Novel Influences of Sex and \u3ci\u3eAPOE\u3c/i\u3e Genotype on Spinal Plasticity and Recovery of Function after Spinal Cord Injury

Spinal cord injuries can abolish both motor and sensory function throughout the body. Spontaneous recovery after injury is limited and can vary substantially between individuals. Despite an abundance of therapeutic approaches that have shown promise in preclinical models, there is currently a lack of effective treatment strategies that have been translated to restore function after SCI in the human population. We hypothesized that sex and genetic background of injured individuals could impact how they respond to treatment strategies, presenting a barrier to translating therapies that are not tailored to the individual. One gene of particular interest is APOE, which has been extensively studied in the brain due to its allele-specific influences on synaptic plasticity, metabolism, inflammation, and neurodegeneration. Despite its prominence as a therapeutic target in brain injury and disease, little is known about how it influences neural plasticity and repair processes in the spinal cord. Utilizing humanized mice, we examined how the ε3 and ε4 alleles of APOE influence the efficacy of therapeutic intermittent hypoxia (IH) in inducing spinally-mediated plasticity after cervical SCI. IH is sufficient to enhance plasticity and restore motor function after experimental SCI in genetically similar rodent populations, but its effect in human subjects is more variable (Golder, 2005; Hayes et al., 2014). Our results demonstrate that both sex and APOE genotype determine the extent of respiratory motor plasticity that is elicited by IH, highlighting the importance of considering these clinically relevant variables when translating therapeutic approaches for the SCI community. Significance Statement There is currently a critical need for therapeutics that restore motor and sensory function effectively after cervical spinal cord injury. Although many therapeutic approaches, including intermittent hypoxia, are being investigated for their potential to enhance spinal plasticity and improve motor outcomes after SCI, it is unknown whether the efficacy of these treatment strategies is influenced by individuals’ genetic background. Here we show that APOE genotype and sex both play a role in determining the propensity for motor plasticity in humanized mice after cervical SCI. These results indicate that sex and genetic background dictate how individuals respond to therapeutic approaches, thereby emphasizing the importance of developing personalized medicine for the diverse SCI population

A Latent Propriospinal Network Can Restore Diaphragm Function After High Cervical Spinal Cord Injury

Spinal cord injury (SCI) above cervical level 4 disrupts descending axons from the medulla that innervate phrenic motor neurons, causing permanent paralysis of the diaphragm. Using an ex vivo preparation in neonatal mice, we have identified an excitatory spinal network that can direct phrenic motor bursting in the absence of medullary input. After complete cervical SCI, blockade of fast inhibitory synaptic transmission caused spontaneous, bilaterally coordinated phrenic bursting. Here, spinal cord glutamatergic neurons were both sufficient and necessary for the induction of phrenic bursts. Direct stimulation of phrenic motor neurons was insufficient to evoke burst activity. Transection and pharmacological manipulations showed that this spinal network acts independently of medullary circuits that normally generate inspiration, suggesting a distinct non-respiratory function. We further show that this “latent” network can be harnessed to restore diaphragm function after high cervical SCI in adult mice and rats

Cost-Effectiveness of Surgically Induced Weight Loss for the Management of Type 2 Diabetes: Modeled Lifetime Analysis

