Testosterone and trenbolone enanthate increase mature myostatin protein expression despite increasing skeletal muscle hypertrophy and satellite cell number in rodent muscle.

The androgen-induced alterations in adult rodent skeletal muscle fibre cross-sectional area (fCSA), satellite cell content and myostatin (Mstn) were examined in 10-month-old Fisher 344 rats (n = 41) assigned to Sham surgery, orchiectomy (ORX), ORX + testosterone (TEST; 7.0 mg week-1 ) or ORX + trenbolone (TREN; 1.0 mg week-1 ). After 29 days, animals were euthanised and the levator ani/bulbocavernosus (LABC) muscle complex was harvested for analyses. LABC muscle fCSA was 102% and 94% higher in ORX + TEST and ORX + TREN compared to ORX (p < .001). ORX + TEST and ORX + TREN increased satellite cell numbers by 181% and 178% compared to ORX, respectively (p < .01), with no differences between conditions for myonuclear number per muscle fibre (p = .948). Mstn protein was increased 159% and 169% in the ORX + TEST and ORX + TREN compared to ORX (p < .01). pan-SMAD2/3 protein was ~30-50% greater in ORX compared to SHAM (p = .006), ORX + TEST (p = .037) and ORX + TREN (p = .043), although there were no between-treatment effects regarding phosphorylated SMAD2/3. Mstn, ActrIIb and Mighty mRNAs were lower in ORX, ORX + TEST and ORX + TREN compared to SHAM (p < .05). Testosterone and trenbolone administration increased muscle fCSA and satellite cell number without increasing myonuclei number, and increased Mstn protein levels. Several genes and signalling proteins related to myostatin signalling were differentially regulated by ORX or androgen therapy.

Effects of testosterone treatment on markers of skeletal muscle ribosome biogenesis.

The effects of testosterone (TEST) treatment on markers of skeletal muscle ribosome biogenesis in vitro and in vivo were examined. C2 C12 myotubes were treated with 100 nm TEST for short-term (24-h) and longer-term (96-h) treatments. Moreover, male 10-month-old Fischer 344 rats were housed for 4 weeks, and the following groups were included in this study: (i) Sham-operated (Sham) rats, (ii) orchiectomised rats (ORX) and (iii) ORX+TEST-treated rats (7.0 mg week-1 ). For in vitro data, TEST treatment increased c-Myc mRNA expression by 38% (P = 0.004) after 96 h, but did not affect total RNA, 47S pre-rRNA, Raptor mRNA, Nop56 mRNA, Bop1 mRNA, Ncl mRNA at 24 h or 96 h following the treatment. For in vivo data, ORX decreased levator ani/bulbocavernosus (LABC) myofibril protein versus Sham (P = 0.006), whereas ORX+TEST (P = 0.015) rescued this atrophic effect. ORX also decreased muscle ribosome content (total RNA) compared to Sham (P = 0.046), whereas ORX+TEST tended to rescue this effect (P = 0.057). However, other markers of ribosome biogenesis including c-Myc mRNA, Nop56 mRNA, Bop1 mRNA, Ncl mRNA decreased with ORX independently of TEST treatments (P < 0.05). Finally, lower phospho-(Ser235/236)-to-total rps6 protein and lower rpl5 protein levels existed in ORX+TEST rats versus other treatments, suggesting that chronic TEST treatment may lower translational capacity.

Bone loss in a new rodent model combining spinal cord injury and cast immobilization.

OBJECTIVES: Characterize bone loss in our newly developed severe contusion spinal cord injury (SCI) plus hindlimb immobilization (IMM) model and determine the influence of muscle contractility on skeletal integrity after SCI. METHODS: Female Sprague-Dawley rats were randomized to: (a) intact controls, (b) severe contusion SCI euthanized at Day 7 (SCI-7) or (c) Day 21 (SCI-21), (d) 14 days IMM-alone, (e) SCI+IMM, or (f) SCI+IMM plus 14 days body weight supported treadmill exercise (SCI+IMM+TM). RESULTS: SCI-7 and SCI-21 exhibited a >20% reduction in cancellous volumetric bone mineral density (vBMD) in the hindlimbs (p⋜0.01), characterized by reductions in cancellous bone volume (cBV/TV%), trabecular number (Tb.N), and trabecular thickness. IMM-alone induced no observable bone loss. SCI+IMM exacerbated cancellous vBMD deficits with values being >45% below Controls (p⋜0.01) resulting from reduced cBV/TV% and Tb.N. SCI+IMM also produced the greatest cortical bone loss with distal femoral cortical area and cortical thickness being 14-28% below Controls (p⋜0.01) and bone strength being 37% below Controls (p⋜0.01). SCI+IMM+TM partially alleviated bone deficits, but values remained below Controls. CONCLUSIONS: Residual and/or facilitated muscle contractility ameliorate bone decrements after severe SCI. Our novel SCI+IMM model represents a clinically-relevant means of assessing strategies to prevent SCI-induced skeletal deficits.

Lung cancer outcomes at a UK cancer unit between 1998-2001.

UNLABELLED: There are few data published on lung cancer survival in the UK. Survival rates for lung cancer at a UK Hospital between 1998-2001 are described. METHODS: Analysis of data collected from multidisciplinary team (MDT) meetings, lung cancer registrations and hospital coding. RESULTS: 835 new lung cancers were diagnosed comprising 597 non-small cell lung cancers (NSCLC) (71%), 133 small cell (SCLC) (16%), and 105 clinical diagnoses (13%). Stage at diagnosis; stage I (25%), II (9%), IIIA (8%), IIIB (23%), IV (35%). Surgery was undertaken in 12%, radical radiotherapy (RT) in 4%, palliative RT in 32%, chemotherapy in 8% and best supportive care (BSC) in 36%. The 3-year cumulative survival for NSCLC was: stage I 39%, stage II 30%, stage III 6%, stage IV 0.5%. Only 46% of patients with stage I-IIIA disease received radical treatment. Reasons included poor lung function (32%), unresectable (24%), co-morbidities (17%), performance status (8%), patient choice (8%), unclear (6%), advanced age (5%). CONCLUSIONS: Survival figures are similar to other UK studies but do not compare favourably with US and European data. This may be because a large proportion of patients with early stage disease receive palliative care only.

