TRPA1‐expressing primary afferents synapse with a morphologically identified subclass of substantia gelatinosa neurons in the adult rat spinal cord

The TRPA1 channel has been proposed to be a molecular transducer of cold and inflammatory nociceptive signals. It is expressed on a subset of small primary afferent neurons both in the peripheral terminals, where it serves as a sensor, and on the central nerve endings in the dorsal horn. The substantia gelatinosa (SG) of the spinal cord is a key site for integration of noxious inputs. The SG neurons are morphologically and functionally heterogeneous and the precise synaptic circuits of the SG are poorly understood. We examined how activation of TRPA1 channels affects synaptic transmission onto SG neurons using whole‐cell patch‐clamp recordings and morphological analyses in adult rat spinal cord slices. Cinnamaldehyde (TRPA1 agonist) elicited a barrage of excitatory postsynaptic currents (EPSCs) in a subset of the SG neurons that responded to allyl isothiocyanate (less specific TRPA1 agonist) and capsaicin (TRPV1 agonist). Cinnamaldehyde evoked EPSCs in vertical and radial but not islet or central SG cells. Notably, cinnamaldehyde produced no change in inhibitory postsynaptic currents and nor did it produce direct postsynaptic effects. In the presence of tetrodotoxin, cinnamaldehyde increased the frequency but not amplitude of miniature EPSCs. Intriguingly, cinnamaldehyde had a selective inhibitory action on monosynaptic C‐ (but not Aδ‐) fiber‐evoked EPSCs. These results indicate that activation of spinal TRPA1 presynaptically facilitates miniature excitatory synaptic transmission from primary afferents onto vertical and radial cells to initiate action potentials. The presence of TRPA1 channels on the central terminals raises the possibility of bidirectional modulatory action in morphologically identified subclasses of SG neurons.     

Locking Compression Plate in Musculoskeletal Oncology 'a Friend in Need'

Background

We are presenting our experience in the use of locking compression plate (LCP) after juxta-articular oncological resections in addition to its use in pathologic fracture.

Methods

A retrospective audit of skeletal reconstruction using LCP in 25 cases of long bone tumors was performed from 2008 to 2010. Reconstruction following limb salvage surgery was done in 17 patients and internal fixation of pathological fracture was done in 8 patients. All patients were available for > 12 months of follow-up, and thus assessed for union at the resected ends.

Results

There were 8 males and 17 females in the study. The average age at the time of surgery was 30 years (range, 9 to 66 years). The minimum follow-up was 12 months (range, 12 to 32 months). All patients except three went on to heal successfully. Complications occurred in those three patients: wound infection in one, nonunion in another, and periprosthetic fracture in the other patient. In the remaining patients, union was achieved at an average of 6.5 months after reconstruction in curative resection and 4.75 months after fixation of pathological fractures.

Conclusions

Joint sparing limb salvage surgery was made successfully possible after sekeletal reconstruction with LCP. Its use was also quite effective in pathological fractures with poor bone quality. Use of locking plates for musculoskeletal oncological reconstruction resulted in a good and predictable rate of union.     

Risk of renal cell carcinoma and polymorphism in phase I xenobiotic metabolizing CYP1A1 and CYP2D6 enzymes

The progressive increase in sporadic renal cell carcinoma (RCC) observed in industrialized countries supports the opinion that certain carcinogens present in the environment (tobacco smoke, drugs, pollutants, and dietary constituents) may affect the occurrence and progression of this disease in developing countries like India. The polymorphism of the enzymes involved in metabolism of such environmental factors may, therefore, confer variable propensity to RCC. The possible association between RCC and a polymorphism of the CYP1A1 and CYP2D6 genes specific to the Indian population was examined using peripheral blood DNA from 196 RCC cases and 250 population controls with detailed data of clinicopathologic characteristics for the disease. The CYP1A1 (val) “variant” genotype, which contains at least 1 copy of the CYP1A1 variant alleles, was found to be associated with a 2.03-fold [GG ver. AA/AG, unadjusted OR = 2.03; 95%CI = 1.233–3.342; P = 0.005] increase in the risk of RCC. There was also a significant association (p^trend = 0.034) between higher frequency of RCC subjects containing at least of copy of the CYP1A1 (val) “variant” genotype with III or IV Fuhrman's grade. Whereas, the CYP2D6 polymorphism did not show any association with RCC risk [TT ver. CT/CC, unadjusted OR = 95%CI = 1.233–3.342; P = 0.005]. There was a significant association (p^trend = 0.001) between the poor metabolizer CYP2D6 (TT) and progression towards higher pathological stage of RCC. Our data demonstrate for the first time a significant association between pharmacogenetic polymorphisms of CYP1A1 and risk of RCC development in the Indian population. The findings suggest that inter-individual variation in the phase I metabolic enzymes involved in the fictionalization and detoxification of specific xenobiotics is an important susceptibility factor for development and progression of RCC in Indians.     

