Reduction of hepatic and adipose tissue glucocorticoid receptor expression with antisense oligonucleotides improves hyperglycemia and hyperlipidemia in diabetic rodents without causing systemic glucocorticoid antagonism

Glucocorticoids (GCs) increase hepatic gluconeogenesis and play an important role in the regulation of hepatic glucose output. Whereas systemic GC inhibition can alleviate hyperglycemia in rodents and humans, it results in adrenal insufficiency and stimulation of the hypothalamic-pituitary-adrenal axis. In the present study, we used optimized antisense oligonucleotides (ASOs) to cause selective reduction of the glucocorticoid receptor (GCCR) in liver and white adipose tissue (WAT) and evaluated the resultant changes in glucose and lipid metabolism in several rodent models of diabetes. Treatment of ob/ob mice with GCCR ASOs for 4 weeks resulted in approximately 75 and approximately 40% reduction in GCCR mRNA expression in liver and WAT, respectively. This was accompanied by approximately 65% decrease in fed and approximately 30% decrease in fasted glucose levels, a 60% decrease in plasma insulin concentration, and approximately 20 and 35% decrease in plasma resistin and tumor necrosis factor-alpha levels, respectively. Furthermore, GCCR ASO reduced hepatic glucose production and inhibited hepatic gluconeogenesis in liver slices from basal and dexamethasone-treated animals. In db/db mice, a similar reduction in GCCR expression caused approximately 40% decrease in fed and fasted glucose levels and approximately 50% reduction in plasma triglycerides. In ZDF and high-fat diet-fed streptozotocin-treated (HFD-STZ) rats, GCCR ASO treatment caused approximately 60% reduction in GCCR expression in the liver and WAT, which was accompanied by a 40-70% decrease in fasted glucose levels and a robust reduction in plasma triglyceride, cholesterol, and free fatty acids. No change in circulating corticosterone levels was seen in any model after GCCR ASO treatment. To further demonstrate that GCCR ASO does not cause systemic GC antagonism, normal Sprague-Dawley rats were challenged with dexamethasone after treating with GCCR ASO. Dexamethasone increased the expression of GC-responsive genes such as PEPCK in the liver and decreased circulating lymphocytes. GCCR ASO treatment completely inhibited the increase in dexamethasone-induced PEPCK expression in the liver without causing any change in the dexamethasone-induced lymphopenia. These studies demonstrate that tissue-selective GCCR antagonism with ASOs may be a viable therapeutic strategy for the treatment of the metabolic syndrome.     

Risk factors for postoperative sepsis in laparoscopic gastric bypass

Introduction

Postoperative sepsis is a rare but serious complication following elective surgery. The purpose of this study was to identify the rate of postoperative sepsis following elective laparoscopic gastric bypass (LGBP) and to identify patients’ modifiable, preoperative risk factors.

Methods

The American College of Surgeons National Surgical Quality Improvement Program database was queried from 2005 to 2013 for factors associated with the development of postoperative sepsis following elective LGBP. Patients who developed sepsis were compared to those who did not. Results were analyzed using the Chi-square test for categorical variables and Wilcoxon two-sample test for continuous variables. A multivariate logistic regression analysis was utilized to calculate adjusted odds ratios for factors contributing to sepsis.

Results

During the study period, 66,838 patients underwent LGBP. Of those, 546 patients developed postoperative sepsis (0.82 %). The development of sepsis was associated with increased operative time (161 ± 77.8 vs. 135.10 ± 56.5 min; p < 0.0001) and a greater number of preoperative comorbidities, including diabetes (39.6 vs. 30.6 %; p < 0.0001), hypertension requiring medication (65.2 vs. 54 %; p < 0.0001), current tobacco use (16.7 vs. 11.5 %; p = 0.0002), and increased pack-year history of smoking (8.6 ± 18.3 vs. 5.6 ± 14.2; p = 0.0006), and the Charlson Comorbidity Index (0.51 ± 0.74 vs. 0.35 ± 0.57, p < 0.0001). Sepsis resulted in an increased length of stay (10.1 ± 14.4 vs. 2.4 ± 4.8 days; p < 0.0001) and a 30 times greater chance of 30-day mortality (4.03 vs. 0.11 %, p < 0.0001). Multivariate logistic regression analysis showed that current smokers had a 63 % greater chance of developing sepsis compared to non-smokers, controlling for age, race, gender, BMI, and CCI score (OR 1.63, 95 % CI 1.23–2.14; p = 0.0006).

