OBJECTIVE -Increasing evidence from a cohort of Caucasians recently suggests that an elevated level of C-reactive protein (CRP) is associated with an increased risk of developing type 2 diabetes. However, Japanese subjects are skewed to lower CRP concentrations than westerners. Therefore, the effect of CRP on the development of type 2 diabetes among Japanese is unclear.RESEARCH DESIGN AND METHODS -We examined 396 male and 551 female nondiabetic Japanese Americans who underwent a 75-g oral glucose tolerance test (GTT) and were then followed for an average of 6.5 years. We investigated whether elevated serum CRP level is a risk factor in the development of type 2 diabetes among these subjects.RESULTS -Subjects with a high CRP level showed a significantly higher incidence of type 2 diabetes compared with subjects with a low level among both men (P ϭ 0.028) and women (P ϭ 0.004) in a log-rank test. In a Cox proportional hazards model dividing quartiles of CRP, the hazard ratios for diabetes development in the highest versus lowest quartile of CRP levels were 2.84 (95% CI 1.09 -7.39) among men and 3.11 (1.25-7.75) among women after adjustment for age, smoking, family history of diabetes, classification of a 75-g GTT, hormone replacement therapy (among women), BMI, and homeostasis model assessment.CONCLUSIONS -Among Japanese Americans, CRP may be a risk factor for development of type 2 diabetes independent of either obesity or insulin resistance. Our results suggest that inflammation may be closely related to the mechanism of type 2 diabetes among Japanese Americans. Diabetes Care 26:2754 -2757, 2003C omplications of diabetes reduce patients' quality of life. Therefore, it is necessary to identify individuals with glucose intolerance as early as possible to prevent its progression into diabetes. Thus, it may be more efficient to intervene when high-risk factors in subjects can be readily identified.C-reactive protein (CRP) is a marker of acute inflammation and is generally used as a measure of inflammatory disease. Recently, CRP increases have been reported in obesity (1,2) and type 2 diabetes (1). Thus, there is increasing evidence to suggest that insulin resistance is a chronic low-grade inflammatory state (3). In prospective case-control studies (4 -9), elevated levels of CRP predict the development of type 2 diabetes, supporting a possible role for inflammation in diabetogenesis (4, 6 -8).According to the literature on Japanese populations (10), Japanese subjects are skewed to lower CRP concentrations than westerners. Therefore, the acutephase response may vary due to racial differences. However, there have been no published reports investigating the relationship between CRP and the development of type 2 diabetes among Japanese. Although Americans of Japanese descent share a virtually identical genetic makeup with native Japanese currently living in Japan, Japanese Americans have approximately twice the incidence of type 2 diabetes compared with Japanese living in Japan, primarily because of a westernized lifestyl...

A significant linear radiation dose response for thyroid nodules, including malignant tumors and benign nodules, exists in atomic bomb survivors. However, there is no significant dose response for autoimmune thyroid diseases.

Peripheral nerve injury induces proliferation of microglia in the spinal cord, which can contribute to neuropathic pain conditions. However, candidate molecules for proliferation of spinal microglia after injury in rats remain unclear. We focused on the colony-stimulating factors (CSFs) and interleukin-34 (IL-34) that are involved in the proliferation of the mononuclear phagocyte lineage. We examined the expression of mRNAs for macrophage-CSF (M-CSF), granulocyte macrophage-CSF (GM-CSF), granulocyte-CSF (G-CSF) and IL-34 in the dorsal root ganglion (DRG) and spinal cord after spared nerve injury (SNI) in rats. RT-PCR and in situ hybridization revealed that M-CSF and IL-34, but not GM- or G-CSF, mRNAs were constitutively expressed in the DRG, and M-CSF robustly increased in injured-DRG neurons. M-CSF receptor mRNA was expressed in naive rats and increased in spinal microglia following SNI. Intrathecal injection of M-CSF receptor inhibitor partially but significantly reversed the proliferation of spinal microglia and in early phase of neuropathic pain induced by SNI. Furthermore, intrathecal injection of recombinant M-CSF induced microglial proliferation and mechanical allodynia. Here, we demonstrate that M-CSF is a candidate molecule derived from primary afferents that induces proliferation of microglia in the spinal cord and leads to induction of neuropathic pain after peripheral nerve injury in rats.

A prominent signaling pathway in the development of neuropathic pain involves ATP acting on microglial purinergic receptors. Among the P2Y metabotropic receptors, we reported before that the P2Y12 receptor is upregulated in microglia following nerve injury and involved in the phosphorylation of p38 MAPK, and in the development of pain behavior. In this study, we examined the expression of P2Y6, P2Y13, and P2Y14 receptors in the spinal cord and whether these receptors are involved in the pathogenesis of neuropathic pain following peripheral nerve injury. We found that spared nerve injury induced a dramatic increase of not only P2Y12, but also P2Y6, 13, and 14 receptor mRNA expression in spinal microglia. The increase continued for at least 2 weeks after injury. To determine whether p38 MAPK can induce the expression of P2Y receptors, we administered intrathecally the p38 MAPK inhibitor SB203580 and found that it significantly suppressed P2Y6, P2Y13, and P2Y14 but not P2Y12 mRNAs. Intrathecal injection of the specific P2Y6 antagonist MRS2578, specific P2Y13 antagonist MRS2211 or P2Y14 antisense LNA, attenuated mechanical pain hypersensitivity. The mixture of three antagonists for P2Y6, 12, and 13 showed a longer suppressive effect on pain behavior than the individual treatments. Our data demonstrate that ATP and other nucleotides may stimulate activated microglia with the upregulation of P2Y6, P2Y12, P2Y13, and P2Y14 receptors following nerve injury and these receptors are involved in the development of neuropathic pain.

The orofacial region is a major focus of chronic neuropathic pain conditions characterized by primary hyperalgesia at the site of injury and secondary hyperalgesia outside the injured zone. We have used a rat model of injury to the maxillary branch (V2) of the trigeminal nerve to produce constant and long-lasting primary hyperalgesia in the V2 territory and secondary hyperalgesia in territories innervated by the mandibular branch (V3). Our findings indicate that the induction of primary and secondary hyperalgesia depended on peripheral input from the injured nerve. In contrast, the maintenance of secondary hyperalgesia depended on central mechanisms. The centralization of the secondary hyperalgesia involved descending 5-HT drive from the rostral ventromedial medulla (RVM) and the contribution of 5-HT3 receptors in the trigeminal nucleus caudalis (Vc), the homolog of the spinal dorsal horn. Electrophysiological studies further indicate that after nerve injury spontaneous responses and enhanced post-stimulus discharges in Vc nociresponsive neurons were time-dependent on descending 5-HT drive and peripheral input. The induction phase of secondary hyperalgesia involved central sensitization mechanisms in Vc neurons that were dependent on peripheral input whereas the maintenance phase of secondary hyperalgesia involved central sensitization in Vc neurons conducted by a delayed descending 5-HT drive and a persistence of peripheral inputs. Our results are the first to show that the maintenance of secondary hyperalgesia and underlying central sensitization associated with persistent pain depend on a transition to supraspinal mechanisms involving the serotonin system in RVM-dorsal horn circuits.