Neuroendocrine Tumors of the Colon and Rectum: Prognostic Relevance and Comparative Performance of Current Staging Systems

Background

With increasing interest in neuroendocrine tumors (NETs), three staging systems for NETs of the colon and rectum have been published. Their prognostic relevance has not been examined and compared in an independent clinical database.

Methods

From the National Cancer Database (NCDB), 5457 patients diagnosed with colorectal neuroendocrine tumor (CRNETs) between 1998 and 2002 were staged according to the staging systems from (1) European Neuroendocrine Tumor Society (ENETS, 2006; n = 1537); (2) American Joint Committee on Cancer (AJCC, 2009; n = 1140); and (3) location-specific staging systems from the Surveillance Epidemiology and End Results (SEER, 2008; n = 942). Stage-stratified overall survival (OS) and Cox-specific concordance indices were calculated for each system. Independent prognostic factors were identified by multivariate analysis.

Results

Five-year OS for stage I, II, III, and IV CRNETs as defined by the ENETS staging system were 90.8, 77.3, 53.1, and 14.8 %, respectively. For well-differentiated CRNETs, the 5-year OS for stage I, II, III, and IV as defined by the AJCC staging system were superior: 90.6, 83.9, 64.8, and 24.9 %, respectively. Both staging systems had a concordance index of 0.72. After specifying location in the colon versus rectum, all three systems demonstrated acceptable performance. Histologic grade was a significant independent predictor of OS not currently incorporated in the staging systems.

Conclusions

The three staging systems showed comparable prognostic stratification of CRNETs, while the AJCC and ENETS systems are the most parsimonious. The current analysis supports the use of the AJCC for well-differentiated disease and ENETS systems for all CRNETs until there is further evidence for modification.     

Runx2 Regulates Endochondral Ossification Through Control of Chondrocyte Proliferation and Differentiation

Synthesis of cartilage by chondrocytes is an obligatory step for endochondral ossification. Global deletion of the Runx2 gene results in complete failure of the ossification process, but the underlying cellular and molecular mechanisms are not fully known. Here, we elucidated Runx2 regulatory control distinctive to chondrocyte and cartilage tissue by generating Runx2 exon 8 floxed mice. Deletion of Runx2 gene in chondrocytes caused failure of endochondral ossification and lethality at birth. The limbs of Runx2^ΔE8/ΔE8 mice were devoid of mature chondrocytes, vasculature, and marrow. We demonstrate that the C‐terminus of Runx2 drives its biological activity. Importantly, nuclear import and DNA binding functions of Runx2 are insufficient for chondrogenesis. Molecular studies revealed that despite normal levels of Sox9 and PTHrP, chondrocyte differentiation and cartilage growth are disrupted in Runx2^ΔE8/ΔE8 mice. Loss of Runx2 in chondrocytes also impaired osteoprotegerin‐receptor activator of NF‐κB ligand (OPG‐RANKL) signaling and chondroclast development. Dwarfism observed in Runx2 mutants was associated with the near absence of proliferative zone in the growth plates. Finally, we show Runx2 directly regulates a unique set of cell cycle genes, Gpr132, Sfn, c‐Myb, and Cyclin A1, to control proliferative capacity of chondrocyte. Thus, Runx2 is obligatory for both proliferation and differentiation of chondrocytes. © 2014 American Society for Bone and Mineral Research.     

Effect of cementation,cement type and vent holes on fit of zirconia copings

Objectives

To investigate the effect of cementation, cement type and vent-holes on the marginal and internal fit of Zirconia (Zr) Copings.

Ondansetron versus placebo for the control of nausea and vomiting during Caesarean section under spinal anaesthesia

This prospective, randomised, placebo-controlled, double-blind study was performed to evaluate the effects of ondansetron on nausea and vomiting during elective Caesarean section under spinal anaesthesia. Seventy-four full-term parturients were studied. After umbilical-cord clamping, ondansetron 4 mg or 0.9% saline was injected intravenously and the study period continued for 2 h. The severity of nausea was graded from 0 = none to 10 = maximum, while that of vomiting was graded from single = once per min to continuous = multiple per min. The incidence of vomiting was lower following ondansetron (36%) compared with the control group (58%, p < 0.028). Neither the severity of vomiting nor the incidence of nausea was influenced by ondansetron. However, for those who experienced nausea, ondansetron reduced its severity (p = 0.05). We conclude that the intra-operative administration of 4 mg ondansetron intravenously during Caesarean section under spinal anaesthesia significantly reduces the incidence of vomiting and the severity of nausea.