Muscle-specific deletion of SOCS3 does not reduce the anabolic response to leucine in a mouse model of acute inflammation.

Excessive inflammation reduces skeletal muscle protein synthesis leading to wasting and weakness. The janus kinase/signal transducers and activators of transcription-3 (JAK/STAT3) pathway is important for the regulation of inflammatory signaling. As such, suppressor of cytokine signaling-3 (SOCS3), the negative regulator of JAK/STAT signaling, is thought to be important in the control of muscle homeostasis. We hypothesized that muscle-specific deletion of SOCS3 would impair the anabolic response to leucine during an inflammatory insult. Twelve week old (n=8 per group) SOCS3 muscle-specific knockout mice (SOCS3-MKO) and littermate controls (WT) were injected with lipopolysaccharide (LPS, 1mg/kg) or saline and were studied during fasted conditions or after receiving 0.5g/kg leucine 3h after the injection of LPS. Markers of inflammation, anabolic signaling, and protein synthesis were measured 4h after LPS injection. LPS injection robustly increased mRNA expression of inflammatory molecules (Socs3, Socs1, Il-6, Ccl2, Tnfα and Cd68). In muscles from SOCS3-MKO mice, the Socs3 mRNA response to LPS was significantly blunted (∼6-fold) while STAT3 Tyr705 phosphorylation was exacerbated (18-fold). Leucine administration increased protein synthesis in both WT (∼1.6-fold) and SOCS3-MKO mice (∼1.5-fold) compared to basal levels. LPS administration blunted this effect, but there were no differences between WT and SOCS3-MKO mice. Muscle-specific SOCS3 deletion did not alter the response of AKT, mTOR, S6 or 4EBP1 under any treatment conditions. Therefore, SOCS3 does not appear to mediate the early inflammatory or leucine-induced changes in protein synthesis in skeletal muscle.

End-of-radiation PSA as a novel prognostic factor in patients undergoing definitive radiation and androgen deprivation therapy for prostate cancer.

BACKGROUND: In men undergoing definitive radiation for prostate cancer, it is unclear whether early biochemical response can provide additional prognostic value beyond pre-treatment risk stratification. METHODS: Prostate cancer patients consecutively treated with definitive radiation at our institution by a single provider from 1993 to 2006 and who had an end-of-radiation (EOR) PSA (n=688, median follow-up 11.2 years). We analyzed the association of an EOR PSA level, obtained during the last week of radiation, with survival outcomes. Multivariable-adjusted cox proportional hazards models were constructed to assess associations between a detectable EOR PSA (defined as ⩾0.1 ng ml-1) and biochemical failure-free survival (BFFS), metastasis-free survival (MFS), prostate cancer-specific survival (PCSS) and overall survival (OS). Kaplan-Meier survival curves were constructed, with stratification by EOR PSA. RESULTS: At the end of radiation, the PSA level was undetectable in 30% of patients. Men with a detectable EOR PSA experienced inferior 10-year BFFS (49.7% versus 64.4%, P<0.001), 10-year MFS (84.8% versus 92.0%, P=0.003), 10-year PCSS (94.3% versus 98.2%, P=0.007) and 10-year OS (75.8% versus 82.5%, P=0.01), as compared to men with an undetectable EOR PSA. Among National Comprehensive Care Network (NCCN) intermediate- and high-risk men who were treated with definitive radiation and androgen deprivation therapy (ADT), a detectable EOR PSA was more strongly associated with PCSS than initial NCCN risk level (EOR PSA: HR 5.89, 95% CI 2.37-14.65, P<0.001; NCCN risk level: HR 2.01, 95% CI 0.74-5.42, P=0.168). Main study limitations are retrospective study design and associated biases. CONCLUSIONS: EOR PSA was significantly associated with survival endpoints in men who received treatment with definitive radiation and ADT. Whether the EOR PSA can be used to modulate treatment intensity merits further investigation.

Diagnosing musculoskeletal tumours: How accurate is CT-guided core needle biopsy?

