaks of syphilis among men who have sex with men (MSM) in major U.S. cities, including San Francisco and Los Angeles, and reported increases in sexual risk behavior have raised concerns about potential increases in HIV transmission. In 2002, MSM accounted for the majority of primary and secondary (P&S) syphilis cases in men reported in San Francisco (93%) and Los Angeles (81%). To investigate a potential change in HIV incidence associated with the syphilis outbreaks in the two cities, local, state, and federal health officials analyzed data from HIV counseling and testing centers and a municipal sexually transmitted disease (STD) clinic. This report describes the results of that investigation, which indicated that, as of 2002, the outbreaks of syphilis had not had a substantial impact on HIV incidence among MSM in these two cities. However, the continued increase in syphilis cases in MSM underscores the need for integrated HIV- and STD-prevention strategies to control syphilis outbreaks and prevent potential increases in HIV infections (6,7) and for further systematic studies of HIV incidence among MSM infected with syphilis.


Computer navigation versus standard instrumentation for TKA: a single-surgeon experience.
Component alignment errors in total knee arthroplasty greater than 3 degrees can be associated with poorer outcomes. This retrospective study seeks to determine if computer navigation can improve accuracy of component alignment in comparable patient populations. The efficiency and safety of the navigated technique is also evaluated. Fifty total knee arthroplasties done using an imageless navigation system and 50 cases using standard instrumentation were compared. The same surgeon used a single system (Zimmer-Natural Knee) in all cases. Long-standing radiographs collected at 6-week followup were measured for component orientation. When the navigation system was used 98% (49 of 50 cases) of all femoral components and 100% (50 of 50 cases) of all tibial components were placed within +/- 3 degrees of the radiographic goal position. There was a decrease in the standard instrumentation group to 90% (45 of 50 cases) and 92% (46 of 50 cases) within +/- 3 degrees , respectively. There was a difference in the standard deviations observed for the navigated cases and the conventional cases when femoral and tibial component position was considered. Average tourniquet time was 68 minutes in the navigated group and 57 minutes in the conventional group. There were no technique specific complications associated with the navigation system. This system affords the surgeon the potential to reduce outliers with regard to component position without an increase in complications. Tourniquet times were increased with the use of the computer. Therapeutic study, Level III-1 (retrospective comparative study). See the Guidelines for authors for a complete description of levels of evidence.


Preservation of vascular access for hemodialysis in acute care settings.
A vascular access for hemodialysis is the client's lifeline. It must be protected and used only for hemodialysis. Clients are knowledgeable about their vascular access and need to be listened to about its care. These clients' greatest fear is that their vascular access will be damaged and rendered nonfunctional. All health care personnel who come in contact with the vascular access and the client need to properly care for the vascular access with the goal of preserving its function. The purpose of this article is to explain the different types of vascular access for hemodialysis and how nurses can preserve and care for them. The vascular access and adjacent body areas need to be assessed regularly for circulatory, neurological, and muscular functions. Adequate perfusion helps to preserve the vascular access. Clients with end-stage renal disease will undergo many invasive procedures to establish and maintain a vascular access. Therefore, it is important to preserve the integrity of the existing vascular access as well as the surrounding vessels for future accesses. Nurses in acute care settings can assist to reduce the human and economic burden of vascular access.


[Resection of the Müller muscle. Indications, technique and results].
From 1987 to 1992, 582 operations for blepharoptosis were performed in our department. Twenty-five cases of superior tarsal muscle resection in 22 patients were reviewed retrospectively and serve as the basis of the present study. The blepharoptosis was mild to moderate (up to 4 mm) in 20/25 cases. Preoperatively, the phenylephrine eye drops test was positive in 20/25 cases. The indication for both congenital and acquired blepharoptosis was independent of the activity of the levator muscle. The resection was performed by a conjunctival approach. Three techniques of muscle stump refixation were tested without any significant difference in the results. A satisfactory eyelid elevation of more than 2 mm was achieved in 16/25 operations. A moderate effect (1-2 mm) was measured in 5/25 and an unsatisfactory effect (< 1 mm) in 4/25 cases. In contrast to the Fasanella-Servat procedure, the above-mentioned technique leaves all other structures of the upper eyelid intact, especially the accessory lacrimal glands.


Lignin Compounds to Monoaromatics: Selective Cleavage of C-O Bonds over a Brominated Ruthenium Catalyst.
The cleavage of C-O linkages in aryl ethers in biomass-derived lignin compounds without hydrogenation of the aromatic rings is a major challenge for the production of sustainable mono-aromatics. Conventional strategies over the heterogeneous metal catalysts require the addition of homogeneous base additives causing environmental problems. Herein, we propose a heterogeneous Ru/C catalyst modified by Br atoms for the selective direct cleavage of C-O bonds in diphenyl ether without hydrogenation of aromatic rings reaching the yield of benzene and phenol as high as 90.3 % and increased selectivity to mono-aromatics (97.3 vs. 46.2 % for initial Ru) during depolymerization of lignin. Characterization of the catalyst indicates selective poisoning by Br of terrace sites over Ru nanoparticles, which are active in the hydrogenation of aromatic rings, while the defect sites on the edges and corners remain available and provide higher intrinsic activity in the C-O bond cleavage.


Importance of psychiatric intervention in intolerances in endoscopic procedures.
Despite the fact that pre-medication, in a number of different drug combinations, has been used for a long time in endoscopy units, and has been subject to extended clinical studies, it is still not possible to claim that it has attained an ideal state with regard to patient tolerance to endoscopy procedures. In this clinical study, we have investigated the effects of psychological intervention in addition to medication, which we used on patients with intolerance to endoscopy. Intolerance was very high in all endoscopic procedures (15.8% total). It was observed that average midazolam doses were significantly higher in intolerant than in tolerant patients. It was found that in patients who had received psychiatric intervention, the decrease in midazolam dose was statistically significant in a subsequent endoscopy procedure.


Tipping the scales: is decision making related to readiness to change in girls with eating disorders?
Thirty-five adolescent girls with eating disorders completed a new brief measure of motivational stage of change and decisional balance. The study supported Prochaska's model of behavioral change demonstrating that decision making was consistently related to stage of readiness to change. The girls generated their individual pros and cons of changing and rated the overall strength of pros and cons. Results showed that the strength of the pros of changing was lowest in Precontemplation and highest in Maintenance. The pros of changing primarily reflected their expectation that "taking action" against the eating disorder would improve their body function and decrease their social anxiety. The cons of changing listed reflected concern that changing would negatively affect their body appearance, and that they were fearful of changing.


Engaging Informal Private Health Care Providers for TB Case Detection: Experiences from RIPEND Project in India.
Informal (unqualified) health care providers are an important source of medical care for persons with presumptive TB (PPTB) in India. A project (titled RIPEND) was implemented to engage informal providers for the identification of PPTBs and TB patients in 4 districts of Telangana State, India, during October 2018-December 2019 project period. Engagement involved sensitizing the informal providers about TB, providing them financial incentives to identify PPTBs, and linking these PPTBs to diagnostic and treatment services provided by the Government of India's National TB Elimination Programme. To describe (a) the characteristics of the informal providers, along with their self-reported practices on TB diagnosis, treatment, and challenges encountered by the RIPEND project staff in engaging them in the project and (b) the outputs and outcomes of this engagement. We used a combination of one-on-one interviews with informal providers, group interviews with RIPEND project staff, and secondary analysis of data available within the project's recording and reporting systems. A total of 555 informal providers were actively engaged under the project. The majority (87%) had a nonmedicine-related graduate degree and had been providing medical care for more than 10 years. Most (95%) were aware that a cough for 2 weeks or more is a symptom of pulmonary TB and that such patients should be referred for sputum-smear microscopy at a government health facility. Challenges in engaging the informal providers included motivating them to participate in the study, suboptimal mobile usage for referral services, and delays in providing financial incentives to them for referring PPTBs. During the project period (October 2018-December 2019), 8342 PPTBs were identified of which 1003 TB patients were detected and linked to TB treatment services. This project showed that engaging informal providers is feasible and that a large number of PPTB and TB patients can be identified through this effort. The Government of India should consider engaging informal providers for the early diagnosis of TB to reduce the missing TB cases in the country.


Schizophrenia and Hyperostosis Frontalis Interna with History of Head Injury.
Hyperostosis frontalis interna is an irregular thickening of the frontal bone. Its etiology is unknown. It has been rarely linked with schizophrenia and head injury. Case Presentation. We describe an unusual case of a 44-year-old female with schizophrenia and hyperostosis frontalis interna having a history of head trauma. At the age of 3 years, she had a head injury that could be classified as mild traumatic brain injury. She presents a family history of schizophrenia. She was admitted for resistant schizophrenic disorder. The cranial computed tomography showed bilateral and asymmetrical hyperostosis of the frontal bone that was more pronounced on the right side. This corresponds to the impact of the trauma with frontal atrophy without any metabolic or endocrinal abnormalities. Conclusion. We surmise that the long-term pathological effects of traumatic brain injury, including hyperostosis frontalis interna, are likely to interact with genetic vulnerability and may lead to schizophrenic disorder.


