Improvement of Segmental Lordosis in Transforaminal Lumbar Interbody Fusion: A Comparison of Two Techniques

Study Design Retrospective review. Objective The purpose of this study was to determine the radiographic impact of a transforaminal lumbar interbody fusion (TLIF) versus a cantilever TLIF technique on segmental lordosis, segmental coronal alignment, and disk height. Methods A retrospective review was done of all patients undergoing TLIF procedures from 2006 to 2011 by three spine surgeons. Traditional TLIF versus cantilever TLIF results were compared, and radiographic outcomes were assessed. Results One hundred one patients were included in the study. Patients undergoing the cantilever TLIF procedure had a significantly greater change in segmental lordosis and disk height compared with those who underwent the traditional procedure (p \u3e 0.0001). Conclusions The cantilever TLIF technique can lead to greater change in segmental lordosis based upon radiographic outcomes

Genetic Predisposition for Type 2 Diabetes, but Not for Overweight/Obesity, Is Associated with a Restricted Adipogenesis

BACKGROUND: Development of Type 2 diabetes, like obesity, is promoted by a genetic predisposition. Although several genetic variants have been identified they only account for a small proportion of risk. We have asked if genetic risk is associated with abnormalities in storing excess lipids in the abdominal subcutaneous adipose tissue. METHODOLOGY/PRINCIPAL FINDINGS: We recruited 164 lean and 500 overweight/obese individuals with or without a genetic predisposition for Type 2 diabetes or obesity. Adipose cell size was measured in biopsies from the abdominal adipose tissue as well as insulin sensitivity (HOMA index), HDL-cholesterol and Apo AI and Apo B. 166 additional non-obese individuals with a genetic predisposition for Type 2 diabetes underwent a euglycemic hyperinsulinemic clamp to measure insulin sensitivity. Genetic predisposition for Type 2 diabetes, but not for overweight/obesity, was associated with inappropriate expansion of the adipose cells, reduced insulin sensitivity and a more proatherogenic lipid profile in non-obese individuals. However, obesity per se induced a similar expansion of adipose cells and dysmetabolic state irrespective of genetic predisposition. CONCLUSIONS/SIGNIFICANCE: Genetic predisposition for Type 2 diabetes, but not obesity, is associated with an impaired ability to recruit new adipose cells to store excess lipids in the subcutaneous adipose tissue, thereby promoting ectopic lipid deposition. This becomes particularly evident in non-obese individuals since obesity per se promotes a dysmetabolic state irrespective of genetic predisposition. These results identify a novel susceptibility factor making individuals with a genetic predisposition for Type 2 diabetes particularly sensitive to the environment and caloric excess

Adipose TriGlyceride Lipase (ATGL) and Hormone-Sensitive Lipase (HSL) protein expression is decreased in the obese insulin resistant state

International audienceAIM/HYPOTHESIS: Obesity is associated with increased triacylglycerol (TAG) storage in adipose tissue and insulin resistance. The mobilization of stored TAG is mediated by hormone-sensitive lipase (HSL) and the recently discovered adipose triglyceride lipase (ATGL). The aim of the present study was to examine whether ATGL and HSL mRNA and protein expression are altered in insulin-resistant conditions. In addition, we investigated whether a possible impaired expression could be reversed by a period of weight reduction. METHODS: Adipose tissue biopsies were taken from obese subjects (n = 44) with a wide range of insulin resistance, before and just after a 10-wk hypocaloric diet. ATGL and HSL protein and mRNA expression was determined by Western blot and quantitative RT-PCR, respectively. RESULTS: Fasting insulin levels and the degree of insulin resistance (using the homeostasis model assessment index for insulin resistance) were negatively correlated with ATGL and HSL protein expression, independent of age, gender, fat cell size, and body composition. Both mRNA and protein levels of ATGL and HSL were reduced in insulin-resistant compared with insulin-sensitive subjects (P < 0.05). Weight reduction significantly decreased ATGL and HSL mRNA and protein expression. A positive correlation between the decrease in leptin and the decrease in ATGL protein level after weight reduction was observed. Finally, ATGL and HSL mRNA and protein levels seem to be highly correlated, indicating a tight coregulation and transcriptional control. CONCLUSIONS: In obese subjects, insulin resistance and hyperinsulinemia are strongly associated with ATGL and HSL mRNA and protein expression, independent of fat mass. Data on weight reduction indicated that also other factors (e.g. leptin) relate to ATGL and HSL protein expression