Predictors of operative death after oesophagectomy for carcinoma.

BACKGROUND: Oesophagectomy for carcinoma provides a chance of cure but carries significant risk. This study defined risk factors for death after oesophageal resection for malignant disease. METHODS: Between 1990 and 2003, 773 oesophagectomies for oesophageal cancer were performed. Continuous variables were categorized into quartiles for analysis. Predictors of operative mortality were identified by univariate and multiple logistic regression analysis. RESULTS: The operative mortality rate was 4.8 per cent (37 of 773). In univariate analysis, advanced age, reduced forced expiratory volume in 1 s (FEV1), reduced forced vital capacity, presence of diabetes and tumour located in the upper third of the oesophagus were associated with a higher mortality rate. Multivariate analysis identified age (highest relative to lowest quartile, odds ratio (OR) 4.87 (95 per cent confidence interval (c.i.) 1.35 to 17.55); P = 0.009), tumour position (upper third relative to other locations, OR 4.23 (95 per cent c.i. 1.06 to 16.86); P = 0.041) and FEV1 (lowest relative to highest quartile, OR 4.72 (95 per cent c.i. 1.01 to 21.99); P = 0.018) as independent predictors of death. CONCLUSION: Advanced age, impaired preoperative respiratory function and a tumour high in the oesophagus are associated with a significantly increased risk of death after oesophagectomy for carcinoma.

Pneumonectomy for non-small cell lung cancer: predictors of operative mortality and survival.

OBJECTIVE: The purpose of this study was to identify predictors of operative mortality and survival following pneumonectomy for non-small cell lung cancer (NSCLC). METHODS: All 206 patients having a pneumonectomy for NSCLC between 1991 and 1997 in our unit were prospectively studied. There were 162 males (79%) and 44 females (21%) with a mean age (+/- standard deviation) of 61+/-7.7 years (range 34-81 years). Squamous cell (75%) and adenocarcinoma (17.0%) were the predominant histological types. The possible impact of 29 parameters on operative mortality and survival was tested with univariate and multivariate analysis. The mean follow-up was 2.3+/-1.2 years, ranging between 0 and 6.8 years, and it was complete. RESULTS: Operative mortality was 6.8% (14 deaths). On multiple logistic regression older age (P=0.04) and the development post-operatively of bronchopleural fistula (BPF) (P=0.01) were independent predictors of operative mortality. The overall, Kaplan-Meier, 1-, 3- and 5-year survival (+/- standard error from the mean), inclusive of operative mortality, was 68+/-3.3, 42+/-4.1 and 35+/-4.5%. On Cox proportional hazards regression adenocarcinoma (P=0.006), the development of BPF (P=0.003), older age (P=0.03) and higher pathological stage (P=0.02) were independent adverse predictors of survival. CONCLUSION: Pneumonectomy for NSCLC carries a considerable, but acceptable, operative mortality and provides an important survival benefit. This study suggests that older age and BPF are major determinants of an unfavourable in-hospital outcome; older age, BPF, adenocarcinoma cell type and higher pathological stage significantly reduce the probability of a long-term survival.

A tailored surgical approach for gastro-oesophageal reflux disease: the Nottingham experience.

OBJECTIVE: The objective was to assess the results which can be achieved by tailoring the anti-reflux procedure to the anatomical and functional situation of the patient with gastro-oesophageal reflux disease (GORD). PATIENTS AND METHODS: Two hundred and seventy six patients undergoing a primary tailored anti-reflux procedure between 1986 and 1996 were evaluated. An anti-reflux procedure was selected on the basis of the anatomical and functional findings assessed by means of barium video, endoscopy, manometry and prolonged pH monitoring. The operations performed were Nissen fundoplication (77), total fundoplication gastroplasty (TFG; 140) and Belsey Mark IV (BMIV; 59). The unit policy is for life-long follow-up. The symptoms at review were assessed and graded according to previously published criteria (Orringer MB, Skinner DB, Besley HR. Long-term results of the mark IV operation for hiatal hernia and analyses of recurrences and their treatment. J Thorac Cardiovasc Surg 1972;63:25-31). Patients with recurrent symptoms were fully re-investigated. RESULTS: Mean hospital stay was 8.2 days (5-32 days). There was one hospital death (0.36%). Mean follow-up was 6.7 years (range, 2.2-13.1 years). Overall excellent or good results were achieved in 247 (89.5%) patients (92.2% in Nissen, 90.7% in TFG and 83.1% in BMIV group, P=0.1). In patients without oesophagitis (n=72), the success rate was 93.1%, while for patients with grade IV oesophagitis (n=89) this was 87.6% (P=0.2). Kaplan-Meier freedom from recurrent or new, operation-induced, symptoms at 10 years was 88.1% (89.5% in Nissen, 87.4% in TFG and 73.8% in BMIV groups, P=0.08). CONCLUSIONS: These data suggest that where the appropriate anti-reflux procedure is selected, surgery can achieve satisfactory mid- and long-term success rates across the spectrum of GORD. When oesophageal shortening is evident, or merely suspected, we favour a TFG. In the presence of impaired motility and no evidence of oesophageal shortening, a BMIV is the preferred approach. The Nissen procedure is used for uncomplicated cases.