Bevacizumab as adjuvant therapy in the management of pterygium: a systematic review and Meta-analysis.
To evaluate the clinical effect of bevacizumab in pterygium treatment. A systematic review and quantitative Meta-analysis was performed. PubMed, EMBASE, Web of Science and Cochrane database were searched for eligible literatures published in English until June 2016. The endpoint was recurrence rate and pooled risk ratio (RR) was calculated. Nine eligible studies were included and Meta-analysis results showed no significantly difference in patients treated with bevacizumab in short term follow-up [3mo: RR=0.70 (0.34, 1.45); 6mo: RR=0.55 (0.23, 1.32)] compared with control groups. No significant effects were observed in favor of bevacizumab in subgroup analyses: patients with subconjunctival injection of bevacizumab [3mo: RR=0.95 (0.70, 1.29); 6mo: RR=0.83 (0.55, 1.28)], primary pterygium [3mo: RR=0.59 (0.23, 1.54; 6mo: RR=0.59 (0.23, 1.53)], simple pterygium excision [3mo: 0.32 (0.05, 2.04), P=0.23; 6mo: 0.27 (0.05, 1.53)] and excision with conjunctival autograft [3mo: 1.51 (0.25, 9.15); 6mo: 1.11 (0.06, 21.69)]. In this Meta-analysis, we did not found the significant effect of bevacizumab in pterygium treatment, at least in short term follow-up (3mo and 6mo).


Laser vaccine adjuvants. History, progress, and potential.
Immunologic adjuvants are essential for current vaccines to maximize their efficacy. Unfortunately, few have been found to be sufficiently effective and safe for regulatory authorities to permit their use in vaccines for humans and none have been approved for use with intradermal vaccines. The development of new adjuvants with the potential to be both efficacious and safe constitutes a significant need in modern vaccine practice. The use of non-damaging laser light represents a markedly different approach to enhancing immune responses to a vaccine antigen, particularly with intradermal vaccination. This approach, which was initially explored in Russia and further developed in the US, appears to significantly improve responses to both prophylactic and therapeutic vaccines administered to the laser-exposed tissue, particularly the skin. Although different types of lasers have been used for this purpose and the precise molecular mechanism(s) of action remain unknown, several approaches appear to modulate dendritic cell trafficking and/or activation at the irradiation site via the release of specific signaling molecules from epithelial cells. The most recent study, performed by the authors of this review, utilized a continuous wave near-infrared laser that may open the path for the development of a safe, effective, low-cost, simple-to-use laser vaccine adjuvant that could be used in lieu of conventional adjuvants, particularly with intradermal vaccines. In this review, we summarize the initial Russian studies that have given rise to this approach and comment upon recent advances in the use of non-tissue damaging lasers as novel physical adjuvants for vaccines.


Impact of alcohol-based, waterless hand antiseptic on the incidence of infection and colonization with methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci.
Colonized and infected inpatients are major reservoirs for methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), and transient carriage of these pathogens on the hands of healthcare workers remains the most common mechanism of patient-to-patient transmission. We hypothesized that use of alcohol-based, waterless hand antiseptic would lower the incidence of colonization and/or infection with MRSA and VRE. On June 19, 2001, alcohol hand antiseptic was introduced at the University campus and not the nearby Memorial campus of the University of Massachusetts Medical School (Worcester, MA), allowing us to evaluate the impact of this antiseptic on the incidence of MRSA and VRE colonization and infection. From January 1 through December 31, 2001, the incidence of MRSA colonization or infection was compared between the 2 campuses before and after the hand antiseptic was introduced. Its effect on VRE colonization and infection was only studied in the medical intensive care unit at the University campus. At the University campus, the incidence of MRSA colonization or infection decreased from 1.26 cases/1,000 patient-days before the intervention to 0.75 cases/1,000 patient-days after the intervention, for a 1.46-fold decrease (95% confidence interval, 1.04-2.58; P = .037). At the Memorial campus, the incidence of MRSA colonization or infection remained virtually unchanged, from 0.34 cases/1,000 patient-days to 0.49 cases/1,000 patient-days during the same period. However, a separate analysis of the University campus data that controlled for proximity to prevalent cases did not show a significant improvement in the rates of infection or colonization. The incidence of nosocomial VRE colonization or infection before and after the hand antiseptic decreased from 12.0 cases/1,000 patient-days to 3.0 cases/1,000 patient-days, a 2.25-fold decrease (P = .018). Compliance with rectal surveillance for detection of VRE was 86% before and 84% after implementation of the hand antiseptic intervention. The prevalences of VRE cases during these 2 periods were 25% and 29%, respectively (P = .017). Alcohol hand antiseptic appears to be effective in controlling the transmission of VRE. However, after controlling for proximity to prevalent cases (ie, for clustering), it does not appear to be more effective than standard methods for controlling MRSA. Further controlled studies are needed to evaluate its effectiveness.


Non-convulsive status epilepticus versus periodic EEG pattern in sporadic Creutzfeldt-Jakob disease: two sides of the same coin?
Sporadic Creutzfeldt-Jakob disease is characterized by rapid cognitive and neuropsychiatric impairment. The Heidenhain variant of Creutzfeldt-Jakob disease is known for isolated visual disturbance that precedes other features. Periodic sharp wave complexes on EEG are typical of sporadic Creutzfeldt-Jakob disease, but at the onset, the electroclinical pattern may be unclear and suggest the hypothesis of a non-convulsive status epilepticus. Furthermore, non-convulsive status epilepticus and sporadic Creutzfeldt-Jakob disease could coexist simultaneously. We report the case of a patient admitted to our hospital for progressive psychiatric and cognitive disorders. In the initial phase, based on clinical, EEG, and neuroradiological features, a diagnosis of possible non-convulsive status epilepticus was made. Subsequently, the rapid neurological degeneration led to the diagnosis of Creutzfeldt-Jakob disease confirmed by cerebrospinal fluid real-time quaking-induced conversion. Non-convulsive status epilepticus could mimic Creutzfeldt-Jakob disease or be present in overlap. Antiseizure drugs may be started when the etiology is unclear, but overtreatment should be avoided when invasive treatment protocols fail, and the neurological progression suggests an encephalopathy.


Incidence, prevalence, and comorbidities of chronic pancreatitis: A 7-year population-based study.
Chronic pancreatitis (CP) is a fibroinflammatory syndrome leading to reduced quality of life and shortened life expectancy. Population-based estimates of the incidence, prevalence, and comorbidities of CP in China are scarce. To characterize the incidence, prevalence, and comorbidities of CP in Sichuan Province, China, with population-based data. Data on CP from 2015 to 2021 were obtained from the Health Information Center of Sichuan Province. During the study period, a total of 38090 individuals were diagnosed with CP in Sichuan Province. The yearly incidence rate and point prevalence rate (December 31, 2021) of CP were calculated. The prevalence of comorbid conditions in CP patients was estimated. The annual number of CP-related hospitalizations, hospital length of stay, and hospitalization costs for CP were evaluated. Yearly incidence rates were standardized for age by the direct method using the permanent population of Sichuan Province in the 2020 census as the standard population. An analysis of variance test for the linearity of scaled variables and the Cochran-Armitage trend test for categorical data were performed to investigate the yearly trends, and a two-sided test with P < 0.05 was considered statistically significant. The 38090 CP patients comprised 23280 males and 14810 females. The mean age of patients at CP diagnosis was 57.83 years, with male patients (55.87 years) being younger than female patients (60.11 years) (P < 0.001). The mean incidence rate of CP during the study period was 6.81 per 100000 person-years, and the incidence of CP increased each year, from 4.03 per 100000 person-years in 2015 to 8.27 per 100000 person-years in 2021 (P < 0.001). The point prevalence rate of CP in 2021 was 45.52 per 100000 individuals for the total population, with rates of 55.04 per 100000 individuals for men and 35.78 per 100000 individuals for women (P < 0.001). Individuals aged 65 years or older had the highest prevalence of CP (113.38 per 100000 individuals) (P < 0.001). Diabetes (26.32%) was the most common comorbidity in CP patients. The number of CP-related hospitalizations increased from 3739 in 2015 to 11009 in 2021. The total costs for CP-related hospitalizations for CP patients over the study period were 667.96 million yuan, with an average of 17538 yuan per patient. The yearly incidence of CP is increasing, and the overall CP hospitalization cost has increased by 1.4 times during the last 7 years, indicating that CP remains a heavy health burden.


Stringlike clusters and cooperative interlayer permeation in smectic liquid crystals formed by colloidal rods.
Using simulations of hard rods in smectic-A states, we find stringlike clusters of up to 10 interlayer rods exhibiting dynamic cooperativity. We also find non-gaussian diffusion and heterogeneous dynamics due to the equilibrium periodic smectic density profiles, which give rise to permanent barriers for layer-to-layer diffusion. This relaxation behavior is surprisingly similar to that of nonequilibrium supercooled liquids, although there the particles are trapped in transient (instead of permanent) cages.