Conclusions

Laparoscopic gastric bypass is uncommonly associated with postoperative sepsis. When it occurs, it portends a 30 times increased risk of death. A patient history of diabetes, hypertension, and increasing pack-years of smoking portend an increased risk of sepsis. Current smoking status, a preoperative modifiable risk factor, is independently associated with the chance of postoperative sepsis. Preoperative patient optimization and risk reduction should be a priority for elective surgery, and patients should be encouraged to stop smoking prior to gastric bypass.

     

A comparative study to evaluate the effect of limited access dressing (LAD) on burn wound healing

Biochemical and histopathological analyses are commonly used objective parameters in research and clinical fields to assess the healing status of burn wounds. In this study, the effect of newer intermittent negative‐pressure wound therapy in combination with moist environment [limited access dressing (LAD)] on burn wound healing is studied. Various biochemical parameters like hydroxyproline, hexosamine and total protein, and antioxidants like reduced glutathione (GSH), glutathione peroxidase (GPx) and oxidative biomarker malondialdhyde (MDA) were measured in the granulation tissue. Histopathologically, necrotic tissue, amount of inflammatory infiltrate, angiogenesis and extracellular matrix deposition (ECM) were studied to determine wound healing. A total of 55 patients were divided into two groups as follows: LAD group (n = 28) and conventional dressing group (n = 27). Patients treated with LAD have shown significant increase in the mean levels of (±SD) hydroxyproline (75·2 ± 26·30 versus 27·8 ± 15·5; P = 0·010), hexosamine (9·0 ± 1·99 versus 8·0 ± 1·18; P = 0·038), total protein (15·6 ± 8·23 versus 10·26 ± 4·94; P = 0·003), GSH (7·40 ± 1·91 versus 5·1 ± 1·28; P = 0·037), GPx (112·6 ± 46·4 versus 92 ± 32·4; P = 0·016), and decrease in MDA (6·5 ± 2·24 versus 1 0·6 ± 3·8; P = 0·002). Histopathologically, between LAD and conventional dressing groups, there was a significant difference after 10 days of treatment (mean±SE) in necrotic tissue of (LAD versus conventional dressing groups = 10 ± 1·8 versus 11·9 ± 2·6; P = 0·033), inflammatory cells (8·4 ± 1·9 versus 13 ± 3·46; P = 0·021), new blood vessels (12·5 ± 2·87 versus 9·4 ± 1·7; P = 0·047), ECM deposit (12·9 ± 2·41 versus 9·68 ± 1·3; P = 0·018) and showed comparatively fewer inflammatory cells, increased and well‐organised extracellular matrix deposit, more angiogenesis in LAD group as compared with that in conventional dressing group. To conclude, LAD exerts its beneficial effects on wound healing by reducing oxidative stress, decreasing necrotic tissue and amount of inflammatory infiltrate, and increasing ECM deposition and angiogenesis.     

Anatomic Bladder Neck Preservation During Robotic-Assisted Laparoscopic Radical Prostatectomy: Description of Technique and Outcomes

Background

Robotic-assisted laparoscopic radical prostatectomy (RALP) has been rapidly adopted despite a daunting learning curve with bladder neck dissection as a challenging step for newcomers.

Objective

To describe an anatomic, reproducible technique of bladder neck preservation (BNP) and associated perioperative and long-term outcomes.

Design, settings, and participants

From September 2005 to May 2009, data from 619 consecutive RALP were prospectively collected and compared on the basis of bladder neck dissection technique with 348 BNP and 271 standard technique (ST).

Surgical procedure

RALP with BNP.

Measurements

Tumor characteristics, perioperative complications, and post-operative urinary control were evaluated at 4, 12 and 24 months using (1) the Expanded Prostate Cancer Index (EPIC) urinary function scale scored from 0–100; and (2) continence defined as zero pads per day.

Results and limitations

Mean age for BNP versus ST was 57.1 ± 6.6 yr versus 58.9 ± 6.7 yr (p = 0.033), while complication rates did not vary significantly by technique. Estimated blood loss was 183.7 ± 95.8 ml versus 224.6 ± 108 ml (p = 0.938) in men who underwent BNP versus ST. The overall positive margin rate was 12.8%, which did not differ at the prostate base for BNP versus ST (1.4% vs. 2.2%, p = 0.547). Mean urinary function scores for BNP versus ST at 4, 12, and 24 mo were 64.6 versus 57.2 (p = 0.037), 80.6 versus 79.0 (p = 0.495), and 94.1 versus 86.8 (p < 0.001). Similarly, BNP versus ST continence rates at 4, 12, and 24 mo were 65.6% versus 26.5% (p < 0.001), 86.4% versus 81.4% (p = 0.303), and 100% versus 96.1% (p = 0.308).

