Treatment of type 2 diabetes with the designer cytokine IC7Fc.

The gp130 receptor cytokines IL-6 and CNTF improve metabolic homeostasis but have limited therapeutic use for the treatment of type 2 diabetes. Accordingly, we engineered the gp130 ligand IC7Fc, in which one gp130-binding site is removed from IL-6 and replaced with the LIF-receptor-binding site from CNTF, fused with the Fc domain of immunoglobulin G, creating a cytokine with CNTF-like, but IL-6-receptor-dependent, signalling. Here we show that IC7Fc improves glucose tolerance and hyperglycaemia and prevents weight gain and liver steatosis in mice. In addition, IC7Fc either increases, or prevents the loss of, skeletal muscle mass by activation of the transcriptional regulator YAP1. In human-cell-based assays, and in non-human primates, IC7Fc treatment results in no signs of inflammation or immunogenicity. Thus, IC7Fc is a realistic next-generation biological agent for the treatment of type 2 diabetes and muscle atrophy, disorders that are currently pandemic.

Timing of surgery and radiotherapy in the management of metastatic spine disease: expert opinion.

BACKGROUND: Combined surgery and radiotherapy, in the treatment of metastatic disease of the spine, is now emerging as the gold standard of care where there is an indication for spinal stabilization and/or surgical decompression. However potential complications related to wound healing can occur with radiation delivered shortly before or after to surgery. The purpose of this study was to understand the practice of leading radiation oncologists and spine surgeons with regards to the timing of radiation (conventional and stereotactic) and surgery for the management of spinal metastases. METHODS: Questionnaires were sent to leading radiation oncologists and spine surgeons throughout North America and completed via mail, email or internet. RESULTS: Eighty-six responses were received from radiation oncologists and 27 from spine surgeons. A total of 58% recommended waiting either 1 or 2 weeks after radiotherapy before operating on patients with spinal metastases. With radiotherapy administered after surgery, 62% of respondents suggested either a 1 or 2 weeks interval was sufficient. CONCLUSIONS: There appeared to be no significant difference in practice with the use of stereotactic radiotherapy though surgeons tend to accept a shorter interval in this subset of patients. We recommend that the interval between radiotherapy and surgery (and vice versa) should ideally be a minimum of 2 weeks.

Health-related quality-of-life outcomes after thoracic (T1-T10) fractures.

BACKGROUND CONTEXT: The thoracic spine exhibits a unique response to trauma as the result of recognized anatomical and biomechanical differences. Despite this response, clinical studies often group thoracic fractures (T1-T10) with more caudal thoracolumbar injuries. Subsequently, there is a paucity of literature on the functional outcomes of this distinct group of injuries. PURPOSE: To describe and identify predictors of health-related quality-of-life outcomes and re-employment status in patients with thoracic fractures who present to a spine injury tertiary referral center. STUDY DESIGN: An ambispective cohort study with cross-sectional outcome assessment. PATIENT SAMPLE: A prospectively collected fully relational spine database was searched to identify all adult (>16 years) patients treated with traumatic thoracic (T1-T10) fractures with and without neurologic deficits, treated between 1995 and 2008. OUTCOME MEASURES: The Short-Form-36, Oswestry Disability Index, and Prolo Economic Scale outcome instruments were completed at a minimum follow-up of 12 months. Preoperative and minimum 1-year postinjury X-rays were evaluated. METHOD: Univariate and multivariate regression analysis was used to identify predictors of outcomes from a range of demographic, injury, treatment, and radiographic variables. RESULTS: One hundred twenty-six patients, age 36±15 years (mean±SD), with 135 fractures were assessed at a mean follow-up of 6 years (range 1-15.5 years). Traffic accidents (45%) and translational injuries (54%) were the most common mechanism and dominant fracture pattern, respectively. Neurologic deficits were frequent-53% had complete (American Spinal Injury Association impairment scale [AIS] A) spinal cord deficits on admission. Operative management was performed in 78%. Patients who sustain thoracic fractures, but escaped significant neurologic injury (AIS D or E on admission) had SF-36 scores that did not differ significantly from population norms at a mean follow-up of 6 years. Eighty-eight percent of this cohort was re-employed. Interestingly, Oswestry Disability Index scores remained inferior to healthy subjects. In contrast, SF-36 scores in those with more profound neurologic deficits at presentation (AIS A, B, or C) remained inferior to normative data. Fifty-seven percent were re-employed, 25% in their previous job type. Using multiple regression analysis, we found that comorbidity status (measured by the Charlson Comorbidity index) was the only independent predictor of SF-36 scores. Neurologic impairment (AIS) and adverse events were independent predictors of the SF-36 physical functioning subscale. Sagittal alignment and number of fused levels were not independent predictors. CONCLUSIONS: At a mean follow-up of 6 years, patients who presented with thoracic fractures and AIS D or E neurologic status recovered a general health status not significantly inferior to population norms. Compared with other neurologic intact spinal injuries, patients with thoracic injuries have a favorable generic health-related quality-of-life prognosis. Inferior outcomes and re-employment prospects were noted in those with more significant neurologic deficits.

Surgeon-industry conflict of interest: survey of opinions regarding industry-sponsored educational events and surgeon teaching: clinical article.