Are pediatric emergency medicine training programs meeting their goals and objectives? A self-assessment of individuals completing fellowship training in 1993.
The purpose of this study was to evaluate the overall training experience of those individuals completing fellowships in pediatric emergency medicine. Specific attention was given to the technical skills portion of training as set forth by the American Academy of Pediatrics Curriculum Committee on Pediatric Emergency Medicine. We surveyed those individuals completing their second year of fellowship training in pediatric emergency medicine. The questionnaire incorporated a self-assessment of the technical skills portion of the Subcommittee on Pediatric Emergency Medicine's most recent curriculum statement. It also contained several questions designed to evaluate the overall training experience. Eighty percent of respondents completing the self-assessment questionnaire rated their overall experience as favorable, whereas those who rated it unfavorable stressed a lack of training in research and teaching. Ninety-two percent of respondents felt they had a good clinical experience, but 80% expressed a need for further training in administration, 74% in research, and 46% in teaching. Although the majority claimed to be comfortable with most technical skills, several skills, including lifesaving procedures such as external pacing, peritoneal lavage, pericardiocentesis, shunt tap, airway foreign body removal, and needle cricothyrotomy, posed a significant degree of discomfort.


Professional indemnity insurance: the NMC and Bar Council requirements.
In 2004, the Nursing and Midwifery Council (NMC) produced an updated version of its Code of Professional Conduct, entitled The NMC Code of Professional Conduct: Standards for Conduct, Performance and Ethics (2004). In part the aim of this latest version was to include for the first time certain groups of nurses. Specialist community public health nurses are named whereas the previous version (2002) referred to nurses and midwives only. However, the updated version also incorporates a new section--paragraph 9--which concentrates the registrant's mind towards the issue of insuring their practice. This article discusses the ramifications of this addition.


Human liver transplantation: analysis of data on 540 patients from four centers.
The results of liver transplantation in a total of 540 patients from four centers in the United States and Western Europe have been collated. Twenty-five per cent of all transplants were performed for neoplastic disease. One- and 3-year survivals for this group were approximately 26 and 12% overall, and survival differed little for patients transplanted before and after January 1, 1980. Among the 44% of patients transplanted for endstage cirrhosis, 3-year survival was lowest for patients with alcoholic cirrhosis (20%). Three-year survival was greater for patients with nonalcoholic cirrhosis (29% overall), did not differ markedly among the various subtypes, and was greater for patients transplanted after January 1, 1980 (42%), as compared with before (22%). Patients with biliary atresia, sclerosing cholangitis, and metabolic and miscellaneous disorders constituted the remaining 30% of patients; 3-year survival varied from about 20 to 44% overall for the various subgroups, with a consistent trend toward improved survival among patients transplanted after January 1, 1980. The use of cyclosporin may not wholly explain this improved survival among more recently transplanted patients. Quality of life for transplant recipients surviving at least 3 months, as judged by a limited amount of data regarding time-in-hospital and functional status, appears to be good.


Oxidative stress contributes to orthopedic trauma-induced acute kidney injury in obese rats.
After trauma, obese patients have an increased risk of developing acute kidney injury (AKI). We have demonstrated that obese Zucker (OZ) rats, but not lean Zucker (LZ) rats, develop AKI 24 h after orthopedic trauma. ROS have been implicated in the pathophysiology of AKI in models of critical illness. However, the contribution of ROS to trauma-induced AKI in the setting of obesity has not been determined. We hypothesized that AKI in OZ rats after trauma is mediated by increased oxidative stress. Male LZ and OZ rats were divided into control and trauma groups, with a subset receiving treatment after trauma with the antioxidant apocynin (50 mg/kg ip, 2 mM in drinking water). The day after trauma, glomerular filtration rate, plasma creatinine, urine kidney injury molecule-1, and albumin excretion as well as renal oxidant and antioxidant activity were measured. After trauma, compared with LZ rats, OZ rats exhibited a significant decrease in glomerular filtration rate along with significant increases in plasma creatinine and urine kidney injury molecule-1 and albumin excretion. Additionally, oxidative stress was significantly increased in OZ rats, as evidenced by increased renal NADPH oxidase activity and urine lipid peroxidation products (thiobarbituric acid-reactive substances), and OZ rats also had suppressed renal superoxide dismutase activity. Apocynin treatment significantly decreased oxidative stress and AKI in OZ rats but had minimal effects in LZ rats. These results suggest that ROS play an important role in AKI in OZ rats after traumatic injury and that ROS may be a potential future therapeutic target in the obese after trauma.


Temperature effect on cephalothin sensitivity of methicillin-resistant Staphylococcus aureus.
Nineteen methicillin-resistant Staphylococcus aureus isolates from clinical specimens were tested for cephalothin sensitivity by disk diffusion and tube-dilution methods using incubation temperatures of 35 C and 30 C. Resistant colonies were observed to grow within the zones of antibiotic inhibition for 17 of the 19 isolates at 30 C but not at 35 C incubation. Twenty control strains known to be methicillin-sensitive did not show these resistant colonies at 30 C. Five of the methicillin-resistant isolates were sensitive, one of intermediate sensitivity to cephalothin, and the rest were resistent by tube-dilution testing at 35 C. At 30 C, however, two isolates were of intermediate sensitivity, and the rest were resistant to cephalothin by tube-dilution testing. These observations strongly suggest that the 30 C incubation temperature is more reliable in detecting in-vitro resistance of methicillin-resistant strains of Staphylococcus aureus to cephalothin in agar as well as in liquid media.


Novel Therapeutic Approaches and Targets for the Treatment of Neutrophilic Dermatoses, Management of Patients with Neutrophilic Dermatoses and Future Directions in the Era of Biologic Treatment.
Neutrophilic dermatoses are a heterogeneous group of inflammatory skin disorders characterized by the presence of a sterile, predominantly neutrophilic infiltrate on histopathology. Universally accepted and validated guidelines for the management of neutrophilic dermatoses do not exist, also given the paucity of randomized controlled study and high-quality data. However, the literature on the effective use of biologic therapies is rapidly expanding. This article reviews the epidemiology, clinical characteristics, histopathologic features, and management of pyoderma gangrenosum as well as Sweet's syndrome, sub-corneal pustular dermatoses and bowel-associated dermatosis arthritis syndrome. The use of biologic agents, including tumor necrosis factor α-inhibitors, anti-IL1, anti-IL-17, and IL-23 are discussed in detail.


Solubilization of peroxidase from porcine thyroids and characterization by photoaffinity labelling.
Peroxidase was solubilized without proteolysis from porcine thyroid particulate fraction with the nonionic detergent, 1-O-n-octyl-beta-D-glucopyranoside. The enzyme was able to catalyze the oxidation of guaiacol and the iodination of bovine serum albumin (33 atoms of iodine per molecule protein). Binding studies performed with the partially purified enzyme indicated that the substrates thyroxine (T4) and tyrosine compete for the same binding site on the enzyme. Dissociation constants of 0.9 nM and 0.5 nM were found for T4 and tyrosine, respectively. After photoaffinity labelling with underivatized 125I-labelled T4, gel chromatography on Sephacryl S-1000 revealed a relative molecular weight of about 100 000 for the solubilized enzyme. The peroxidase activity and haem-absorbance peak coeluted from the Sephacryl S-1000 column. SDS-polyacrylamide gel electrophoresis under reducing conditions indicated two major radiolabelled polypeptides, Mr 83 000 and Mr 42 600, as well as a smaller peak at Mr 15 400. The 15 400 molecular weight species is probably not part of the peroxidase complex, since it could partially be removed by Sephadex G-25 prechromatography . Further analyses confirmed that the partially purified enzyme is a haemoprotein absorbing maximally at 412 nm. The Soret band is shifted to 423 nm by reducing agents and the haem-cyanide complex has a maximum absorbance at 416 nm.


Presence of the Dr receptor in normal human tissues and its possible role in the pathogenesis of ascending urinary tract infection.
The Dr hemagglutinin of uropathogenic Escherichia coli recognizes the Dra blood group antigen, a component of the IFC or Cromer-related blood group complex. The present report used the Dr hemagglutinin to demonstrate location of the Dr receptor in selected human tissues and to evaluate the possible use of this lectin as a tissue marker recognizing sites sensitive for bacterial colonization. It was found that the Dr receptor was expressed in different parts of the digestive, urinary, genital, and respiratory tracts, and skin. Intense staining by Dr hemagglutinin was shown in colonic, bronchial, and endometrial glands, and skin eccrine sweat glands. Structures of the urinary tract showing strong fluorescence were renal tubular basement membrane, Bowmans' capsule, and transitional epithelium. The role of Dra antigen as receptor for adhesion for Dr-positive E. coli in ascending colonization of urinary tract and the possible importance of Dra in human pathology is discussed.


Targeting multiple signal transduction pathways in lung cancer.
Growth factor signals are propagated from the cell surface to intracellular processes that control critical functions such as growth, differentiation, angiogenesis, and inhibition of apoptosis via sequential kinase signaling. These kinases are receptor kinases, which are transmembrane proteins such as epidermal growth factor receptor or cytoplasmic kinases such as Src kinase. In malignancies, these signaling pathways are often exploited to optimize tumor growth and metastasis. Thus, they represent attractive targets for cancer therapy. This review will summarize current knowledge of the small-molecule multiple-kinase inhibitors in lung cancer therapy. These inhibitors generally hinder the phosphorylation of several protein kinases of membrane receptors, such as vascular endothelial growth factor receptors, platelet-derived growth factor receptors, the human epidermal growth factor receptor family, and cytoplasmic receptors such as c-Kit, Raf kinase, and FLT3. These inhibitors include ZD6474, SU11248, AEE 788, sorafenib, vatalanib, and AG-013736.