INTRODUCTION: Biopsy is a critical juncture in the diagnostic process for evaluating musculoskeletal tumours. The traditional diagnostic standard of open biopsy yields highly accurate diagnoses but associated with it is a significant rate of procedural complications. Imaging-guided needle biopsy is now being widely adopted as a competitive and minimally-invasive alternative with significantly lower complication rates. We assess its diagnostic outcomes at a tertiary referral centre in Melbourne, Australia. METHOD: Data pertaining to biopsy and surgical histology were retrieved from the musculoskeletal tumour database at St Vincent's Hospital, Fitzroy following approval from the Human Research Ethics Committee (HREC 091/13). Data analyses were performed in STATA 12 to assess diagnostic parameters and related outcomes. RESULTS: Bone tumours (n = 380) yielded accuracy of 80.8% with diagnostic error of 7.1% and undiagnostic rates of 12.1%. Soft-tissue tumours (n = 751) yielded accuracy of 83.2% with diagnostic error of 10.5% and undiagnostic rates of 6.3%. Biopsy of benign tumours (n = 648, accuracy = 85.3%, error = 5.9%, undiagnostic 8.8%) was more accurate than malignant tumours (n = 501, accuracy = 75.8%, error 14.0%, undiagnostic 7.4%). The overall procedural complication rate was 0.7%. DISCUSSION: CT-guided core needle biopsy is a safe, accurate, and highly effective procedure that obviates the need for open and surgical biopsy in a significant number of cases. When combined with fusion imaging, CT guidance is an accurate method of targeting specific regions of interest.

Radiological review of intercostal artery: Anatomical considerations when performing procedures via intercostal space.

INTRODUCTION: The aim of this study was to closely examine the course of the intercostal arteries within the intercostal spaces particularly with regard to where the arteries were located in relation to their adjacent ribs. The degree of tortuosity of the arteries was also examined, along with anatomical differences in different age groups. METHODS: A total of 81 patients between the age of 30 and 90 years who had underwent a CT examination of the chest for any indication were included in the study. All studies were performed on a dual source 64 slice CT (Siemens Definition Erlangen Germany). Analysis of the intercostal arteries was performed on a CT workstation using volume rendered 3D reconstructions F, or each patient the 10'n intercostals pacesb ilaterally were examined for the course and tortuosity of the intercostal arteries. RESULTS: The ICA is located relatively inferiorly in the intercostal space at costovertebral junction and it gradually becomes more superiorly positioned within the intercostal space it as courses laterally. This finding was consistent in all age groups. In addition, analysis of the data demonstrated increasing intercostal artery tortuosity with advancing age. CONCLUSION: In this study we have examined the course of the posterior intercostal arteries using MDCT. This study confirms the classical description of the course of ICA. We have shown that in the medial chest, posteriorly, the artery is located in the inferior half of the intercostal space. As it moves away from the costovertebral junction it travels closer to the inferior border of the rib above and reaches the intercostal groove. We have also shown that the artery tends to be more tortuous in elderly patients, decreasing the area of "safe" space for interventions. Both of these findings are relevant to radiologists and non-radiologists performing interventional procedures via the intercostal space.

Co-expression of the P75 neurotrophin receptor and neurotrophin receptor-interacting melanoma antigen homolog in the mature rat brain.

The p75 neurotrophin receptor (p75(NTR)) is involved in the regulation of neuronal survival and phenotype, but its signal transduction mechanisms are poorly understood. Recent evidence has implicated the cytoplasmic protein NRAGE (neurotrophin receptor-interacting MAGE (from Melanoma AntiGEn) homolog) in p75(NTR) signaling. To gain further insight into the role of NRAGE, we investigated the co-expression of NRAGE and p75(NTR) in mature rat brain. In all areas examined, NRAGE appeared to be confined to neurons. In the basal forebrain cholinergic complex, NRAGE immunoreactivity was evident in all p75(NTR)-positive neurons. There were many more NRAGE-positive than p75(NTR)-positive neurons in these regions, however. NRAGE was also expressed in areas of the basal forebrain that did not express p75(NTR), including the lateral septal nucleus and the nucleus accumbens. A finding in marked contrast to previous studies was the presence of p75(NTR) immunoreactivity in neuronal cell bodies in the hippocampus. Hippocampal p75(NTR) immunoreactivity was apparent in rats 6 months and older, and was localized to the dentate gyrus and stratum oriens. All p75(NTR)-positive neurons in the dentate gyrus and hippocampal formation were positive for NRAGE. The majority of granular cells of the dentate gyrus and pyramidal cells in the hippocampal formation were positive for NRAGE and negative for p75(NTR). NRAGE was also present in some neuronal populations that express p75(NTR) after injury, including striatal cholinergic interneurons, and motor neurons. A region of marked disparity was the cerebral cortex, in which NRAGE immunoreactivity was widespread whereas p75(NTR) was absent. The results are consistent with an important role for NRAGE in p75(NTR) signaling, as all cells that expressed p75(NTR) also expressed NRAGE. The wider distribution of NRAGE expression suggests that NRAGE may also participate in other signaling processes.