Association between gross motor function (GMFCS) and manual ability (MACS) in children with cerebral palsy. A population-based study of 359 children

<p>Abstract</p> <p>Background</p> <p>The Gross Motor Function Classification System (GMFCS) has become an important tool to describe motor function in children with Cerebral Palsy (CP). The Manual Ability Classification System (MACS) was developed recently as a corresponding classification of manual ability. The aim of this study was to describe the association between gross motor function and manual ability in a total population of children with cerebral palsy.</p> <p>Methods</p> <p>365 children, born 1992 to 2001, who were registered in a population-based health care programme (CPUP) for children with CP living in the south of Sweden were included in the study. GMFCS was evaluated by the child's physiotherapist and MACS by the occupational therapist. CP diagnosis and subtype were determined by the neuropaediatrician at or after the age of four.</p> <p>Results</p> <p>GMFCS levels were available in all 365 children, MACS levels in 359 (98%). There was a poor overall correlation between gross motor function and manual ability. However, different associations between gross motor function and manual ability were found in the different diagnostic subtypes. Children with spastic hemiplegia generally had a lower level of manual ability than gross motor function (p < 0.001). The reverse association was generally found in children with spastic diplegia (p < 0.001). Children with dyskinetic CP had large limitations in both gross motor function and manual ability, with no significant discrepancy between GMFCS and MACS levels.</p> <p>Conclusion</p> <p>Gross motor function and manual ability are often discrepant in children with CP, and the patterns seem to vary across the different subgroups based on the predominant neurological findings. To give a complete clinical picture when evaluating these children, both aspects have to be described. The GMFCS and the MACS seem to work well in this context and seem very useful in population-based studies, in health care registers for children with CP, and in clinical practice.</p

Metabolic Remodeling of Human Skeletal Myocytes by Cocultured Adipocytes Depends on the Lipolytic State of the System

Adipocyte infiltration of the musculoskeletal system is well recognized as a hallmark of aging, obesity, and type 2 diabetes. Intermuscular adipocytes might serve as a benign storage site for surplus lipid or play a role in disrupting energy homeostasis as a result of dysregulated lipolysis or secretion of proinflammatory cytokines. This investigation sought to understand the net impact of local adipocytes on skeletal myocyte metabolism. Interactions between these two tissues were modeled using a coculture system composed of primary human adipocytes and human skeletal myotubes derived from lean or obese donors. Metabolic analysis of myocytes was performed after coculture with lipolytically silent or activated adipocytes and included transcript and metabolite profiling along with assessment of substrate selection and insulin action. Cocultured adipocytes increased myotube mRNA expression of genes involved in oxidative metabolism, regardless of the donor and degree of lipolytic activity. Adipocytes in the basal state sequestered free fatty acids, thereby forcing neighboring myotubes to rely more heavily on glucose fuel. Under this condition, insulin action was enhanced in myotubes from lean but not obese donors. In contrast, when exposed to lipolytically active adipocytes, cocultured myotubes shifted substrate use in favor of fatty acids, which was accompanied by intracellular accumulation of triacylglycerol and even-chain acylcarnitines, decreased glucose oxidation, and modest attenuation of insulin signaling. The effects of cocultured adipocytes on myocyte substrate selection and insulin action depended on the metabolic state of the system. These findings are relevant to understanding the metabolic consequences of intermuscular adipogenesis