Perfluorooctane sulfonic acid, a persistent organic pollutant, inhibits iodide accumulation by thyroid follicular cells in vitro.
Poly- and perfluoroalkyl substances (PFAS) are a class of endocrine disrupting chemicals (EDCs) reported to alter thyroid function. Iodide uptake by thyroid follicular cells, an early step in the synthesis of thyroid hormones, is a potential target for thyroid disruption by EDCs. The aim of the present study was to evaluate the acute effects of perfluorooctane sulfonic acid (PFOS) and perfluorooctane carboxylic acid (PFOA), two of the most abundant PFAS in the environment, on iodide transport by thyroid follicular cells in vitro. Dynamic changes in intracellular iodide concentration were monitored by live cell imaging using YFP-H148Q/I152, a genetically encoded fluorescent iodide biosensor. PFOS, but not PFOA, acutely and reversibly inhibited iodide accumulation by FRTL-5 thyrocytes, as well as by HEK-293 cells transiently expressing the Sodium Iodide Symporter (NIS). PFOS prevented NIS-mediated iodide uptake and reduced intracellular iodide concentration in iodide-containing cells, mimicking the effect of the NIS inhibitor perchlorate. PFOS did not affect iodide efflux from thyroid cells. The results of this study suggest that disruption of iodide homeostasis in thyroid cells may be a potential mechanism for anti-thyroid health effects of PFOS. The study also confirms the utility of the YFP-H148Q/I152 cell-based assay to screen environmental PFAS, and other EDCs, for anti-thyroid activity.


Thoracic radiation therapy and suitability of internal thoracic arteries for myocardial revascularization.
Myocardial revascularization using internal thoracic arteries (ITAs) has been associated with superior clinical outcome. This study addresses the question of whether internal mammary arteries are unsuitable for grafting due to radiation-based damage in patients with history of thoracic radiation therapy. We review our experience in this subset of surgical candidates. Forty-nine patients undergoing elective coronary artery bypass grafting with use of at least one ITA were enrolled and matched to 49 comparable nonirradiated individuals by propensity scoring system. Preoperative and postoperative data were collected and compared. A 18-month clinical follow-up was performed. Intraoperative mammary artery flow was assessed by transthoracic Doppler echocardiography probe, and there was no significant difference between irradiated and nonirradiated individuals (36 +/- 8.3 mL/min vs 39 +/- 7.2 mL/min, p = 0.15). The two study groups were also comparable in terms of survival (overall mortality, 2%) and recurrence of angina and perfusion defect at control stress perfusion nuclear scan (p = 0.99 and p = 0.77, respectively). One arterial graft showed stenosis at postoperative angiography. The dose of radiation therapy administered did not correlate with graft flow values after anastomosis. Our data suggest that the use of a monolateral or bilateral ITA is not associated with early graft failure in patients with history of chest/mediastinal irradiation. Skeletonization harvesting technique might be recommended because of the frequent presence of fibrous tissue around the in situ vessel. Arterial graft stenosis in thorax-irradiated patients should be attributed to the primary atherosclerotic disease rather than to irradiation itself.


Bacterial lipopolysaccharides stimulate production of XCL1, a calcium-dependent lipopolysaccharide-binding serum lectin, in Xenopus laevis.
Xenopus laevis serum lectin XCL1 is a newly identified molecule of the XCGL (or X-lectin) family, a unique group of Ca(2+)-dependent lectins that have a fibrinogen-like domain. The XCL1 protein was purified from lipopolysaccharide (LPS)-stimulated frog sera by sequential affinity chromatography on heparin-acrylic beads and galactose-Sepharose. XCL1 comprises multiple oligomeric proteins consisting of 37-kDa subunit polypeptides, as revealed by sodium dodecyl sulfate-polyacrylamide electrophoresis (SDS-PAGE) and Western blot analyses using the monoclonal antibody (mAb) produced against the recombinant XCL1 polypeptide. In the presence of Ca(2+), the protein bound to Escherichia coli, Staphylococcus aureus, LPS and galactose and the bound XCL1 was competitively eluted using ribose and xylose, and the elution was as efficient as that using EDTA, whereas elution using hexoses, GalNAc or GlcNAc was less effective. In reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analyses, XCL1 expression was ubiquitously detected in frog tissues, with relatively high levels in hematopoietic tissues including the spleen, liver and kidney. Intraperitoneal injection of E. coli, S. aureus or 100-300μg S-type LPS from various bacteria induced several-fold increases in serum XCL1 concentrations on day 3, and the elevated levels retained up to day 12. It also caused a remarkable increase of the splenic XCL1 expression on day 3, followed by a rapid decline to nearly nonstimulated control levels by day 7. The R-type LPS with shortened polysaccharide chains was less effective in inducing the serum XCL1 response, indicating that the sugar chains of LPS were important, if not essential, for the stimulation of XCL1 production. These results suggest that XCL1 is a pathogen recognition molecule involved in antimicrobial innate immunity in Xenopus.


Utilization of sludge in building material.
Several thermal solidification processes have been developed mainly in Japan. They are lightweight aggregates, brick, interlocking tile, char, and slag. A full-scale plant of them has been successfully operated for more than 10 years. The quality of the end products is better than the traditional ones. They are all substitutive to existing ones. The Japanese experience proves that all the processes are technically feasible, but not economically. Their manufacturing cost is always higher than market price. In addition, they consume large amounts of energy. However, if they are identified for a process of sludge disposal, all of them are worth considering for a big city where there is no place for the sludge to go. The end products can be reused inside the city. A new alternative is "Portland cement". A Portland cement manufacturer accepts sewage sludge, if being paid some amount of money. An average payment is US$100 each 1,000 kg of ash or sludge cake. The Portland cement manufacturer accepts either cake or ash at the same price. It is about 50 to 30% of the energy cost of thermal solidification. The question is which is the better, dewatered cake or incinerated ash, for the Portland cement application. The answer is "it depends on the distance between the sewage plant and the Portland cement plant."


Monitoring neuromuscular transmission.
Persistent neuromuscular blockade is not uncommon in the recovery room and contributes to postoperative morbidity and possibly mortality. The use of neuromuscular monitoring and intermediate rather than long-acting neuromuscular blocking drugs have been shown to reduce its incidence. Clinically available methods of detecting and quantitating neuromuscular blockade are reviewed. The writer concludes that such monitoring should be routine when neuromuscular blocking drugs are used.


Efficacy and safety of magnetic resonance-guided focused ultrasound treatment for refractory chronic pain of medial knee osteoarthritis.
To elucidate the efficacy and safety of MRgFUS in the treatment for refractory pain derived from medial knee OA. Twenty patients with medial knee OA eligible for total knee arthroplasty were included in this prospective, non-controlled study (UMIN000010193). MRgFUS treatment was provided at the site of most severe tenderness around the medial femorotibial joint of each patient under real-time monitoring of temperature. The goal temperature of the targeted bone surface was 55 °C. Numerical rating scale (NRS) worst pain scores, Western Ontario and McMaster Universities osteoarthritis index (WOMAC) scores, EuroQol 5 dimensions index (EQ-5D) scores and pressure pain threshold (PPT) were evaluated before treatment (baseline) and at 1 week and 1, 3, 6, and 12 months post-treatment, respectively. Complications and adverse events were also assessed clinically and radiographically. Treatment response (a 50% or greater decrease in NRS score) was seen in 14 patients (14/19, 73.7%) at 12 months post-treatment. Mean NRS score rapidly decreased at 1 month after treatment and continued to decline through the following 12 months. At final follow-up, mean NRS score was 3.2 ± 1.9, significantly lower than at baseline (p = 0.0013). Mean WOMAC and EQ-5D scores also improved significantly from 1 month after treatment. Fifteen patients showed significant sustained increases in PPTs at the sites of most severe tenderness. No serious adverse events were observed during and after treatment. MRgFUS treatments were effective not only for managing refractory pain, but also for improving physical functions without adverse events in elderly patients with medial knee OA.


Sickness presenteeism: prevalence, attendance-pressure factors, and an outline of a model for research.
Sickness presence, that is, going to work despite judging one's current state of health as such that sick leave should be taken, was investigated in relation to different work and background factors. The study group comprised a random sample of 3136 persons who responded to a questionnaire administered in conjunction with Statistics Sweden's labor market survey. Logistic regressions were used in the analyses. Fifty-three percent reported the presence of sickness (on more than one occasion during the preceding year). Having a health problem is a strong determinant of sickness presenteeism (odds ratio = 3.32). For any given health status, there are certain other factors (personally and work-related demands) that impact on the risk of sickness presence, such as difficulties in staff replacement, time pressure, insufficient resources, and poor personal financial situation. The study has identified different types of determinants of sickness presence. Under the assumption that there is a connection between high sickness presence and risk for future ill health, the results may provide assistance in the formulation of preventive measures.


