Direction of action is represented in the ventral premotor cortex

The ventral premotor area (PMv) is a major source of input to the primary motor cortex (M1). To examine the potential hierarchical processing between these motor areas, we recorded the activity of PMv neurons in a monkey trained to perform wrist movements in different directions with the wrist in three different postures. The task dissociated three major variables of wrist movement: muscle activity, direction of joint movement and direction of movement in space. Many PMv neurons were directionally tuned. Nearly all of these neurons (61/65, 94%) were 'extrinsic-like'; they seemed to encode the direction of movement in space independent of forearm posture. These results are strikingly different from results from M1 of the same animal, and suggest that intracortical processing between PMv and M1 may contribute to a sensorimotor transformation between extrinsic and intrinsic coordinate frames.     

Sensorimotor transformations in cortical motor areas

A central problem in motor research has been to understand how sensory signals are transformed to generate a goal-directed movement. This problem has been formulated as a set of coordinate transformations that begins with an extrinsic coordinate frame representing the spatial location of a target and ends with an intrinsic coordinate frame describing muscle activation patterns. Insight into this process of sensorimotor transformation can be gained by examining the coordinate frames of neuronal activity in interconnected regions of the brain. We recorded the activity of neurons in primary motor cortex (M1) and ventral premotor cortex (PMv) in a monkey trained to perform a task which dissociates three major coordinate frames of wrist movement: muscle, wrist joint, and an extrinsic coordinate frame. We found three major types of neurons in M1 and PMv. The first type was termed 'extrinsic-like'. The activity of these neurons appeared to encode the direction of movement in space independent of the patterns of wrist muscle activity or joint movement that produced the movements. The second type was termed 'extrinsic-like with gain modulation'. The activity of these neurons appeared to encode the direction of movement in space, but the magnitude (gain) of neuronal activity depended on the posture of the forearm. The third type was termed 'muscle-like' since their activity co-varied with muscle activity. The great majority of the directionally-tuned neurons in the PMv were classified as 'extrinsic-like' (48/59, 81%). A smaller group was classified as 'extrinsic-like with gain modulation' (7/59, 12%). In M1, the three types of neurons were more equally represented. Our results raise the possibility that cortical processing between M1 and PMv may contribute to a sensorimotor transformation between extrinsic and intrinsic coordinate frames. Recent modeling studies have demonstrated the computational plausibility of such a process.     

Tea polyphenols inhibit rat osteoclast formation and differentiation

Matrix metalloproteinases (MMPs) play an important role in degeneration of the matrix associated with bone and cartilage. Regulation of osteoclast activity is essential in the treatment of bone disease, including osteoporosis and rheumatoid arthritis. Polyphenols in green tea, particularly epigallocatechin-3-gallate (EGCG), inhibit MMPs expression and activity. However, the effects of the black tea polyphenol, theaflavin-3,3'-digallate (TFDG), on osteoclast and MMP activity are unknown. Therefore, we examined whether TFDG and EGCG affect MMP activity and osteoclast formation and differentiation in vitro. TFDG or EGCG (10 and 100 μM) was added to cultures of rat osteoclast precursors cells and mature osteoclasts. Numbers of multinucleated osteoclasts and actin rings decreased in polyphenol-treated cultures relative to control cultures. MMP-2 and MMP-9 activities were lower in TFDG- and EGCG-treated rat osteoclast precursor cells than in control cultures. MMP-9 mRNA levels declined significantly in TFDG-treated osteoclasts in comparison to control osteoclasts. TFDG and EGCG inhibited the formation and differentiation of osteoclasts via inhibition of MMPs. TFDG may suppress actin ring formation more effectively than EGCG. Thus, TFDG and EGCG may be suitable agents or lead compounds for the treatment of bone resorption diseases.     