Conclusions

BNP versus ST is associated with quicker recovery of urinary function and similar cancer control.     

Radiographic findings in tuberculosis of the calvarium

We reviewed the pattern of involvement of the calvarium by tuberculosis (TB) in five patients and the role of imaging in its management. Four patients presented with localised scalp swelling and one with generalized seizures. Radiographs revealed lucent lesions with minimal surrounding sclerosis in the frontal (2), parietal (2) and occipital (1) bones. CT showed lesions involving the entire thickness of the calvarium and accompanying contrast-enhancing soft tissue. The patient presenting with seizures had a ring-enhancing lesion in the parietal lobe in addition to the extra-axial lesions. Although radiographs in all cases demonstrated calvarial TB, CT showed the extent of the defect, involvement of adjacent soft tissues, and in one case an intra-axial lesion. Radiographs suffice for follow-up of these patients. Received: 23 July 1999 Accepted: 20 September 1999     

Imaging in isolated sacral tuberculosis: a review of 15 cases

Objective. To review imaging studies of isolated involvement of the sacrum due to tuberculosis and determine the role of imaging in the diagnosis and management of these patients. Design and patients. A retrospective analysis of 15 cases of isolated sacral tuberculosis imaged with MR imaging was performed. The CT images were also reviewed where available, and the various lesion characteristics were identified. We also reviewed the medical records in an attempt to determine the impact of the imaging studies on the management of these patients. Results. Fifteen patients (5 male, 10 female) presented with symptoms of 3–15 months’ duration. Chronic localized backache with muscle spasm was the commonest presenting symptom; discharging sinuses with abscess formation was found in six patients, five of whom were children. MR imaging of the sacrum revealed a hypointense marrow signal on T1-weighted images and hyperintense signal on T2-weighted images in 14 of 15 patients, the S2 vertebra being always involved. CT revealed osteolytic changes in the sacrum in all the five patients in whom CT was performed. All patients showed marked clinical improvement within 1 year of anti-tuberculous chemotherapy. Conclusion. Isolated tuberculosis of the sacrum is uncommon but should be suspected in patients presenting with chronic low backache or children with discharging sinuses/abscesses and showing sacral destruction on CT or MR imaging. MR imaging can identify cases and enables early institution of anti- tuberculous chemotherapy. Received: 31 August 1999 Revision requested: 1 November 1999 Revision received: 27 March 2000 Accepted: 14 April 2000     

Marsupialization of intramyocardial left anterior descending artery: a novel approach for easy access during revascularization

The left anterior descending (LAD) artery is the most important vessel bypassed during coronary revascularization procedures. This artery usually runs a superficial course, making it easy for localization and grafting. However, many times it takes a course deep in the myocardium or is embedded in thick epicardial fat, which results in technical challenges to the surgeon for localization and grafting. So far, many techniques are described for overcoming these problems, but all require cardiopulmonary bypass (CPB), and in fact, intramyocardial LAD is considered a relative contraindication for off-pump coronary artery bypass grafting (OPCAB). In the present era of enhanced interest in OPCAB, these techniques are not as helpful as they are for conventional CABG with CPB. Here, we describe a novel approach of marsupialization of the LAD for revascularization of intramyocardial LAD that is useful for off-pump as well as conventional revascularization procedures and makes grafting simple and reproducible.     

Twenty years' experience of steroids in infantile hemangioma—a developing country's perspective

Background

Hemangioma is a common vascular tumor. Though it involutes spontaneously, results are unpredictable. Steroid therapy is an effective mode of its regression. We present our experience of largest series and possible recommendations for treatment.

Materials and methods

A total of 2398 patients were treated during the study period of 20 years. They were given oral prednisolone, intralesional triamcinolone, or combination of both as per the protocol and followed for the response. Response to the treatment was graded as excellent, good, poor, or no response.

Results

The male-to-female ratio was 1:2.3. In 81% of patients, hemangioma was noticed within first month of life. The commonest site of involvement was head and neck (57%). The commonest clinical presentation was discoloration and swelling. Mean age and size were 8.43 ± 7.04 months and 23.64 ± 20.13 cm². Response rate was highest for superficial type using any modality of treatment. Patients younger than 1 year showed better response (90.3%) in comparison with children older than 1 year (80.8%). The specific complications occurring were infections in 249 (12.4%), cushingoid facies and growth delay in 62 (3.1%), and hypertension in 51 (2.5%) patients.

Conclusion

Steroid therapy either oral or intralesional as per the requirement is an easy and safe modality. Results are good to satisfactory in most patients. The complications are minimal. If treatment is needed, it should be used as a first-line therapy, especially when cost is an important concern.