Persistent pulsatile release of glutamate induced by N-methyl-D-aspartate in neonatal rat hippocampal neurones.
1. Intracellular recordings were made from CA3 hippocampal neurones in vitro, during the first ten days of postnatal life and in adulthood. 2. Repeated (three to six) applications of N-methyl-D-aspartate (NMDA), in the presence of tetrodotoxin (TTX, 1-3 microM) and K+ channel blockers (tetraethylammonium chloride or bromide (TEA), 10 mM, and Cs+, 2 mM; or 4-aminopyridine (4-AP), 30-50 microM, and Cs+, 2 mM) induced in neonatal but not in adult neurones, periodic inward currents (PICs) which persisted for several hours after the last application of NMDA. 3. PICs which were due to non-specific cation currents had a frequency of 0.10 +/- 0.04 Hz, and an amplitude of 1.1 +/- 0.28 nA at holding potentials between -40 and -50 mV. The amplitude was a linear function of the membrane potential over the range -70 to +20 mV. They reversed polarity at 4.1 +/- 9.8 mV. 4. K+ channel blockers alone failed to induce PICs. Repeated (three to six) brief applications of high (12 mM) K+ medium also induced PICs. The frequency and amplitude of K(+)-induced PICs were however considerably reduced by concomitant applications of the NMDA receptor antagonist D,L-3-[( +/- )-2-carboxypiperazin-4-yl-]propyl-1-phosphonic acid (CPP, 20 microM). PICs could be induced also by caffeine (1 mM) in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (IBMX, 200 microM), TTX, TEA and Cs+. 5. Intracellular injection of the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) did not prevent the induction of PICs by NMDA. However PICs were blocked by removal of the external calcium and by the calcium antagonists cobalt (2 mM) and cadmium (50 microM). 6. In spite of blockade of propagated synaptic activity by TTX, PICs were synchronous in a pair of intracellularly recorded cells. They were also synchronous with extracellular spikes recorded by electrodes located into stratum pyramidal or stratum radiatum. 7. Once established, PICs were unaffected by NMDA receptor antagonists D(-)2-amino-5-phosphonovaleric acid (AP-5, 50 microM), CPP (20 microM) and the NMDA channel blocker ketamine (10 microM). They were reversibly blocked by the broad spectrum excitatory amino acid antagonist kynurenic acid (1 mM) and by the selective non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM). 8. It is concluded that PICs are generated in neonatal neurones by a synchronous, pulsatile release of glutamate from presynaptic nerve terminals, secondary to oscillations in intracellular calcium.


Enzyme-Site Blocking Combined with Optimization of Molecular Docking for Efficient Discovery of Potential Tyrosinase Specific Inhibitors from Puerariae lobatae Radix.
Enzyme inhibitors from natural products are becoming an attractive target for drug discovery and development; however, separating enzyme inhibitors from natural-product extracts is highly complex. In this study, we developed a strategy based on tyrosinase-site blocking ultrafiltration integrated with HPLC-QTOF-MS/MS and optimized molecular docking to screen tyrosinase inhibitors from Puerariae lobatae Radix extract. Under optimized ultrafiltration parameters, we previously used kojic acid, a known tyrosinase inhibitor, to block the tyrosinase active site in order to eliminate false-positive results. Using this strategy, puerarin, mirificin, daidzin and genistinc were successfully identified as potential ligands, and after systematic evaluation by several docking programs, the rank of the identified compounds predicted by computational docking was puerarin > mirificin > kojic acid > daidzin ≈ genistin, which agreed with the results of tyrosinase-inhibition assays. Structure-activity relationships indicated that C-glycosides showed better tyrosinase inhibition as compared with O-glycosides, with reduced inhibition achieved through the addition of glycosyl, which provides ideas about the screen of leading compounds and structural modification.


Weapons of mass destruction: biological.
Humans are susceptible to microbial infections from many sources. Biological warfare is the use of microbial forms of life to diminish the capabilities, disrupt the organization, and terrorize the noncombatant population of an adversary. This form of warfare has been used throughout history and has gained renewed interest with the current use of asymmetrical warfare. The civilized world has condemned its use by the implementation of treaties specifically against it. This is a brief review of some of the more easily used biological agents such as anthrax, plague, tularemia, Q fever, and smallpox. Each agent's biology, infectious route, and disease course will be discussed. Possible delivery systems and signs of outbreak will also be reviewed. There are few real neurosurgery-related implications in biological warfare. Neurosurgeons, as members and leaders of the healthcare community, must have the ability to recognize and initiate treatment when biological agents have been deployed. If there is widespread use of these inhumane agents, the neurosurgical community will not be able to practice the surgical art for which we have trained. New knowledge must be acquired so that we can best serve our patients and communities during times of extreme need.


Staff versus physician vaccine protocols for influenza immunization during pregnancy.
Pregnant women and their fetuses are known to be at increased risk for influenza-associated morbidity and mortality. The Advisory Committee on Immunization Practices and others have recommended influenza vaccination for all pregnant women at any gestational age, but vaccination rates for pregnant women remain low, near 45%. A retrospective chart review was performed at each of 4 sites during the 2010 to 2011 and 2011 to 2012 influenza seasons to examine the rates of flu vaccination offering and provision. The 4 separate clinics used for this study included 3 sites within a large university academic center and one private community practice. A nurse-driven (licensed vocational nurse or medical assistant staff) protocol for offering the flu vaccine was used at one site the first year of review and then used at 2 sites during the second year of review. We compared the vaccination offering and provision rates when nurse-driven or physician-driven protocols were used. With the nurse-driven protocol, the average offering rate was 99.7%, but of those who were offered the vaccine, only 38.2% received it, for a total effective vaccination rate of 38.1% of the patients. With the physician-driven protocol, 54.5% patients were offered the vaccine, and 70.7% of those received it, for an effective total vaccination rate of 38.5%. In this retrospective observational report, a nurse-driven protocol did not improve vaccination rates across varying practice sites. Thus, a simple protocol change to staff alone offering vaccine is unlikely to improve rates of maternal influenza vaccination. Additional studies looking at interventions to increase the number of pregnant women vaccinated against influenza are needed.


Life events and onset of a new phase in bipolar affective disorder.
There is an increasing focus on the impact of psychosocial factors and stressors on the course of bipolar affective disorder. The life event research has revealed many biases and the results are conflicting. In a prospective study we examined the relationship between life events and affective phases in a group of bipolar patients with a long duration of the disease. A group of patients with at least three admissions to hospital for bipolar disorder was followed every 3 months for up to 3 years. At each examination an evaluation of affective phase was made according to the Hamilton Depression Scale, the Newcastle Depression Rating Scale and the Bech-Rafaelsen Mania Rating Scale. Moreover, the patients were rated according to the Paykel Life Events Scale. Their current medical treatment was noted. Fifty-six patients (19 men and 37 women) were included in the study. Women experienced a significantly higher number of life events than men. In 21% of the 353 examinations of women, a new phase was preceded by life events whereas this was the case only in 8% of the 152 examinations of men. In 13% of the male examinations the patients were in a manic phase and in 5% in a depressive phase. In 5% of the female examinations the patients were in a manic phase and in 15% in a depressive phase. Half of the women's depressive phases were preceded by life events, but none of the depressive phases of men. The categories of life events preceding the depressive phases presented a significant overweight of somatic ill health and conflicts in the family. We found a gender difference in the course of bipolar affective disorder, as women had a significantly higher number of depressive episodes than men and men had a higher number of manic episodes than women. In bipolar patients with long duration of disease a significant number of depressive episodes in women were preceded by negative life events. Somatic health problems and conflicts in the family were significant factors preceding new depressive phases.


Pathological diagnosis of Coronavirus-related nephropathy: insight from postmortem studies.
A novel coronavirus pneumonia first occurred in Wuhan, China in early December 2019; the causative agent was identified and named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the World Health Organization (WHO), and the resulting disease termed coronavirus disease 2019 (COVID-19), according to the WHO coronavirus disease situation reports. This condition has spread rapidly all over the world and caused more than 125 million cases globally, with more than 2 million related deaths. Two previous outbreaks due to zoonotic coronaviruses have occurred in the last 20 years, namely the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV), causing high morbidity and mortality in human populations upon crossing the species barriers. SARS-CoV-2, SARS-CoV, and MERS-CoV show several similarities in pathogenicity and clinical presentations, the latter ranging from asymptomatic infection to severe acute respiratory distress syndrome (ARDS) and multiorgan impairment. Acute kidney injury (AKI) has been commonly reported in patients with CoV infections; therefore, pathological analysis of renal parenchyma in these patients has been carried out in order to improve knowledge about underlying mechanisms. Viral infection has been demonstrated in the renal tubular epithelial cells by electron microscopy (EM), immunohistochemistry (IHC), and in situ hybridization (ISH), although with conflicting results. Light microscopy (LM) changes have been described in the renal parenchyma primarily in the form of acute renal tubular damage, possibly due to direct viral cytopathic effect and immune-mediated mechanisms such as cytokine storm syndrome. In this review, we describe and discuss the spectrum of histological, ultrastructural, and molecular findings in SARS-CoV, MERS-CoV, and SARS-CoV-2-related renal pathology obtained from postmortem studies, as well as intrinsic limitations and pitfalls of current diagnostic techniques.