Genetic Variation in Selenoprotein Genes, Lifestyle, and Risk of Colon and Rectal Cancer

BACKGROUND: Associations between selenium and cancer have directed attention to role of selenoproteins in the carcinogenic process. METHODS: We used data from two population-based case-control studies of colon (n = 1555 cases, 1956 controls) and rectal (n = 754 cases, 959 controls) cancer. We evaluated the association between genetic variation in TXNRD1, TXNRD2, TXNRD3, C11orf31 (SelH), SelW, SelN1, SelS, SepX, and SeP15 with colorectal cancer risk. RESULTS: After adjustment for multiple comparisons, several associations were observed. Two SNPs in TXNRD3 were associated with rectal cancer (rs11718498 dominant OR 1.42 95% CI 1.16,1.74 pACT 0.0036 and rs9637365 recessive 0.70 95% CI 0.55,0.90 pACT 0.0208). Four SNPs in SepN1 were associated with rectal cancer (rs11247735 recessive OR 1.30 95% CI 1.04,1.63 pACT 0.0410; rs2072749 GGvsAA OR 0.53 95% CI 0.36,0.80 pACT 0.0159; rs4659382 recessive OR 0.58 95% CI 0.39,0.86 pACT 0.0247; rs718391 dominant OR 0.76 95% CI 0.62,0.94 pACT 0.0300). Interaction between these genes and exposures that could influence these genes showed numerous significant associations after adjustment for multiple comparisons. Two SNPs in TXNRD1 and four SNPs in TXNRD2 interacted with aspirin/NSAID to influence colon cancer; one SNP in TXNRD1, two SNPs in TXNRD2, and one SNP in TXNRD3 interacted with aspirin/NSAIDs to influence rectal cancer. Five SNPs in TXNRD2 and one in SelS, SeP15, and SelW1 interacted with estrogen to modify colon cancer risk; one SNP in SelW1 interacted with estrogen to alter rectal cancer risk. Several SNPs in this candidate pathway influenced survival after diagnosis with colon cancer (SeP15 and SepX1 increased HRR) and rectal cancer (SepX1 increased HRR). CONCLUSIONS: Findings support an association between selenoprotein genes and colon and rectal cancer development and survival after diagnosis. Given the interactions observed, it is likely that the impact of cancer susceptibility from genotype is modified by lifestyle

Use of manual and powered wheelchair in children with cerebral palsy: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Mobility is important for the cognitive and psychosocial development of children. Almost one third of children with cerebral palsy (CP) are non-ambulant. Wheelchairs can provide independent mobility, allowing them to explore their environment. Independent mobility is vital for activity and participation and reduces the dependence on caregivers. The purpose of this study was to describe the use of manual and powered wheelchair indoors and outdoors in relation to the degree of independent wheelchair mobility or need for assistance in a total population of children with CP.</p> <p>Methods</p> <p>A cross-sectional study was performed including all children aged 3-18 years with CP living in southern Sweden during 2008. Data was extracted from a register and health care programme for children with CP (CPUP). There were a total of 562 children (326 boys, 236 girls) in the register. Information on the child's use of manual and powered wheelchair indoors and outdoors and the performance in self-propelling or need for assistance were analysed related to age, CP subtype and gross motor function.</p> <p>Results</p> <p>Wheelchairs for mobility indoors were used by 165 (29%) of the 562 children; 61 used wheelchair for independent mobility (32 using manual only, 12 powered only, 17 both) and 104 were pushed by an adult. For outdoor mobility wheelchairs were used by 228 children (41%); 66 used a wheelchair for independent mobility (18 using manual only, 36 powered only, 12 both) and 162 were pushed. The use of wheelchair increased with age and was most frequent in the spastic bilateral and dyskinetic subtypes. Most powered wheelchairs were operated by children at GMFCS level IV.</p> <p>Conclusion</p> <p>In this total population of children with CP, aged 3-18 years, 29% used a wheelchair indoors and 41% outdoors. A majority using manual wheelchairs needed adult assistance (86%) while powered wheelchairs provided independent mobility in most cases (86%). To achieve a high level of independent mobility, both manual and powered wheelchairs should be considered at an early age for children with impaired walking ability.</p