OBJECTIVE--To estimate the cost-effectiveness of surgically induced weight loss relative to conventional therapy for the management of recently diagnosed type 2 diabetes in class VII obese patients. RESEARCH DESIGN AND METHODS--This study builds on a within-trial cost-efficacy analysis. The analysis compares the lifetime costs and quality-adjusted life-years (QALYs) between the two intervention groups. Intervention costs were extrapolated based on observed resource utilization during the trial. The proportion of patients in each intervention group with remission of diabetes at 2 years was the same as that observed in the trial. Health care costs for patients with type 2 diabetes and outcome variables required to derive estimates of QALYs were sourced from published literature. A health care system perspective was adopted. Costs and outcomes were discounted annually at 3%. Costs are presented in 2006 Australian dollars (AUD) (currency exchange: 1 AUD = 0.74 USD). RESULTS--The mean number of years in diabetes remission over a lifetime was 11.4 for surgical therapy patients and 2.1 for conventional therapy patients. Over the remainder of their lifetime, surgical and conventional therapy patients lived 15.7 and 14.5 discounted QALYs, respectively. The mean discounted lifetime costs were 98,900 AUD per surgical therapy patient and 101,400 AUD per conventional therapy patient. Relative to conventional therapy, surgically induced weight loss was associated with a mean health care saving of 2,400 AUD and 1.2 additional QALYs per patient. CONCLUSIONS--Surgically induced weight loss is a dominant intervention (it both saves health care costs and generates health benefits) for managing recently diagnosed type 2 diabetes in class IBI obese patients in Australia. <br /

Are Surgical Trials with Negative Results Being Interpreted Correctly?

BACKGROUND: Many published accounts of clinical trials report no differences between the treatment arms, while being underpowered to find differences. This study determined how the authors of these reports interpreted their findings. STUDY DESIGN: We examined 54 reports of surgical trials chosen randomly from a database of 110 influential trials conducted in 2008. Seven that reported having adequate statistical power (b 0.9) were excluded from further analysis, as were the 32 that reported significant differences between the treatment arms. We examined the remaining 15 to see whether the authors interpreted their negative findings appropriately. Appropriate interpretations discussed the lack of power and/or called for larger studies. RESULTS: Three of the 7 trials that did not report an a priori power calculation offered inappropriate interpretations, as did 3 of the 8 trials that reported an a priori power < 0.90. However, we examined only a modest number of trial reports from 1 year. CONCLUSIONS: Negative findings in underpowered trials were often interpreted as showing the equivalence of the treatment arms with no discussion of the issue of being underpowered. This may lead clinicians to accept new treatments that have not been validated

Cost-Efficacy of Surgically Induced Weight Loss for the Management of Type 2 Diabetes: A randomized controlled trial

OBJECTIVE -- To determine the within-trial cost-efficacy of surgical therapy relative to conventional therapy for achieving remission of recently diagnosed type 2 diabetes in class I and II obese patients. RESEARCH DESIGN AND METHODS -- Efficacy results were derived from a 2-year randomized controlled trial. A health sector perspective was adopted, and within-trial intervention costs included gastric banding surgery, mitigation of complications, outpatient medical consultations, medical investigations, pathology, weight loss therapies, and medication. Resource use was measured based on data drawn from a trial database and patient medical records and valued based on private hospital costs and government schedules in 2006 Australian dollars (AUD). An incremental cost-effectiveness analysis was undertaken. RESULTS -- Mean 2-year intervention costs per patient were 13,400 AUD for surgical therapy and 3,400 AUD for conventional therapy, with laparoscopic adjustable gastric band (LAGB) surgery accounting for 85% of the difference. Outpatient medical consultation costs were three times higher for surgical patients, whereas medication costs were 1.5 times higher for conventional patients. The cost differences were primarily in the first 6 months of the trial. Relative to conventional therapy, the incremental cost-effectiveness ratio for surgical therapy was 16,600 AUD per case of diabetes remitted (currency exchange: 1 AUD = 0.74 USD). CONCLUSIONS -- Surgical therapy appears to be a cost-effective option for managing type 2 diabetes in class I and II obese patients.<br /

Effect of Contemporary Bariatric Surgical Procedures on Type 2 Diabetes Remission. A Population-Based Matched Cohort Study.