Identification of 86 candidates for small non-messenger RNAs from the archaeon Archaeoglobus fulgidus.
In a specialized cDNA library from the archaeon Archaeoglobus fulgidus we have identified a total of 86 different expressed RNA sequences potentially encoding previously uncharacterized small non-messenger RNA (snmRNA) species. Ten of these RNAs resemble eukaryotic small nucleolar RNAs, which guide rRNA 2'-O-methylations (C/D-box type) and pseudouridylations (H/ACA-box type). Thereby, we identified four candidates for H/ACA small RNAs in an archaeal species that are predicted to guide a total of six rRNA pseudouridylations. Furthermore, we have verified the presence of the six predicted pseudouridines experimentally. We demonstrate that 22 snmRNAs are transcribed from a family of short tandem repeats conserved in most archaeal genomes and shown previously to be potentially involved in replicon partitioning. In addition, four snmRNAs derived from the rRNA operon of A. fulgidus were identified and shown to be generated by a splicing/processing pathway of pre-rRNAs. The remaining 50 RNAs could not be assigned to a known class of snmRNAs because of the lack of known structure and/or sequence motifs. Regarding their location on the genome, only nine were located in intergenic regions, whereas 33 were complementary to an ORF, five were overlapping an ORF, and three were derived from the sense orientation within an ORF. Our study further supports the importance of snmRNAs in all three domains of life.


Autologous adipose tissue-derived stem cells for the treatment of complex perianal fistulas not associated with Crohn's disease: a phase II clinical trial for safety and efficacy.
Injection of adipose tissue-derived stem cells (ASCs) is a novel method for the treatment of complex perianal fistulas. We aimed to evaluate the safety and efficacy of ASCs in the treatment of complex anal fistulas not associated with Crohn's disease. A phase II clinical trial was performed comparing two different doses of ASCs (group 1: 1 × 107 cells/mL and group 2: 2 × 107 cells/mL). Eligible patients were administered an amount of ASCs proportional to the length of the fistula by injection into the submucosal layer surrounding the internal opening and inside of the fistula tract. ASCs at twice the initial concentration were administered if complete closure was not achieved within 8 weeks. The efficacy endpoint was the complete closure of fistulas 8 weeks after injection. Patients demonstrating complete closure at week 8 were subjected to follow-up for 6 months. Fifteen patients were injected with ASCs; thirteen completed the study. Complete closure was observed in 69.2% (9/13) of patients at 8 weeks. Three of five patients in group 1, and six of eight in group 2 displayed complete closure; no significant differences were observed between the groups. Six of nine patients who showed complete closure participated in additional follow-up; five (83.3%) showed persistent response at 6 months. No grade 3 or 4 adverse events (AEs) were observed; observed AEs were not related to ASC treatment. ASCs might be a good option for the treatment of complex perianal fistulas are not healed by conventional operative procedures.


Facile Synthesis of Nanosized Lithium-Ion-Conducting Solid Electrolyte Li1.4Al0.4Ti1.6(PO4)3 and Its Mechanical Nanocomposites with LiMn2O4 for Enhanced Cyclic Performance in Lithium Ion Batteries.
Nanoparticles of fast lithium-ion-conducting solid electrolyte Li1.4Al0.4Ti1.6(PO4)3 (LATP) are prepared by a modified citric-acid-assisted sol-gel method that involves a two-step heat treatment in which the dry gel is calcined first in argon and then in air. The obtained LATP exhibits smaller particle size (down to 40 nm) with a narrower size distribution and less aggregation than LATP prepared by a conventional sol-gel method because of a polymeric network that preserves during LATP crystallization. It has a high relative density of 97.0% and a high room-temperature conductivity of 5.9 × 10-4 S cm-1. The as-prepared superfine LATP is further used to composite with a spinel LiMn2O4 cathode in lithium ion batteries by simple grinding. This noncoating speckled layer over the LiMn2O4 particle surface has a minimal effect on the electronic conductivity of the electrode while offering excellent ionic conductivity. The cycling stability and rate capability of LiMn2O4 are greatly improved at both ambient and elevated temperatures. After 100 cycles at 25 and 55 °C, the capacity retentions are 96.0% and 89.0%, respectively, considerably higher than the values of pristine LiMn2O4 (61.0% at 25 °C; 51.5% at 55 °C) and mechanical LiMn2O4 composite with LATP made by a conventional sol-gel method (85.0% at 25 °C; 71.4% at 55 °C).


An examination of factors related to aspiration and silent aspiration in older adults requiring long-term care in rural Japan.
Swallowing disorders are a growing problem among the elderly in long-term care (LTC), and they can cause aspiration pneumonia. In order to detect swallowing disorders early, simple tools are needed to assess aspiration and silent aspiration (SA). To compile a sample of elderly people requiring LTC, and categorise them as having suspected aspiration and/or SA using simple screening tools. In addition, oral ability, severity of dementia, vital functions and nutritional status were compared in these groups. A total of 393 elderly people in LTC (89 men and 304 women; age ranging from 65 to 100 years) were included in the study. The modified water swallow test, cervical auscultation and cough test were used to assess swallowing function. The participants were categorised as having suspected aspiration and/or SA, and the following assessments were performed: (i) oral ability (lips function, tongue function, rinsing and gargling ability), (ii) dementia severity, (iii) vital functions and (iv) nutritional status. Suspected aspiration was apparent in 50.5% of patients, of which 24.0% had suspected SA. Those with suspected aspiration showed worsened oral ability, dementia severity, vital functions and nutritional status. Similarly, those with suspected SA showed worsened dementia severity, vital functions and nutritional status. Logistic regression analysis revealed that lip closure, lingual movement and rinsing ability were significantly associated with suspected aspiration. Dementia severity was the best predictor of suspected SA. Simple screening tools can be used to identify suspected aspiration and SA, which may facilitate early detection of aspiration pneumonia or swallowing disorder risk.


[What am I and (which are) the illusions of my self consciousness?].
Departing from Daniel Dennett's and Douglas Hofstadter's ideas, the present paper explores what the self and consciousness are and puts forward a possible explanation of their relationship with the brain. The paper deconstructs the illusions of my self and those of my consciousness, how they are produced and which the key elements to understand our reluctance to see ourselves as brains are. The self is considered a powerful myth but, at the same time, from a functionalist perspective, also an indispensable device in our daily life and in our explanations about others and about ourselves.


[Treatment of infra-vesical obstructions in neurologic bladders. 27 cases].
Of a total of 176 cases of spina bifida observed from a urological standpoint, we detected an infra-vesical obstruction in 27, the diagnosis being based upon urological findings alone: dysuria, residue and infection. The 11 boys had a disorder of the striated sphincter justifying sphincterotomy, the technique and results of which are discussed, in terms of symptoms and signs resulting from the obstruction, with respect to continence and the effects on the upper tract. 16 of our patients were female and the nature of the infra-vesical obstruction was far more uncertain. A disorder of the striated sphincter was present in the girl treated by a Y-V plasty of the anterior aspect of the bladder neck passing low down on the anterior aspect of the urethra. We also present results relating to residue, retention, dysuria, continence and the upper urinary tract. Overall, these results are too recent and difficult and no definite conclusions may be drawn.


Recognition and treatment of autonomic disturbances in Parkinson's disease.
Symptoms of dysautonomia are common in Parkinson's disease (PD), and almost all the functional autonomic subsystems can be involved in PD. However, they are still under-recognized in everyday clinical practice. Autonomic dysfunction can be observed in the early stages of PD, affect a substantial proportion of patients, impact quality of life and can also help in differential diagnosis. This review aims to provide an overview of the pathophysiology, clinical manifestations, relevant examination and treatment of cardiovascular, gastrointestinal, urogenital, thermoregulatory and pupil autonomic dysfunctions in Parkinson's disease.


Insulin-like growth factor binding protein 7 mediates glioma cell growth and migration.
Insulin-like growth factor binding protein 7 (IGFBP-7) is the only member of the IGFBP superfamily that binds strongly to insulin, suggesting that IGFBP-7 may have different functions from other IGFBPs. Unlike other IGFBPs, the expression and functions of IGFBP-7 in glioma tumors have not been reported. Using cDNA microarray analysis, we found that expression of IGFBP-7 correlated with the grade of glioma tumors and the overall patient survival. This finding was further validated by real-time reverse transcription-polymerase chain reaction and Western blot analysis. We used RNAi to examine the role of IGFBP-7 in glioma cells, inhibiting IGFBP-7 expression by short interfering RNA transfection. Cell proliferation was suppressed after IGFBP-7 expression was inhibited for 5 days, and glioma cell growth was stimulated consistently by the addition of recombinant IGFBP-7 protein. Moreover, glioma cell migration was attenuated by IGFBP-7 depletion but enhanced by IGFBP-7 overexpression and addition. Overexpression of AKT1 in IGFBP-7-overxpressed cells attenuated the IGFBP-7-promoted migration and further enhanced inhibition of IGFBP-7 depletion on the migration. Phosphorylation of AKT and Erk1/2 was also inversely regulated by IGFBP-7 expression. These two factors together suggest that IGFBP-7 can regulate glioma cell migration through the AKT-ERK pathway, thereby playing an important role in glioma growth and migration.


