Heterozygous mutations in the PALB2 hereditary breast cancer predisposition gene impact on the three‐dimensional nuclear organization of patient‐derived cell lines

PALB2/FANCN is a BRCA1‐ and BRCA2‐interacting Fanconi Anemia (FA) protein crucial for key BRCA2 genome caretaker functions. Heterozygous germline mutations in PALB2 predispose to breast cancer and biallelic mutations cause FA. FA proteins play a critical role in the telomere maintenance pathway, with telomeric shortening observed in FA cells. Less is known about telomere maintenance in the heterozygous state. Here, we investigate the roles of PALB2 heterozygous mutations in genomic instability, an important carcinogenesis precursor. Patient‐derived lymphoblastoid (LCL) and fibroblast (FCL) cell lines with monoallelic truncating PALB2 mutations were investigated using a combination of molecular imaging techniques including centromeric FISH, telomeric Q‐FISH and spectral karyotyping (SKY). Mitomycin C and Cisplatin sensitivity was assayed via cellular metabolism of WST‐1. The PALB2 c.229delT FCL showed increases in telomere counts associated with increased mean intensity compared with two wild‐type FCLs generated from first‐degree relatives (P =1.04E‐10 and P =9.68E‐15) and it showed evidence of chromosomal rearrangements. Significant differences in centromere distribution were observed in one of three PALB2 heterozygous FCLs analyzed when compared with PALB2 wild‐type, BRCA1 and BRCA2 heterozygous FCLs. No significant consistently increased sensitivity to Mitomycin C or Cisplatin was observed in LCLs. Our results are suggestive of an altered centromere distribution profile and a telomere instability phenotype. Together, these may indicate critical nuclear organization defects associated with the predisposition to transformation and early stage development of PALB2‐related cancers. © 2013 Wiley Periodicals, Inc.     

Scoping Review on Search Queries and Social Media for Disease Surveillance: A Chronology of Innovation

Background

The threat of a global pandemic posed by outbreaks of influenza H5N1 (1997) and Severe Acute Respiratory Syndrome (SARS, 2002), both diseases of zoonotic origin, provoked interest in improving early warning systems and reinforced the need for combining data from different sources. It led to the use of search query data from search engines such as Google and Yahoo! as an indicator of when and where influenza was occurring. This methodology has subsequently been extended to other diseases and has led to experimentation with new types of social media for disease surveillance.

Objective

The objective of this scoping review was to formally assess the current state of knowledge regarding the use of search queries and social media for disease surveillance in order to inform future work on early detection and more effective mitigation of the effects of foodborne illness.

Methods

Structured scoping review methods were used to identify, characterize, and evaluate all published primary research, expert review, and commentary articles regarding the use of social media in surveillance of infectious diseases from 2002-2011.

Results

Thirty-two primary research articles and 19 reviews and case studies were identified as relevant. Most relevant citations were peer-reviewed journal articles (29/32, 91%) published in 2010-11 (28/32, 88%) and reported use of a Google program for surveillance of influenza. Only four primary research articles investigated social media in the context of foodborne disease or gastroenteritis. Most authors (21/32 articles, 66%) reported that social media-based surveillance had comparable performance when compared to an existing surveillance program. The most commonly reported strengths of social media surveillance programs included their effectiveness (21/32, 66%) and rapid detection of disease (21/32, 66%). The most commonly reported weaknesses were the potential for false positive (16/32, 50%) and false negative (11/32, 34%) results. Most authors (24/32, 75%) recommended that social media programs should primarily be used to support existing surveillance programs.

Conclusions

The use of search queries and social media for disease surveillance are relatively recent phenomena (first reported in 2006). Both the tools themselves and the methodologies for exploiting them are evolving over time. While their accuracy, speed, and cost compare favorably with existing surveillance systems, the primary challenge is to refine the data signal by reducing surrounding noise. Further developments in digital disease surveillance have the potential to improve sensitivity and specificity, passively through advances in machine learning and actively through engagement of users. Adoption, even as supporting systems for existing surveillance, will entail a high level of familiarity with the tools and collaboration across jurisdictions.     