Association of monocyte chemoattractant protein-1 with renal tubular damage in diabetic nephropathy

Monocyte chemoattractant protein-1 (MCP-1), is a chemokine that mediates renal interstitial inflammation, tubular atrophy, and interstitial fibrosis by recruiting monocytes/macrophages into renal tubulointerstitium. Recent studies have demonstrated that protein overload in renal tubular cells up-regulates MCP-1 gene and its protein expression. Therefore, we hypothesized that increased expression of MCP-1 in renal tubuli, probably triggered by an increase in the leakage of plasma protein from glomerular capillary to tubular fluid, may contribute to renal tubular damage and accelerate the progression of diabetic nephropathy. To test this hypothesis, we examined urinary excretion levels of MCP-1 and N-acetylglucosaminidase (NAG), a sensitive marker of renal tubular damage, in Japanese Type II diabetic patients with normoalbuminuria (n=29), microalbuminuria (n=25), and macroalbuminuria (n=18). The median urinary excretion level of MCP-1 in patients with macroalbuminuria (394.4 ng/g creatinine) was significantly elevated compared to the levels in patients with normoalbuminuria and microalbuminuria (159.6 and 193.9 ng/g creatinine, respectively). Furthermore, the urinary MCP-1 excretion level was positively correlated with urinary excretion levels of albumin (r=.816, P<.001) and NAG (r=.569, P<.001) in all subjects. These results suggest that MCP-1 is produced in renal tubular cells and released into urine in proportion to the degree of proteinuria (albuminuria), and that increased MCP-1 expression in renal tubuli contributes to renal tubular damage. Therefore, we conclude that heavy proteinuria itself may accelerate the progression of diabetic nephropathy by increasing the MCP-1 expression in renal tubuli.     

Effectiveness of Prior Use of Beta-Blockers for Preventing Adverse Influences of Severe Hypoglycemia in Patients With Diabetes: An Observational Study

The study aimed to identify predictors of severe acute hypertension (≥180/110 mmHg) during severe hypoglycemia and to assess the efficacy of prior use of catecholamine-blocking agents for preventing adverse influences in diabetic patients with severe hypoglycemia. We performed a retrospective study between January 2006 and March 2012 to assess diabetic patients with severe hypoglycemia at a single center in Japan. Severe hypoglycemia was defined as the presence of any hypoglycemic symptoms that required the medical assistance of another person after visiting the emergency room by ambulance. Multivariate logistic regression analysis was performed to identify possible predictors of severe hypertension due to severe hypoglycemia and to assess whether prior use of alpha- or beta-blockers is beneficial for the prevention of severe hypertension in diabetic patients with severe hypoglycemia. Multivariate adjustments were made for age, sex, preexisting hypertension, history of ischemic heart disease, blood glucose level upon arrival, estimated GFR, and prior use of alpha- or beta-blockers. A total of 59,602 patients who visited the emergency room were screened and 352 diabetic patients with severe hypoglycemia were enrolled. Incidences of severe hypertension before and at 3 and 6 hours after the initiation of antihypoglycemic treatment were 21.3%, 6.7%, and 0% in patients with type 1 diabetes (n = 61) and 38.8%, 18.2%, and 8.2% in patients with type 2 diabetes (n = 291), respectively. Aging was positively (odds ratio [OR], 1.02; 95% confidence interval [CI], 1.00−1.03; P = 0.02) and female sex was negatively (OR, 0.50; 95% CI, 0.29−0.86; P = 0.01) associated with occurrence of severe hypertension during severe hypoglycemia. In addition, prior use of beta-blockers was negatively associated with occurrence of severe hypertension during severe hypoglycemia using multivariate logistic regression analysis (OR, 0.31; 95% CI, 0.11−0.83; P = 0.02). None of the patients with prior use of beta-blockers had hypokalemia (<3.0 mEq/L). Prior use of beta-blockers may prevent adverse influences such as severe hypertension and hypokalemia during severe hypoglycemia in diabetic patients.     