OBJECTIVE: The objective of the study is to evaluate the effect of gastric banding, gastric bypass and sleeve gastrectomy on medium to long-term diabetes control in obese participants with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: Matched cohort study using primary care electronic health records from the UK Clinical Practice Research Datalink. Obese participants with type 2 diabetes who received bariatric surgery from 2002 to 2014 were compared with matched control participants who did not receive BS. Remission was defined for each year of follow-up as HbA1c <6.5 % and no antidiabetic drugs prescribed. RESULTS: There were 826 obese participants with T2DM who received bariatric surgery including adjustable gastric banding (LAGB) 220; gastric bypass (GBP) 449; or sleeve gastrectomy (SG) 153; with four procedures undefined. Mean HbA1c declined from 8.0 % before BS to 6.5 % in the second postoperative year; proportion with HbA1c <6.5 % (<48 mmol/mol) increased from 17 to 47 %. The proportion of patients in remission was 30 % in the second year, being 20 % for LAGB, 34 % for GBP and 38 % for SG. The adjusted relative rate of remission over the first six postoperative years was 5.97 (4.86 to 7.33, P < 0.001) overall; for LAGB 3.32 (2.27 to 4.86); GBP 7.16 (5.64 to 9.08); and SG 6.82 (5.05 to 9.19). Rates of remission were maintained into the sixth year of follow-up. CONCLUSIONS: Remission of diabetes may continue for up to 6 years after bariatric surgical procedures. Diabetes outcomes are generally more favourable after gastric bypass or sleeve gastrectomy than LAGB

Younger age as a prognostic indicator in breast cancer: A cohort study

<p>Abstract</p> <p>Background</p> <p>The debate continues as to whether younger women who present with breast cancer have a more aggressive form of disease and a worse prognosis. The objectives of this study were to determine the incidence of breast cancer in women under 40 years old and to analyse the clinicopathological characteristics and outcome compared to an older patient cohort.</p> <p>Methods</p> <p>Data was acquired from a review of charts and the prospectively reviewed GUH Department of Surgery database. Included in the study were 276 women diagnosed with breast cancer under the age of forty and 2869 women over forty. For survival analysis each women less than 40 was matched with two women over forty for both disease stage and grade.</p> <p>Results</p> <p>The proportion of women diagnosed with breast cancer under the age of forty in our cohort was 8.8%. In comparison to their older counterparts, those under forty had a higher tumour grade (p = 0.044) and stage (p = 0.046), a lower incidence of lobular tumours (p < 0.001), higher estrogen receptor negativity (p < 0.001) and higher <it>HER2 </it>over-expression (p = 0.002); there was no statistical difference as regards tumour size (p = 0.477). There was no significant difference in overall survival (OS) for both groups; and factors like tumour size (p = 0.026), invasion (p = 0.026) and histological type (p = 0.027), PR (p = 0.031) and <it>HER2 </it>(p = 0.002) status and treatment received were independent predictors of OS</p> <p>Conclusion</p> <p>Breast cancer in younger women has distinct histopathological characteristics; however, this does not result in a reduced survival in this population.</p

