Relationship between circulating levels of monocyte chemoattractant protein-1 and systolic dysfunction in patients with hypertrophic cardiomyopathy

BackgroundProgression of hypertrophic cardiomyopathy (HCM) to left ventricular dilatation and systolic dysfunction sometimes occurs. However, the mechanism of the transition from hypertrophy to dysfunction has not been elucidated. It has been reported that circulating levels of monocyte chemoattractant protein-1 (MCP-1), which is a major factor promoting the accumulation of macrophages, are increased in patients with congestive heart failure. We measured circulating levels of MCP-1 in patients with HCM and examined whether MCP-1 was expressed in the myocardium of HCM patients. We also examined whether circulating levels of MCP-1 were correlated with left ventricular dysfunction.MethodsCirculating levels of MCP-1 were measured by an enzyme immunoassay in 26 patients with HCM (60±2 years old) and 20 control subjects (57±2 years old). Cardiac function was evaluated by two-dimensional echocardiography and cardiac catheterization.ResultsHCM patients had significantly elevated levels of MCP-1 (HCM: 309±30 vs. control: 178±8 pg/ml, P<.001). MCP-1 levels in patients with systolic dysfunction were significantly higher than those in patients without systolic dysfunction (P<.05) and were also significantly higher than those in patients with outflow obstruction (P<.05). Immunohistochemical analysis revealed that MCP-1 was expressed in endomyocardial biopsy samples obtained from HCM patients with systolic dysfunction. Furthermore, MCP-1 levels were inversely correlated with fractional shortening (r=?.401, P<.05) and correlated with left ventricular end-diastolic pressure (r=?.579, P<.01).ConclusionThese results show that MCP-1 is associated with, and might be involved in the pathogenesis of, left ventricular systolic dysfunction in patients with HCM.     

Proteomics analysis in lung cancer: challenges and opportunities

Recent technological developments in proteomic analysis are bringing us new insights into the molecular classification of tumours. Although proteomic analysis in cancer profiling is still under development both in terms of the instruments used and the data analytical tools, this method has great potential advantages for the analysis of biospecimens of many types. Direct measurement of abnormally expressed or modified proteins in the tumour tissue and/or patient blood may be an effective approach for discovering new biomarkers. Proteomics has the significant advantage of being able to discern not only changes in expression levels but also in post-translational modifications. Thus, the proteomics approach to protein profiling and biomarker discovery uncovers biomarkers from a different viewpoint than microarray analysis. This review summarizes the range of proteomics technologies employed for cancer profiling, and how they have been used to derive new classification models for human lung cancer.     

Deprivation of mother-pup interaction by early weaning alters myelin formation in male, but not female, ICR mice

We previously reported that early-weaned Balb/c mice develop a persistent increase in anxiety as well as aggression, and we suggested that deprivation of mother-pup interaction from postnatal days 15 to 21 might account for this phenomenon. In the present study, we investigated developmental changes in myelin formation and behavioral effects of early weaning in male and female ICR mice. Early weaning was associated with decreased numbers of open-arm entries in an elevated plus-maze for both male and female mice at 3 weeks of age (W3); this effect was persistently observed in males, but ceased after W3 in females. Compared to the brains of normally weaned mice, the brains of the early-weaned males at W8 and of the females at W5 were of lesser mass. Western blotting with whole-brain homogenates identified four isoforms of myelin basic protein (MBP; 21.5, 18.5, 17.0, and 14.0 kDa). Expression of these MBPs increased gradually in normally weaned mice. In contrast, in the early-weaned male mice, but not the early-weaned female mice, it increased robustly at W3 and then declined at W5, as compared to the normally weaned mice. These results suggest that early weaning influences not only anxiety-related behavior but also myelin formation in the brain during the developmental period, particularly between 3 and 5 weeks of age, and male mice are more vulnerable than females to early-weaning effects on behavior and myelin formation.     

RNA interference-mediated knock-down of transient receptor potential vanilloid 1 prevents forepaw inflammatory hyperalgesia in rat

Transient receptor potential vanilloid (TRPV)1 is a ligand-gated cation channel expressed by primary sensory neurons, including those in the dorsal root ganglia (DRG). TRPV1 plays an essential role in development of inflammatory thermal hyperalgesia after tissue injury and its expression in rat lumbar DRG is increased after hindpaw inflammation. However, the identity of factors mediating forepaw inflammatory hyperalgesia has remained elusive. Here, we examined behavioral responses to noxious thermal stimuli after forepaw inflammation in rats and found that inflammation induced by intraplantar injection of complete Freund's adjuvant significantly reduced hot-plate latency (HPL) at 50 degrees C. TRPV1 expression levels in the ipsilateral cervical DRG were also elevated after forepaw inflammation. By contrast, HPL at 56 degrees C was not shortened after forepaw inflammation and expression of TRPV2, a TRPV1 homolog, in the DRG was not increased. Paratracheal injection of short interfering RNA targeting TRPV1 blocked TRPV1 up-regulation in cervical DRG and abolished inflammation-mediated HPL reductions seen at 50 degrees C. However, thermal hyperalgesia previously established by inflammation was not reversed by short interfering RNA injection. These results indicate that: (i) enhanced TRPV1 expression in cervical DRG is closely associated with development of inflammatory thermal hyperalgesia in the forepaw after tissue injury and (ii) RNA interference targeting TRPV1 prevents inflammatory thermal hyperalgesia after forepaw injuries but does not ameliorate it when already established in a rat model of nociceptive pain representing upper limb injury in humans.     

