Combined systemic and local morpholino treatment rescues the phenotype of the SMA Delta 7 mouse model

Spinal muscular atrophy (SMA) is a childhood fatal motor neuron disease caused by mutations in the Survival Motor Neuron 1 (SMN1) gene, currently without effective treatment. One possible therapeutic approach is the use of antisense oligonucleotides (ASOs) to redirect the splicing of a paralogous gene, SMN2, to increase the production of functional SMN protein. A range of ASOs with different chemical properties is suitable for these applications, including a morpholino (MO) variant, which has a particularly excellent safety, and efficacy profile. We used a 25- nt MO oligomer sequence against the ISS-N1 region of SMN2 (HSMN2Ex7D(-10-34)) with superior efficacy to previously described sequences also in transgenic SMA Δ7 mice. The combined local and systemic administration of MO (bare or conjugated to octa-guanidine) is necessary to increase full-length SMN expression, leading to robust neuropathological features improvement and survival rescue. Additionally, several snRNA levels that are dysregulated in SMA mice could be restored by MO treatment. These results demonstrate that MO therapy is efficacious and can result in phenotypic rescue. These data provide important insights for the development of therapeutic strategies in SMA patients.

Novel radiotherapy techniques for involved-field and involved-node treatment of mediastinal Hodgkin lymphoma: when should they be considered and which questions remain open?

PURPOSE Hodgkin lymphoma (HL) is a highly curable disease. Reducing late complications and second malignancies has become increasingly important. Radiotherapy target paradigms are currently changing and radiotherapy techniques are evolving rapidly. DESIGN This overview reports to what extent target volume reduction in involved-node (IN) and advanced radiotherapy techniques, such as intensity-modulated radiotherapy (IMRT) and proton therapy-compared with involved-field (IF) and 3D radiotherapy (3D-RT)- can reduce high doses to organs at risk (OAR) and examines the issues that still remain open. RESULTS Although no comparison of all available techniques on identical patient datasets exists, clear patterns emerge. Advanced dose-calculation algorithms (e.g., convolution-superposition/Monte Carlo) should be used in mediastinal HL. INRT consistently reduces treated volumes when compared with IFRT with the exact amount depending on the INRT definition. The number of patients that might significantly benefit from highly conformal techniques such as IMRT over 3D-RT regarding high-dose exposure to organs at risk (OAR) is smaller with INRT. The impact of larger volumes treated with low doses in advanced techniques is unclear. The type of IMRT used (static/rotational) is of minor importance. All advanced photon techniques result in similar potential benefits and disadvantages, therefore only the degree-of-modulation should be chosen based on individual treatment goals. Treatment in deep inspiration breath hold is being evaluated. Protons theoretically provide both excellent high-dose conformality and reduced integral dose. CONCLUSION Further reduction of treated volumes most effectively reduces OAR dose, most likely without disadvantages if the excellent control rates achieved currently are maintained. For both IFRT and INRT, the benefits of advanced radiotherapy techniques depend on the individual patient/target geometry. Their use should therefore be decided case by case with comparative treatment planning.

Effect of Combined Systemic and Local Morpholino Treatment on the Spinal Muscular Atrophy Δ7 Mouse Model Phenotype

BACKGROUND: Spinal muscular atrophy (SMA) is a fatal motor neuron disease of childhood that is caused by mutations in the SMN1 gene. Currently, no effective treatment is available. One possible therapeutic approach is the use of antisense oligos (ASOs) to redirect the splicing of the paralogous gene SMN2, thus increasing functional SMN protein production. Various ASOs with different chemical properties are suitable for these applications, including a morpholino oligomer (MO) variant with a particularly excellent safety and efficacy profile. OBJECTIVE: We investigated a 25-nt MO sequence targeting the negative intronic splicing silencer (ISS-N1) 10 to 34 region. METHODS: We administered a 25-nt MO sequence against the ISS-N1 region of SMN2 (HSMN2Ex7D[-10-34]) in the SMAΔ7 mouse model and evaluated the effect and neuropathologic phenotype. We tested different concentrations (from 2 to 24 nM) and delivery protocols (intracerebroventricular injection, systemic injection, or both). We evaluated the treatment efficacy regarding SMN levels, survival, neuromuscular phenotype, and neuropathologic features. RESULTS: We found that a 25-nt MO sequence against the ISS-N1 region of SMN2 (HSMN2Ex7D[-10-34]) exhibited superior efficacy in transgenic SMAΔ7 mice compared with previously described sequences. In our experiments, the combination of local and systemic administration of MO (bare or conjugated to octaguanidine) was the most effective approach for increasing full-length SMN expression, leading to robust improvement in neuropathologic features and survival. Moreover, we found that several small nuclear RNAs were deregulated in SMA mice and that their levels were restored by MO treatment. CONCLUSION: These results indicate that MO-mediated SMA therapy is efficacious and can result in phenotypic rescue, providing important insights for further development of ASO-based therapeutic strategies in SMA patients.