Strengthening the Effectiveness of National, State, and Local Efforts to Improve HPV Vaccination Coverage in the United States: Recommendations From the National Vaccine Advisory Committee.
In February 2018, recognizing the suboptimal rates of human papillomavirus (HPV) vaccination in the United States, the assistant secretary for health of the US Department of Health and Human Services charged the National Vaccine Advisory Committee (NVAC) with providing recommendations on how to strengthen the effectiveness of national, state, and local efforts to improve HPV vaccination coverage rates. In the same month, the NVAC established the HPV Vaccination Implementation Working Group and assigned it to develop these recommendations. The working group sought advice from federal and nonfederal partners. This NVAC report recommends ways to improve HPV vaccination coverage rates by focusing on 4 areas of activity: (1) identifying additional national partners, (2) guiding coalition building for states, (3) engaging integrated health care delivery networks, and (4) addressing provider needs in rural areas.


Hormonal control of collagen metabolism--Part I.
The collagens are a group of the connective tissue proteins widely distributed in human and animal body. The collagens together with other components of the tissue form a complex regulatory system, and are subject to hormonal control. The present paper reviews the effect of thyroid hormone and thyroid-stimulating hormone (thyrotropin) on collagen. Thyroid hormone influences collagen biosynthesis and degradation, and this effect is responsible for various pathophysiological phenomena, including alterations in urinary excretion of hydroxyproline and hydroxylysine, hyperthyroid acropachy, pretibial myxedema, impaired wound repair and other fibrosis-associated processes as well as a tadpole tail resorption in amphibians. Thyrotropin also directly affects the connective tissue, and is responsible for exophthalmos caused by acumulation of certain components of the tissue in retrobulbar space. Collagen fibres are present in the thyroid gland, and take part in the embryogenesis of the gland.


Rounded and velvety epidermal naevus, report of a verrucous form in axillary location.
Rounded and velvety epidermal naevus, naevoid acanthosis nigricans, also called the acanthosis nigricans form of epidermal naevus is an extremely rare entity, with fewer than 15 cases described in the literature. We report the case of a 23-year-old woman with asymptomatic velvety verrucous plaques on her left axilla starting at the age of 14. As far as we know this is the first case of such a verrucous form with only axillar involvement of naevoid acanthosis nigricans. We report this rare case, and we make a brief review of the clinical pathophysiology and treatment of this uncommon tumour.


Effective combination therapies in preclinical endocrine resistant breast cancer models harboring ER mutations.
Although endocrine therapy is successfully used to treat patients with estrogen receptor (ER) positive breast cancer, a substantial proportion of this population will relapse. Several mechanisms of acquired resistance have been described including activation of the mTOR pathway, increased activity of CDK4 and activating mutations in ER. Using a patient derived xenograft model harboring a common activating ER ligand binding domain mutation (D538G), we evaluated several combinatorial strategies using the selective estrogen receptor degrader (SERD) fulvestrant in combination with chromatin modifying agents, and CDK4/6 and mTOR inhibitors. In this model, fulvestrant binds WT and MT ER, reduces ER protein levels, and downregulated ER target gene expression. Addition of JQ1 or vorinostat to fulvestrant resulted in tumor regression (41% and 22% regression, respectively) though no efficacy was seen when either agent was given alone. Interestingly, although the CDK4/6 inhibitor palbociclib and mTOR inhibitor everolimus were efficacious as monotherapies, long-term delayed tumor growth was only observed when co-administered with fulvestrant. This observation was consistent with a greater inhibition of compensatory signaling when palbociclib and everolimus were co-dosed with fulvestrant. The addition of fulvestrant to JQ1, vorinostat, everolimus and palbociclib also significantly reduced lung metastatic burden as compared to monotherapy. The combination potential of fulvestrant with palbociclib or everolimus were confirmed in an MCF7 CRISPR model harboring the Y537S ER activating mutation. Taken together, these data suggest that fulvestrant may have an important role in the treatment of ER positive breast cancer with acquired ER mutations.


Mechanism of nonlinear flow pattern selection in moderately non-Boussinesq mixed convection.
Nonlinear (non-Boussinesq) variations in fluid's density, viscosity, and thermal conductivity caused by a large temperature gradient in a flow domain lead to a wide variety of instability phenomena in mixed convection channel flow of a simple gas such as air. It is known that in strongly nonisothermal flows, the instabilities and the resulting flow patterns are caused by competing buoyancy and shear effects [see S. A. Suslov and S. Paolucci, J. Fluid Mech. 302, 91 (1995)]. However, as is the case in the Boussinesq limit of small temperature gradients, in moderately non-Boussinesq regimes, only a shear instability mechanism is active. Yet in contrast to Boussinesq flows, multiple instability modes are still detected. By reducing the system of full governing Navier-Stokes equations to a dynamical system of coupled Landau-type disturbance amplitude equations we compute a comprehensive parametric map of various shear-driven instabilities observed in a representative moderately non-Boussinesq regime. Subsequently, we analyze nonlinear interaction of unstable modes and reveal physical reasons for their appearance.


Nasopharyngeal profile and velopharyngeal valve mechanism.
Proper management of velopharyngeal insufficiency requires an understanding of normal velopharyngeal anatomy and function. The present cephalometric study correlates the nasopharyngeal profile at rest with velopharyngeal function as observed by nasendoscopy and fluorographic and videofluoroscopic studies. Fifty-two normal individuals and 23 patients with insufficient velopharyngeal valves were examined. A correlation was found between nasopharyngeal profiles at rest and the closure patterns of the velopharyngeal valve. It was found that when existent, Passavant's ridge is subsequently formed where thick soft tissue corresponding to the superior constrictor muscle is found beneath the mucosa of the posterior pharyngeal wall at rest. Our conclusion is that Passavant's ridge is formed by the superior constrictor. The present study represents additional confirmation that differences in velopharyngeal closure patterns are the result of differences in anatomy. A biomechanical model of velopharyngeal valving is presented based on individual spatial muscular orientation and the hierarchical recruitment of the velopharyngeal muscles. This recruitment is progressive and is dependent on the effort required to achieve tighter velopharyngeal sealing.


Osteitis fibrosa: treatment trends.
Renal osteodystrophy is frequently seen in patients with end stage renal disease. Osteitis fibrosa associated with secondary hyperparathyroidism is often diagnosed. Treatment options vary based on disease severity. Individual patient considerations need to be addressed to determine the best therapeutic plan. Medical management with calcitriol, dietary modifications, and administration of phosphate binders continues to be the best treatment for most patients. Parathyroidectomy should be reserved for patients with complications related to severe irreversible hyperparathyroidism and/or failure of medical management. Total resection of all parathyroid tissue with or without autotransplant is the most common surgery for hyperparathyroid bone disease.


Quantitative comparison of wear debris from UHMWPE that has and has not been sterilised by gamma irradiation.
Ultra-high-molecular-weight polyethylene (UHMWPE) components for total joint replacement generate wear particles which cause adverse biological tissue reactions leading to osteolysis and loosening. Sterilisation of UHMWPE components by gamma irradiation in air causes chain scissions which initiate a long-term oxidative process that degrades the chemical and mechanical properties of the polyethylene. Using a tri-pin-on-disc tribometer we studied the effect of ageing for ten years after gamma irradiation in air on the volumetric wear, particle size distribution and the number of particles produced by UHMWPE when sliding against a stainless-steel counterface. The aged and irradiated material produced six times more volumetric wear and 34 times more wear particles per unit load per unit sliding distance than non-sterilised UHMWPE. Our findings indicate that oxidative degradation of polyethylene after gamma irradiation in air with ageing produces more wear.


Liposome-catalyzed unfolding of acetylcholinesterase from Bungarus fasciatus.
The kinetics of thermal inactivation of acetylcholinesterase from the venom of the snake, Bungarus fasciatus, were studied at 45-54 degrees C. An Arrhenius plot reveals an activation energy of 113 kcal/mol. The thermally denatured enzyme displays the spectroscopic characteristics of a partially unfolded 'molten globule' state. The rate of thermal denaturation is greatly enhanced in the presence of unilamellar vesicles of dimyristoylphosphatidylcholine, the energy barrier for the transition being lowered from 113 to 52 kcal/mol. In contrast to our findings for partially unfolded Torpedo californica acetylcholinesterase [Shin et al. (1997) Proc. Natl. Acad. Sci. U.S.A. 94, 2848-2852], the thermally denatured snake enzyme does not remain bound to the liposomes but is released after unfolding and subsequently aggregates. The liposomes thus serve as catalysts for unfolding of the snake enzyme, and its rate of unfolding in the presence of liposomes can be described by the Michaelis-Menten equation (Km = 8 x 10(-7) M). The phospholipid vesicles display a catalytic turnover number of kcat approximately 4 min-1, assuming 15 binding sites per vesicle for the snake acetylcholinesterase.