Effects of antidiabetic treatment with metformin and insulin on serum and adipose tissue adiponectin levels in db/db mice

Decreased circulating levels of adiponectin, a novel adipose-derived adipocytokine, in obesity possibly contribute to the development of insulin resistance which is a major factor in the pathogenesis of type 2 diabetes. The present study was conducted to examine whether circulating and adipose tissue adiponectin levels are modulated by chronic treatment with metformin and intensive treatment with insulin in murine models of obesity and type 2 diabetes, db/db mice with a C57BL/KsJ genetic background. Nine-week-old male db/db mice were treated with metformin, insulin, and vehicle for 4 weeks. Expectedly, metformin treatment led to inhibition of weight gain and improvement of hyperinsulinemia. Insulin treatment lowered fasting blood glucose levels to normal values, although it sustained hyperinsulinemic state. However, after 4 weeks of treatment, serum adiponectin levels were not significantly elevated in either metformin-treated or insulin-treated db/db mouse group (14.2 +/- 0.7 and 16.7 +/- 1.0 microg/ml, respectively) compared to vehicle-treated group (14.9 +/- 0.6 microg/ml). Similarly, adipose tissue adiponectin levels determined by Western blot analysis were not increased in either metformin-treated or insulin-treated group relative to vehicle-treated group. Recent studies have shown that adiponectin possibly has the same physiological effects on lipid and glucose metabolism that metformin has. Therefore, an elevation in blood concentration of metformin following the treatment might lead to suppression in adiponectin synthesis in adipose tissue, independent of inhibition in weight gain and improvement in hyperinsulinemia by metformin treatment. The present results indicate that adiponectin is not involved in the mechanism by which metformin treatment enhances insulin sensitivity. Moreover, our results suggest that adiponectin synthesis in adipose tissue may be suppressed under hyperinsulinemic state sustained by insulin treatment, even though hyperglycemia is markedly reduced. We conclude that antidiabetic treatment with metformin and insulin does not affect circulating and adipose tissue adiponectin levels.     

DNA mutilation of the pepsin 1 gene during rat glandular stomach carcinogensis induced by N-methyl-N'-nitro-N-nitrosoguanidine or catechol

The methylation patterns of the rat pepsinogen 1 (Pg1) genein preneoplastic and neoplastic stomach lesions induced by genotoxicN-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or the non-genotoxiccarcinogen catechol were investigated. Male WKY/Ncrj rats weregiven MNNG in their drinking water (50 mg/l) for 30 weeks or0.8% catechol throughout the experiment (60 weeks). MNNG inducedPg1 altered pyloric glands (PAPG), adenomatous hyperplasiasand well-differentiated adenocarcinomas. Catechol also inducedPAPG and adenomatous hyperplasias although cancers did not develop.Adenomatous hyperplasias and adenocarcinomas all consideredof gastric type cells resembling surface mucous cells or pyloricgland cells with little or no Pg1 expression. In MNNG-inducedstomach cancers generally lacking Pg1, altered Pg1 gene methylationwas observed with both CCGG and GCGC sites being methylatedmore than normal pyloric mucosa. MNNG or catechol-induced adenomatoushyperplasias also demonstrated essentially the same methylationchanges in the CCGG, but not in the GCGC sites. In the mucosacontaining PAPG in groups treated with MNNG or catechol themethylation patterns of the Pg1 gene were quite similar to thoseof normal pyloric mucosa, although the CCGG sites tended todemonstrate slightly increased methylation. The results suggestthat the altered methylation of the Pg1 gene observed in stomachcancers is acquired early in the carcinogenic process and progressivemethylation changes occur with tumor development.     

Success of dental implants in patients with large bone defect and analysis of risk factors for implant failure: a non-randomized retrospective cohort study

Clinical Oral Investigations - This study aimed to retrospectively investigate the success and survival rates of dental implants used for dentomaxillary prostheses at our hospital and the risk...