Pharmacokinetics of 4′-cyano-2′-deoxyguanosine,a novel nucleoside analog inhibitor of the resistant hepatitis B virus,in a rat model of chronic kidney disease

IntroductionThe novel nucleoside analog, 4′-cyano-2′-deoxyguanosine (CdG), possesses inhibitory activity against both the wild-type and resistant hepatitis B virus. Since the dosage of the currently available nucleoside analog preparations needs to be adjusted, depending on renal function, we investigated the effect of renal dysfunction on the pharmacokinetics of CdG in a rat model of chronic kidney disease (CKD).MethodsCKD model rats were either intravenously or orally administered CdG at a dose of 1 mg/kg. The concentration of CdG in plasma, organs (liver and kidney) and urine samples were determined by means of a UPLC system interfaced with a TOF-MS system.ResultsFollowing intravenous administration, the plasma retention of CdG was prolonged in CKD model rats compared to healthy rats. In addition, the clearance of CdG was well correlated with plasma creatinine levels in CKD model rats. Similar to the results for intravenous administration, the plasma concentration profiles of CdG after oral administration were also found to be much higher in CKD model rats than in healthy rats. However, the results for the organ distribution and urinary excretion of CdG, the profiles of which were similar to that of healthy rats, indicated that CdG did not accumulate to a significant extent in the body.ConclusionThe extent of renal dysfunction has a direct influence on the pharmacokinetics (plasma retention) of CdG without a significant accumulation, indicating that the dosage of CdG will be dependent on the extent of renal function. .     

Emotion regulation ability varies in relation to intrinsic functional brain architecture

This study investigated the neural basis of individual variation in emotion regulation, specifically the ability to reappraise negative stimuli so as to down-regulate negative affect. Brain functions in young adults were measured with functional Magnetic Resonance Imaging during three conditions: (i) attending to neutral pictures; (ii) attending to negative pictures and (iii) reappraising negative pictures. Resting-state functional connectivity was measured with amygdala and dorsolateral prefrontal cortical (DLPFC) seed regions frequently associated with emotion regulation. Participants reported more negative affect after attending to negative than neutral pictures, and less negative affect following reappraisal. Both attending to negative vs neutral pictures and reappraising vs attending to negative pictures yielded widespread activations that were significantly right-lateralized for attending to negative pictures and left-lateralized for reappraising negative pictures. Across participants, more successful reappraisal correlated with less trait anxiety and more positive daily emotion, greater activation in medial and lateral prefrontal regions, and lesser resting-state functional connectivity between (a) right amygdala and both medial prefrontal and posterior cingulate cortices, and (b) bilateral DLPFC and posterior visual cortices. The ability to regulate emotion, a source of resilience or of risk for distress, appears to vary in relation to differences in intrinsic functional brain architecture.     

复用医疗器械灭菌信息记录系统的开发与追溯效果评价

目的开发复用医疗器械灭菌信息记录系统,提高信息记录质量与可追溯性。方法在供应室管理系统基础上,按C/S结构应用Power Builder语言建立复用医疗器械灭菌信息记录系统,包括器械回收、清洗与包装、灭菌、发放、使用登记、跟踪查询模块。结果应用复用医疗器械灭菌信息记录系统后,灭菌物品记录时间、漏记录数及灭菌包可追溯率显著优于手工记录(均P0.01)。结论复用医疗器械灭菌信息记录系统可明显提高器械灭菌信息记录质量与可追溯性,进一步确保医疗安全。     

Expression change of Flk-2/Flt-3 on murine hematopoietic stem cells in an activating state

OBJECTIVE: The receptor tyrosine kinase Flk-2/Flt-3 (Flt-3) represents an important molecule involved in early hematopoiesis. Murine hematopoietic stem cells (HSCs) have been shown to be negative for the expression of Flt-3. We now present clear evidence for the expression change of Flt-3(-) HSCs in an activating state, and the reversibility of Flt-3 expression by HSCs in vivo. MATERIALS AND METHODS: Bone marrow cells isolated from Ly5.1 mice were sorted on the basis of Flt-3 expression and transplanted into lethally irradiated Ly5.2 recipients. After 24 weeks, peripheral blood was analyzed for donor contribution by flow cytometry. RESULTS: Although long-term engraftment was predominantly detected in Flt-3(-) populations as previously described, a 6-day cultivation of Lin(-/low)c-kit(+)Sca-1(+) Flt-3(-) bone marrow cells with stem cell factor and interleukin-11 resulted in the generation of Flt-3(+) HSCs with long-term engraftment capabilities. However, the Flt-3 ligand had no significant effect on self-renewal of the Flt-3(+) HSCs. Next, to examine reversible expression of this receptor molecule, Flt-3(+) cells converted in vitro from Ly5.1 Lin(-/low)c-kit(+)Sca-1(+) Flt-3(-) bone marrow cells were isolated and transplanted into Ly5.2 primary recipients. After 24 weeks, Ly5.1 Lin(-/low) bone marrow cells were again separated into Flt-3(-) and Flt-3(+) cells and retransplanted into Ly5.2 secondary recipients. The majority of donor HSCs with long-term engraftment capabilities were detected in the Flt-3(-) populations, indicating the reversion of Flt-3(+) to Flt-3(-) HSCs. CONCLUSIONS: These observations suggest that Flt-3 is a useful cell-surface marker of HSC activation and that this phenotypic change is reversible.     