Thapsigargin induces mitochondrial dysfunction and apoptosis in the mastocytoma P815 cell line and in mouse thymocytes.
Thapsigargin is a plant-derived inhibitor of the endoplasmic reticulum Ca(2+)-ATPase.Treatment with thapsigargin leads to a rapid, large and prolonged increase in the intracellular calcium ion concentration ([Ca(2+)](i)). Previously thapsigargin has been shown to inhibit proliferation and induce apoptosis. Here we report the results of thapsigargin treatment in thymocytes harvested from 10-day-old mice and in the P815 mastocytoma cell line. In thapsigargin-treated cells we observed enlarged mitochondria with disrupted cristae structure. These mitochondria closely resembled those observed after the induction of phase transition. To determine if the mitochondria were functioning normally the cells were stained with rhodamine 123 (R123) and analysed with flow cytometry. After thapsigargin treatment the R123 staining decreased, indicative of a loss of mitochondrial membrane potential. Furthermore intracellular ATP concentrations were also found to be reduced in cells treated with thapsigargin. Taken together these results indicate an increase in the [Ca(2+)](i) caused by thapsigargin treatment results in dysfunctional mitochondria and reduced ATP. We propose that this decrease in the concentration of ATP provokes the onset of thapsigargin-induced apoptosis. To investigate the effect of thapsigargin treatment on the cell cycle, rapidly cycling P815 cells were sorted into populations enriched for either G(0)/G(1) or S/G(2)/M phases, and these populations were then treated with thapsigargin. Thapsigargin treatment induced a cell cycle block before S phase. We propose that the block in the cell cycle induced by thapsigargin was a result of the decreased intracellular ATP concentration interfering with the energy requiring processes of DNA replication. The block could also be related to the high intracellular calcium ion concentration that would interfere with the subtle calcium transients involved in the cell's preparations for replication and mitosis. Apoptosis occurred to an equal extent in both populations of cells.


Antioxidant and Anticholinesterase Activities of Essential Oils of Cinnamomum griffithii and C. macrocarpum.
The essential oils of Cinnamomum griffithii and C. macrocarpum were analyzed by GC and GC-MS and evaluated for their antioxidant and anticholinesterase activities. The essential oils of leaf and bark of C. grffithii were characterized by the presence of 30 components, with methyl eugenol (38.5-43.8%) as the major component. A total of 11 components were characterized in.the leaf and bark of C. macrocarpum essential oil with the most abundant component was safrole (54.5-59.5%). The bark oil of C. griffithii demonstrated significant activity on DPPH (IC50 73.4 microg/mL) and a high phenolic content (192.0%), while the leaf oil inhibited oxidation of β-carotene/linoleic acid with an inhibition value of 65.5 μg/mL. Acetylcholinesterase and butyrylcholinesterase inhibition were assessed and the results showed that C. macrocarpun bark oil exhibited significant activity with inhibition values of 55.8% and 66.1%, respectively at a concentration of 1 mg/mL.


[A case of rapidly fatal gastric cancer with disseminated carcinomatosis of the bone marrow].
A 50-year-old man underwent thorough examination for a chief complaint of melena. Gastric cancer and right kidney cancer were diagnosed. The gastric cancer was in the antrum, and poorly differentiated adenocarcinoma was diagnosed by biopsy. The right kidney cancer was diagnosed as clear cell carcinoma by computed tomography-guided biopsy. We performed right nephrectomy and distal gastrectomy. The final diagnosis of the gastric cancer was por2, pT3( ss), pN3b( 46/ 61), M0, pStage IIIB, R0, and that of the kidney cancer was clear cell carcinoma, pT3a, pN0, pM0. The patient reported lower back pain approximately 2 months after surgery. Several examinations revealed that the patient had multiple bone metastases, disseminated carcinomatosis of the bone marrow, and disseminated intravascular coagulation (DIC).We treated the bone metastasis with denosumab and palliative radiation therapy and the gastric cancer with weekly paclitaxel (PTX). The DIC subsided during the first course but recurred during the discontinuation period. We attempted additional trastuzumab treatment but did not achieve a curative effect, and the patient died. It is necessary to provide appropriate medical care while taking into consideration the possibility of disseminated carcinomatosis of the bone marrow in cases with a high likelihood of lymph node metastasis.


Genetic mutations linked to Parkinson's disease differentially control nucleolar activity in pre-symptomatic mouse models.
Genetic mutations underlying neurodegenerative disorders impair ribosomal DNA (rDNA) transcription suggesting that nucleolar dysfunction could be a novel pathomechanism in polyglutamine diseases and in certain forms of amyotrophic lateral sclerosis/frontotemporal dementia. Here, we investigated nucleolar activity in pre-symptomatic digenic models of Parkinson's disease (PD) that model the multifactorial aetiology of this disease. To this end, we analysed a novel mouse model mildly overexpressing mutant human α-synuclein (hA53T-SNCA) in a PTEN-induced kinase 1 (PINK1/PARK6) knockout background and mutant mice lacking both DJ-1 (also known as PARK7) and PINK1. We showed that overexpressed hA53T-SNCA localizes to the nucleolus. Moreover, these mutants show a progressive reduction of rDNA transcription linked to a reduced mouse lifespan. By contrast, rDNA transcription is preserved in DJ-1/PINK1 double knockout (DKO) mice. mRNA levels of the nucleolar transcription initiation factor 1A (TIF-IA, also known as RRN3) decrease in the substantia nigra of individuals with PD. Because loss of TIF-IA, as a tool to mimic nucleolar stress, increases oxidative stress and because DJ-1 and PINK1 mutations result in higher vulnerability to oxidative stress, we further explored the synergism between these PD-associated genes and impaired nucleolar function. By the conditional ablation of TIF-IA, we blocked ribosomal RNA (rRNA) synthesis in adult dopaminergic neurons in a DJ-1/PINK1 DKO background. However, the early phenotype of these triple knockout mice was similar to those mice exclusively lacking TIF-IA. These data sustain a model in which loss of DJ-1 and PINK1 does not impair nucleolar activity in a pre-symptomatic stage. This is the first study to analyse nucleolar function in digenic PD models. We can conclude that, at least in these models, the nucleolus is not as severely disrupted as previously shown in DA neurons from PD patients and neurotoxin-based PD mouse models. The results also show that the early increase in rDNA transcription and nucleolar integrity may represent specific homeostatic responses in these digenic pre-symptomatic PD models.


Cardiovascular effects of Althesin. Changes in systolic time intervals and peripheral tissue blood flow.
Systolic time intervals were studied and peripheral blood flow measurements made in twelve healthy patients before and after intravenous induction of anaesthesia with Althesin 0.05 ml per kg. The changes in systolic time intervals observed were considered to reflect the cardio-depressive properties of the drug. The reduction in peripheral blood flow which occurs in Althesin anaesthesia was confirmed. Measurement of systolic time intervals and peripheral blood flow constitute a simple and sensitive method for the evaluation of the effects of drugs on the cardiovascular system.


Maturation of a key resource - the germanium-68/gallium-68 generator: development and new insights.
(68)Ge/(68)Ga radionuclide generators have been investigated for almost fifty years, since the cyclotron-independent availability of positron emitting (68)Ga via the (68)Ge/(68)Ga system had always attracted researches working in basic nuclear chemistry as well as radiopharmaceutical chemistry. However, it took decades and generations of research (and researchers) to finally reach a level of (68)Ge/(68)Ga radionuclide generator designs adequate to the modern requirements of radiometal labelling chemistry. Nevertheless, most of the existing commercial generator systems address aspects of (68)Ge breakthrough and safe synthesis of (68)Ga radiopharmaceuticals by adopting eluate post-processing technologies. Among the strategies to purify (68)Ga eluates, the cation exchange based version is relevant in terms of purification efficiency. In addition, it offers more options towards further developments of (68)Ga radiopharmaceuticals. Today, one may expect that the (68)Ge/(68)Ga radionuclide generator systems could contribute to the clinical impact of nuclear medicine diagnoses for PET similar to the established (99)Mo/(99m)Tc generator system for SPECT. The exciting perspective for the (68)Ge/(68)Ga radionuclide generator system, in turn, asks for systematic chemical, radiochemical, technological and radiopharmaceutical efforts, to guarantee reliable, highly-efficient and medically approved (68)Ge/(68)Ga generator systems.


Comparison of GOME-2 UVA Satellite Data to Ground-Based UVA Measurements in South Africa.
Satellite estimates of surface ultraviolet A (UVA) (315-400 nm) from the Global Ozone Monitoring Experiment (GOME)-2 were compared to ground-based measurements at four stations in South Africa for 2015. The comparison of daily exposure and daily maximum irradiance was completed for all-sky and clear-sky conditions. There is a strong linear correlation between the satellite and ground-based data with a correlation coefficient (r) between 0.86 and 0.97 for all-sky conditions. However, at three of the stations the satellite data are underestimated compared to ground-based data with a mean bias error (MBE) between -8.7% and -20.6%. A seasonal analysis indicated that there is a link between the bias in ground-based and GOME-2 UVA and cloud fraction. Factors such as aerosols, surface albedo, altitude and data resolution may contribute to the underestimations found at the three sites. These results indicate that satellite estimates of surface UVA over South Africa do not exhibit the same behavior as other stations around the world and therefore require further validation.