From Matterhorn to Mt Everest: empowering rescuers and improving medical care in Nepal.

This article describes a private initiative in which professional Swiss rescuers, based at the foot of the Matterhorn, trained Nepalese colleagues in advanced high altitude helicopter rescue and medical care techniques. What started as a limited program focused on mountain safety has rapidly developed into a comprehensive project to improve rescue and medical care in the Mt Everest area for both foreign travelers and the local Nepalese people.

Disclosing and reporting medical errors: Cross-sectional survey of Swiss anaesthesiologists.

BACKGROUND There is limited research on anaesthesiologists' attitudes and experiences regarding medical error communication, particularly concerning disclosing errors to patients. OBJECTIVE To characterise anaesthesiologists' attitudes and experiences regarding disclosing errors to patients and reporting errors within the hospital, and to examine factors influencing their willingness to disclose or report errors. DESIGN Cross-sectional survey. SETTING Switzerland's five university hospitals' departments of anaesthesia in 2012/2013. PARTICIPANTS Two hundred and eighty-one clinically active anaesthesiologists. MAIN OUTCOME MEASURES Anaesthesiologists' attitudes and experiences regarding medical error communication. RESULTS The overall response rate of the survey was 52% (281/542). Respondents broadly endorsed disclosing harmful errors to patients (100% serious, 77% minor errors, 19% near misses), but also reported factors that might make them less likely to actually disclose such errors. Only 12% of respondents had previously received training on how to disclose errors to patients, although 93% were interested in receiving training. Overall, 97% of respondents agreed that serious errors should be reported, but willingness to report minor errors (74%) and near misses (59%) was lower. Respondents were more likely to strongly agree that serious errors should be reported if they also thought that their hospital would implement systematic changes after errors were reported [(odds ratio, 2.097 (95% confidence interval, 1.16 to 3.81)]. Significant differences in attitudes between departments regarding error disclosure and reporting were noted. CONCLUSION Willingness to disclose or report errors varied widely between hospitals. Thus, heads of department and hospital chiefs need to be aware of the importance of local culture when it comes to error communication. Error disclosure training and improving feedback on how error reports are being used to improve patient safety may also be important steps in increasing anaesthesiologists' communication of errors.

Gingival labial recessions and the post-treatment proclination of mandibular incisors

INTRODUCTION A prerequisite for development of gingival recession is the presence of alveolar bone dehiscence. Proclination of mandibular incisors can result in thinning of the alveolus and dehiscence formation. OBJECTIVE To assess an association between proclination of mandibular incisor and development of gingival recession. METHODS One hundred and seventeen subjects who met the following inclusion criteria were selected: 1. age 11-14 years at start of orthodontic treatment (TS), 2. bonded retainer placed immediately after treatment (T0), 3. dental casts and lateral cephalograms available pre-treatment (TS), post-treatment (T0), and 5 years post-treatment (T5), and 4. post-treatment (T0) lower incisor inclination (Inc_Incl) <95° or >100.5°. Two groups were formed: non-proclined (N = 57; mean Inc_Incl = 90.8°) and proclined (N = 60; mean Inc_Incl = 105.2°). Clinical crown heights of mandibular incisors and the presence of gingival recession sites in this region were assessed on plaster models. Fisher's exact tests, t-tests, and regression models were computed for analysis of inter-group differences. RESULTS The mean increase of clinical crown heights (from T0 to T5) of mandibular incisors ranged from 0.75 to 0.83mm in the non-proclined and proclined groups, respectively (P = 0.273). At T5, gingival recession sites were present in 12.3% and 11.7% patients from the non-proclined and proclined groups, respectively. The difference was also not significant (P = 0.851). CONCLUSIONS The proclination of mandibular incisors did not increase a risk of development of gingival recession during five-year observation in comparison non-proclined teeth.

Detection of Chlamydia pneumoniae in a collection of captive snakes and response to treatment with marbofloxacin.

In a collection of 58 snakes comprising predominantly Eurasian vipers in Switzerland, five snakes died unexpectedly during hibernation from 2009 to 2012. In one snake, organisms resembling chlamydiae were detected by immunohistochemistry in multiple histiocytic granulomas. Real-time quantitative PCR and microarray analysis were used to determine the presence of Chlamydia pneumoniae in tissue samples and cloacal/choanal swabs from snakes in the collection; 8/53 (15.1%) of the remaining snakes were positive. Although one infected snake had suppurative periglossitis, infection with C. pneumoniae did not appear to be associated with specific clinical signs in snakes. Of seven snakes treated with 5 mg/kg marbofloxacin IM once daily, five became PCR negative for C. pneumoniae following treatment, whereas one animal remained positive and one snake was lost to follow-up.