Toxicology evaluation of radiotracer doses of 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT) for human PET imaging: Laboratory analysis of serial blood samples and comparison to previously investigated therapeutic FLT doses

Background: 18F-FLT is a novel PET radiotracer which has demonstrated a strong potential utility for imaging cellular proliferation in human tumors in vivo. To facilitate future regulatory approval of 18F-FLT for clinical use, we wished to demonstrate the safety of radiotracer doses of 18F-FLT administered to human subjects, by: 1) performing an evaluation of the toxicity of 18F-FLT administered in radiotracer amounts for PET imaging, 2) comparing a radiotracer dose of FLT to clinical trial doses of FLT. Methods: Twenty patients gave consent to a 18F-FLT injection, subsequent PET imaging, and blood draws. For each patient, blood samples were collected at multiple times before and after 18F-FLT PET. These samples were assayed for a comprehensive metabolic panel, total bilirubin, complete blood and platelet counts. 18F-FLT doses of 2.59 MBq/Kg with a maximal dose of 185 MBq (5 mCi) were used. Blood time-activity curves were generated for each patient from dynamic PET data, providing a measure of the area under the FLT concentration curve for 12 hours (AUC12). Results: No side effects were reported. Only albumin, red blood cell count, hematocrit and hemoglobin showed a statistically significant decrease over time. These changes are attributed to IV hydration during PET imaging and to subsequent blood loss at surgery. The AUC12 values estimated from imaging data are not significantly different from those found from serial measures of FLT blood concentrations (p = 0.66). The blood samples-derived AUC12 values range from 0.232 ng*h/mL to 1.339 ng*h/mL with a mean of 0.802 � 0.303 ng*h/mL. This corresponds to 0.46% to 2.68% of the lowest and least toxic clinical trial AUC12 of 50 ng*h/mL reported by Flexner et al (1994). This single injection also corresponds to a nearly 3,000-fold lower cumulative dose than in Flexner's twice daily trial. Conclusion: This study shows no evidence of toxicity or complications attributable to 18F-FLT injected intravenously.This study was supported by NIH grant R01 CA115559, 1R01 CA107264, and 1R01 CA80907

dATF4 regulation of mitochondrial folate-mediated one-carbon metabolism is neuroprotective.

Neurons rely on mitochondria as their preferred source of energy. Mutations in PINK1 and PARKIN cause neuronal death in early-onset Parkinson's disease (PD), thought to be due to mitochondrial dysfunction. In Drosophila pink1 and parkin mutants, mitochondrial defects lead to the compensatory upregulation of the mitochondrial one-carbon cycle metabolism genes by an unknown mechanism. Here we uncover that this branch is triggered by the activating transcription factor 4 (ATF4). We show that ATF4 regulates the expression of one-carbon metabolism genes SHMT2 and NMDMC as a protective response to mitochondrial toxicity. Suppressing Shmt2 or Nmdmc caused motor impairment and mitochondrial defects in flies. Epistatic analyses showed that suppressing the upregulation of Shmt2 or Nmdmc deteriorates the phenotype of pink1 or parkin mutants. Conversely, the genetic enhancement of these one-carbon metabolism genes in pink1 or parkin mutants was neuroprotective. We conclude that mitochondrial dysfunction caused by mutations in the Pink1/Parkin pathway engages ATF4-dependent activation of one-carbon metabolism as a protective response. Our findings show a central contribution of ATF4 signalling to PD that may represent a new therapeutic strategy. A video abstract for this article is available at https://youtu.be/cFJJm2YZKKM