Breast Cancer in Young Women: Poor Survival Despite Intensive Treatment

The general aim of the thesis was to gain increased insight into the long-term prognosis for young women with breast cancer. In a population-based cohort of 22,017 women with breast cancer, we studied prognosis by age. Women aged <35 (n=471), 35–39 (n=858) and 40–49 (n=4789) were compared with women aged 50–69. The cumulative 5-year relative survival ratio (RSR) and the relative excess risk (RER) of mortality were calculated. Women <35 years of age had a worse survival than middle-aged women, partly explained by a later stage at diagnosis. After correction for stage, tumor characteristics and treatment, young age remained an independent risk factor for death. The excess risk of death in young women was only present in stage I-II disease and was most pronounced in women with small tumors. For in-depth studies on a large subpopulation from the original cohort (all 471 women aged <35 and a random sample of 700 women aged 35–69), we collected detailed data from the medical records, re-evaluated slides and produced TMAs from tumor tissue. Breast cancer- specific survival (BCSS), distant disease-free survival (DDFS) and locoregional recurrence- free survival (LRFS) by age were analysed. In a multivariate analysis, age <35 and age 35– 39 years conferred a risk in LRFS but not in DDFS and BCSS. The age-related differences in prognosis were most pronounced in early stage luminal Her2-negative tumors, where low age was an independent prognostic factor also for DDFS (HR 1.87 (1.03–3.44)). To study the importance of proliferation markers for the long-term prognosis in young women, protein expression of Ki-67, cyclin A2, B1, D1 and E1 was analysed in 504 women aged <40 and in 383 women aged ≥40. The higher expression of proliferation markers in young women did not have a strong impact on the prognosis. Proliferation markers are less important in young women, and Ki-67 was prognostic only in young women with Luminal PR+ tumors. Age <40 years was an independent risk factor of DDFS exclusively in this subgroup (adjusted HR 2.35 (1.22-4.50)). The only cyclin adding prognostic value beyond subtype in young women was cyclin E1. In a cohort of 469 women aged <40 and 360 women aged ≥40 we examined whether Her2 status assessed by silver enhanced in situ hybridization (SISH) for all cases, would reveal a proportion of women undiagnosed by routine Her2 testing and whether this would affect their prognosis. With SISH testing for all women, the Her2-positive rate increased from 20.0% to 24.4% (p<0.001), and similarly for women aged <40 and ≥40 years. Young women had Her2+ breast cancer twice as often as middle-aged women. Her2 amplification was present in 4.6% of cases scored 0 with IHC, while the corresponding proportions for scores 1+, 2+ and 3+ were 36.0%, 83.7% and 96.8%, respectively. All Her2 amplified cases, both true positive and false negative, had a significantly worse BCSS than the true negative cases

Avoiding or Reversing Hartmann’s Procedure Provides Improved Quality of Life After Perforated Diverticulitis

# 2010 The Author(s). This article is published with open access at Springerlink.com Introduction The existing literature regarding acute perforated diverticulitis only reports about short-term outcome; longterm following outcomes have not been assessed before. The aim of this study was to assess long-term quality of life (QOL) after emergency surgery for perforated diverticulitis. Patients and Methods Validated QOL questionnaires (EQ-VAS, EQ-5D index, QLQ-C30, and QLQ-CR38) were sent to all eligible patients who had undergone emergency surgery for perforated diverticulitis in five teaching hospitals between 199

Frequent overexpression of HMGA1 and 2 in gastroenteropancreatic neuroendocrine tumours and its relationship to let-7 downregulation

The molecular pathogenesis of gastroenteropancreatic (GEP) neuroendocrine tumours (NETs) remains to be elucidated. High-mobility group A (HMGA) proteins play important roles in the regulation of transcription, differentiation, and neoplastic transformation. In this study, the expression of HMGA1 and HMGA2 was studied in 55 GEP NETs. Overexpression of HMGA1 and 2 was frequently detected in GEP NETs compared with normal tissues. Nuclear immunostaining of HMGA1 and 2 was observed in GEP NETs (38 of 55, 69%; 40 of 55, 73%, respectively). High-mobility group A2 expression increased from well-differentiated NET (WNET) to well-differentiated neuroendocrine carcinoma (WNEC) and poorly differentiated NEC (PNEC) (P<0.005) and showed the highest level in stage IV tumours (P<0.01). In WNECs, the expression of HMGA1 and 2 was significantly higher in metastatic tumours than those without metastasis (P<0.05). Gastroenteropancreatic NETs in foregut showed the highest level of HMGA1 and 2 expressions. MIB-1 labelling index (MIB-1 LI) correlated with HMGA1 and 2 overexpression (R=0.28, P<0.05; R=0.434, P<0.001; respectively) and progressively increased from WNETs to WNECs and PNECs (P<0.001). Let-7 expression was addressed in 6 normal organs, 30 tumour samples, and 24 tumour margin non-tumour tissues. Compared with normal tissues, let-7 downregulation was frequent in NETs (19 of 30, 63%). Higher expression of HMGA1 and 2 was frequently observed in tumours with let-7 significant reduction (53, 42%, respectively). The reverse correlation could be detected between HMGA1 and let-7 (P<0.05). Our findings suggested that HMGA1 and 2 overexpression and let-7 downregulation might relate to pathogenesis of GEP NETs