Changes in energy metabolism after induction therapy in patients with severe or moderate ulcerative colitis

We investigated the changes in energy expenditure during induction therapy in patients with severe or moderate ulcerative colitis. Thirteen patients (10 men, 3 women; mean age, 36.5 years) with ulcerative colitis admitted to the Shiga University Hospital were enrolled in this study. We measured the resting energy expenditure and respiratory quotients of these patients before and after induction therapy with indirect calorimetry. We analyzed the changes of nutritional status and serum inflammatory cytokine levels and also evaluated the relationship between energy metabolism and disease activity by using the Seo index and Lichtiger index. The resting energy expenditure was 26.3 ± 3.8 kcal/kg/day in the active stage and significantly decreased to 23.5 ± 2.4 kcal/kg/day after induction therapy (p<0.01). The resting energy expenditure changed in parallel with the disease activity index and C-reactive protein and inflammatory cytokine levels. The respiratory quotient significantly increased after induction therapy. Thus, moderate to severe ulcerative colitis patients had a hyper-metabolic status, and the energy metabolism of these patients significantly changed after induction therapy. Therefore, we recommend that nutritional management with 30–34 kcal/kg/day (calculated as measured resting energy expenditure × activity factor, 1.3) may be optimal for hospitalized ulcerative colitis patients.     

护理干预对中老年人骨质疏松症的认知及自我管理疾病能力的影响

[目的]分析护理干预对中老年人骨质疏松症的认知及自我管理疾病能力的影响。[方法]80例骨质疏松症病人,按随机数字表法分为观察组和对照组,每组40例。观察组在药物治疗的基础上进行护理干预。对照组只进行药物治疗。比较两组治疗后新发骨折率、生活质量评分、生化检测结果等,并对疗效进行评价。[结果]观察组新发骨折率2.5%(1/40),对照组新发骨折率32.5%(13/40),差异有统计学意义(χ2=5.24,P <0.05)。两组治疗后生活质量评分、生化检测结果等比较差异有统计学意义(P <0.05),且观察组优于对照组。[结论]在药物治疗的基础上,护理干预对治疗中老年人骨质疏松症具有很高的安全性和有效性,能够缓解病人的痛苦和改善治疗效果,降低病人的就医成本。     

Variation of plantar pressure in Chinese diabetes mellitus

To investigate dynamic changes in plantar pressure in Chinese diabetes mellitus patients and to provide a basis for further preventing diabetic foot. This is a cross‐sectional investigation including 649 Chinese diabetes mellitus patients (diabetes group) and 808 “normal” Chinese persons (nondiabetes group) with normal blood glucose levels. All the subjects provided a complete medical history and underwent a physical examination and a 75‐g oral glucose tolerance test. All subjects walked barefoot with their usual gait, and their dynamic plantar forces were measured using the one‐step method with a plantar pressure measurement instrument; 5 measurements were performed for each foot. No significant differences were found in age, height, body weight, or body mass index between the two groups. The fasting blood glucose levels, plantar contact time, maximum force, pressure‐time integrals and force‐time integrals in the diabetes group were significantly higher than those in the nondiabetes group (p < 0.05). However, the maximum pressure was significantly higher in the nondiabetes group than in the diabetes group (p < 0.05). No difference was found in the contact areas between the two groups (p > 0.05). The maximum plantar force distributions were essentially the same, with the highest force found for the medial heel, followed by the medial forefoot and the first toe. The peak plantar pressure was located at the medial forefoot for the nondiabetes group and at the hallucis for the diabetes group. In the diabetes group, the momentum in each plantar region was higher than that in the nondiabetes group; this difference was especially apparent in the heel, the lateral forefoot and the hallucis. The dynamic plantar pressures in diabetic patients differ from those in nondiabetic people with increased maximum force and pressure, a different distribution pattern and significantly increased momentum, which may lead to the formation of foot ulcers.