Lymphatic Microvessel Density is an Independent Prognostic Factor in Colorectal Cancer

Purpose Although lymph node metastasis via lymphatic vessels often is related with an adverse outcome, it is not well known whether lymphatic spread to lymph node needs the development of the new lymphatic formation. In addition, the correlation between lymphangiogenesis and prognosis has not been well documented. This study was designed to assess the prognostic value of lymphangiogenesis and lymphatic vessel invasion in colorectal cancer. Methods We examined 106 colorectal cancer specimens by immunostaining for podoplanin, lymphatic endothelial specific marker. We evaluated lymphangiogenesis, as measured by lymphatic microvessel density, and lymphatic vessel invasion. We next investigated the association of these two parameters with the clinicopathologic findings and prognosis. Results A significant correlation was observed between high lymphatic microvessel density and positive lymphatic vessel invasion (P = 0.0003). Positive lymphatic vessel invasion was significantly associated with the presence of lymph node metastasis (P = 0.0071). The survival curves demonstrated that both high lymphatic microvessel density and positive lymphatic vessel invasion were correlated with an adverse outcome (P = 0.0004 and P = 0.009, respectively). In a univariate analysis, high lymphatic microvessel density and positive lymphatic vessel invasion were negatively associated with the overall survival (P = 0.0011 and P = 0.0118, respectively). Furthermore, high lymphatic microvessel density, but not lymphatic vessel invasion, correlated with a poor outcome in a multivariate analysis (P = 0.0114). Conclusions Our data suggested that lymphatic vessel invasion was related with lymph node metastasis and that both lymphatic microvessel density and lymphatic vessel invasion were related with an adverse outcome in colorectal cancer. Furthermore, lymphatic microvessel density may be a useful prognostic factor in colorectal cancer. *Deceased. The Poster presentation at the meeting of the Japanese Society of Gastroenterology, Sapporo, Japan, October 11 to 14, 2006. Reprints are not available.     

Brain and spinal cord preconditioning for the protection against ischemic injury

Recent studies have suggested that the brain preconditioning could induce tolerance to ischemia in humans. It has been believed that newly synthesized proteins are required for the acquisition of delayed tolerance in the brain and spinal cord. However, the mechanism other than the synthesis of neuroprotective proteins may also play a pivotal role. Preconditioning may reprogram the response to ischemic injury as seen during hibernation. Preconditioning with hyperbaric oxygen, volatile anesthetics, and xenon seems to be the focus of the attention from the standpoint of the clinical setting. Strong neuroprotection by the preconditioning with isoflurane and xenon is reported in animal experiments and may change the traditional idea of neuroprotection by anesthetics. The discovery that erythropoietin exerts neuroprotective properties has opened new therapeutic avenues. Erythropoietin is induced in the brain by hypoxic preconditioning and by the pharmacological preconditioning. In addition, the intravenous administration of erythropoietin has been shown to be safe and beneficial for acute stroke in humans. Therefore, erythropoietin is now one of the most promising neuroprotective agents. The research in the brain and spinal cord preconditioning will contribute to the elucidation of the mechanism of ischemic injury and to the establishment of new therapies for neuroprotection.     

A case of AFP-producing gastric cancer resected after efficient S-1/CDDP combination chemotherapy

A 62-year-old male was diagnosed as AFP-producing gastric cancer with lymph node metastases and multiple liver metastases. He was treated with S-1 and CDDP combination chemotherapy. At the end of the first course, both primary and metastatic lesions were remarkably decreased in size, and the serum AFP level was also decreased. The chemotherapy was effective against the cancer and led to a partial response (PR) according to the RECIST guideline. Following the nine months of PR, the primary lesion which had once nearly disappeared, emerged again. Because distant lymph node metastases and liver metastases were considered to have disappeared, distal gastrectomy with D2 lymphadenectomy was performed. The patient received S-1 monotherapy for 6 months after the operation. At present the patient has achieved progression-free survival for 1 year and 3 months after the operation. Though AFP-producing gastric cancer is known for its poor prognosis, combination treatment such as operation or hepatic arterial infusion chemotherapy may improve the prognosis in patients with advanced AFP-producing gastric cancer when systemic chemotherapy is effective.