The medical malpractice insurance "crises" and federal medical malpractice tort reform: Collection and analysis of bills passed by the United States House of Representatives from 1995--2005

There have been three medical malpractice insurance "crises" in the United States over a time spanning roughly the past three decades (Poisson, 2004, p. 759-760). Each crisis is characterized by a number of common features, including rapidly increasing medical malpractice insurance premiums, cancellation of existing insurance policies, and a decreased willingness of insurers to offer or renew medical malpractice insurance policies (Poisson, 2004, p. 759-760). Given the recurrent "crises," many sources argue that medical malpractice insurance coverage has become too expensive a commodity—one that many physicians simply cannot afford (U.S. Department of Health and Human Services [HHS], 2002, p. 1-2; Physician Insurers Association of America [PIAA], 2003, p. 1; Jackiw, 2004, p. 506; Glassman, 2004, p. 417; Padget, 2003, p. 216). ^ The prohibitively high cost of medical liability insurance is said to limit the geographical areas and medical specializations in which physicians are willing to practice. As a result, the high costs of medical liability insurance are ultimately said to affect whether or not people have access to health care services. ^ In an effort to control the medical liability insurance crises—and to preserve or restore peoples' access to health care—every state in the United States has passed "at least some laws designed to reduce medical malpractice premium rates" (GAO, 2003, p.5-6). More recently, however, the United States has witnessed a push to implement federal reform of the medical malpractice tort system. Accordingly, this project focuses on federal medical malpractice tort reform. This project was designed to investigate the following specific question: Do the federal medical malpractice tort reform bills which passed in the House of Representatives between 1995 and 2005 differ in respect to their principle features? To answer this question, the text of the bills, law review articles, and reports from government and private agencies were analyzed. Further, a matrix was compiled to concisely summarize the principle features of the proposed federal medical malpractice tort reform bills. Insight gleaned from this investigation and matrix compilation informs discussion about the potential ramifications of enacting federal medical malpractice tort reform legislation. ^

Influence of trust on HIV diagnosis and care practices

Many factors have been studied as potential correlates in delayed HIV diagnosis and delayed linkage to HIV healthcare. Few studies have analyzed the association of trust as a correlate in HIV diagnosis and HIV medical treatment delays. This study sought to assess the effect of patient trust in physicians and trust in the healthcare system, and whether diminished levels of trust affect delays in HIV diagnosis and/or linking to HIV healthcare, among a cohort of newly diagnosed HIV-infected persons, in Harris County, Texas.^ This study is a secondary data analysis from the Attitude and Beliefs and the Steps of HIV Care Study, also known as the Steps Study, a prospective observational cohort study. From January 2006 to October 2007 patients newly diagnosed with HIV infection and not yet in HIV primary care were recruited from publically funded HIV testing sites in Houston, Texas.^ Two outcomes were assessed in this study. The first outcome sought to determine the influence of trust and whether decreased levels of trust predicted delays in HIV diagnosis. Trust in physicians and trust in the healthcare system were measured via 2 validated trust scales. Trust scores of those with late diagnosis (CD4 counts <200 cells/mm3) were compared statistically with those with early diagnosis (CD4 counts ≥ 200 cells/mm3) in a cross sectional study design. Trust was not found to be predictive of delays in HIV diagnosis. ^ The second outcome utilized the same trust scales and a prospective cohort study design to assess whether there were differences in trust scores between those who successfully linked to HIV healthcare, compared to those who failed to link to HIV healthcare, within 6 months of diagnosis. Patients with higher trust in physicians and trust in the healthcare system were significantly more likely to be linked to HIV healthcare than those with lower trust.^ Overall, this study showed that among low-income persons with undiagnosed HIV infection, low trust is not a barrier to timely diagnosis of HIV infection. Trust may be a factor in promoting a prompt linkage to HIV healthcare among those who are newly diagnosed.^

AN EMPIRICAL ESTIMATION OF MEDICAL AND NON-MEDICAL INPUTS IN THE PRODUCTION OF CARDIO-RESPIRATORY PHYSICAL HEALTH STATUS

The purpose of this study was to examine, in the context of an economic model of health production, the relationship between inputs (health influencing activities) and fitness.^ Primary data were collected from 204 employees of a large insurance company at the time of their enrollment in an industrially-based health promotion program. The inputs of production included medical care use, exercise, smoking, drinking, eating, coronary disease history, and obesity. The variables of age, gender and education known to affect the production process were also examined. Two estimates of fitness were used; self-report and a physiologic estimate based on exercise treadmill performance. Ordinary least squares and two-stage least squares regression analyses were used to estimate the fitness production functions.^ In the production of self-reported fitness status the coefficients for the exercise, smoking, eating, and drinking production inputs, and the control variable of gender were statistically significant and possessed theoretically correct signs. In the production of physiologic fitness exercise, smoking and gender were statistically significant. Exercise and gender were theoretically consistent while smoking was not. Results are compared with previous analyses of health production. ^