OBJECT: Conflict of interest (COI) as it applies to medical education and training has become a source of considerable interest, debate, and regulation in the last decade. Companies often pay surgeons as faculty for educational events and often sponsor and give financial support to major professional society meetings. Professional medical societies, industry, and legislators have attempted to regulate potential COI without consideration for public opinion. The practice of evidence-based medicine requires the inclusion of patient opinion along with best available evidence and expert opinion. The primary goal of this study was to assess the opinion of the general population regarding surgeon-industry COI for education-related events. METHODS: A Web-based survey was administered, with special emphasis on the surgeon's role in industry-sponsored education and support of professional societies. A survey was constructed to sample opinions on reimbursement, disclosure, and funding sources for educational events. RESULTS: There were 501 completed surveys available for analysis. More than 90% of respondents believed that industry funding for surgeons' tuition and travel for either industry-sponsored or professional society educational meetings would either not affect the quality of care delivered or would cause it to improve. Similar results were generated for opinions on surgeons being paid by industry to teach other surgeons. Moreover, the majority of respondents believed it was ethical or had no opinion if surgeons had such a relationship with industry. Respondents were also generally in favor of educational conferences for surgeons regardless of funding source. Disclosures of a surgeon-industry relationship, especially if it involves specific devices that may be used in their surgery, appears to be important to respondents. CONCLUSIONS: The vast majority of respondents in this study do not believe that the quality of their care will be diminished due to industry funding of educational events, for surgeon tuition, and/or travel expenses. The results of this study should help form the basis of policy and continued efforts at surgeon-industry COI management.

Comparison of atherosclerotic plaque burden and composition between diabetic and non diabetic patients by non invasive CT angiography.

Type 2 diabetes mellitus (DM) is associated with a higher risk of cardiovascular disease and atherosclerotic burden. However little data exists in regards to plaque distribution and plaque composition in these patients. To assess for differences in the coronary plaques burden and composition among symptomatic patients with and without type 2 DM using multidetector computed tomography angiography (MDCTA). The 416 symptomatic patients (64% males, mean age: 61 +/- 13 years) with 61 (15%) reporting type 2 DM, who underwent contrast-enhanced MDCTA were studied. Enrolled patients had an intermediate to high pre-test probability of obstructive coronary artery disease. Multivariate analysis was used to correct for differences in age and gender. Patients with type 2 DM were more likely to have significant stenosis >or=70% in at least one coronary segments (33% in type 2 DM vs. 18% in non diabetic, P = 0.013), whereas 11% of both type 2 DM and non diabetics had stenosis of 50-70% (P = NS). Also type 2 DM patients had a higher number of coronary segments with mixed plaques compared to nondiabetic patients (1.67 +/- 2.01 vs. 1.23 +/- 1.61, P = 0.05), whereas no such differences were observed for non-calcified or calcified plaques. Nearly half (43%) of type 2 DM had coronary artery calcium scores (CACS) >or=400 vs. 29% in non diabetic patients (P = 0.03). Patients with type 2 DM tend to have atherosclerotic plaques which are more likely to be mixed in nature. Future studies need to elucidate the prognostic value of differences in plaque characteristics observed according to type 2 diabetic status.

Inbred FVB/N mice are mutant at the cp49/Bfsp2 locus and lack beaded filament proteins in the lens.

PURPOSE: FVB/N is considered an ideal inbred mouse strain for transgenic mouse production because of the ease of pronuclear microinjection and its overall fecundity. It is well established that vertebrate lens fiber cells normally express a modified intermediate filament network consisting of the proteins filensin and CP49, and it was recently reported that the mouse strain 129 harbors mutations in CP49 that have the potential to confound the interpretation of gene knockout studies of the lens. The purpose of this study was to evaluate the status of the CP49/Bfsp2 gene in the FVB/N strain. METHODS: PCR analysis of genomic DNA was used to evaluate the status of the CP49 gene in FVB/N mice procured from the four major US distributors of these animals--Harlan Laboratories, Taconic Farms, Jackson Laboratory, and the NIH/NCI/DCT production facility run by Charles River Laboratories. The structure of the CP49 transcript was evaluated by RT-PCR, and the presence of CP49 protein in the lens was evaluated by immunofluorescence. RESULTS: FVB/N mice obtained from all four US distributors were shown to harbor a 6-kb deletion of the CP49 gene identical with that previously reported in mouse strain 129; C57BL/6 mice did not have this modification. Immunofluorescence demonstrated that FVB/N mice do not have detectable CP49 or filensin protein in the lens, whereas C57BL/6 mice have the expected protein distribution. CONCLUSIONS: In humans, mutations in the CP49/BFSP2 gene have been linked to familial, congenital cataract, demonstrating an important role of this gene in lens transparency. The demonstration that FVB/N mice lack CP49 protein in the lens suggests that it may be necessary to reevaluate the mechanisms underlying lens phenotypes obtained as a result of transgenic manipulation of this strain.

Torsion of an indirect hernia sac causing acute scrotum.

A 6-year-old boy presented with an acute scrotum and was found at surgical exploration to have torsion and infarction of an indirect hernia sac. This represents the sixth reported case of this entity in the literature. The pediatric surgical specialist and those in the acute care setting should be aware of this consideration in the differential diagnosis of the acute scrotum.

Osteosarcoma associated with diamond-blackfan anaemia: a case of a child receiving growth hormone therapy.

PURPOSE: Diamond-Blackfan anaemia (DBA) is a rare pure congenital red cell aplasia, usually presenting in infancy or early childhood. The literature suggests a predisposition to haemopoietic malignancy but in addition solid tumours have been reported, with five cases of osteosarcoma described. PATIENT: A sixth case of a 12-year-old girl with DBA who developed an osteosarcoma of the distal femur is presented. RESULTS: She was treated with methotrexate followed by tumour excision and distal femoral replacement. The patient is currently alive with multiple pulmonary metastases. DISCUSSION: We discuss the association between the administration of growth hormone and future development of malignancy in patients with DBA.