Pathophysiology of Neuropathic Pain in Type 2 Diabetes: Skin denervation and contact heat�Cevoked potentials

OBJECTIVE

Neuropathic pain due to small-fiber sensory neuropathy in type 2 diabetes can be diagnosed by skin biopsy with quantification of intra-epidermal nerve fiber (IENF) density. There is, however, a lack of noninvasive physiological assessment. Contact heat–evoked potential (CHEP) is a newly developed approach to record cerebral responses of Aδ fiber–mediated thermonociceptive stimuli. We investigated the diagnostic role of CHEP.

RESEARCH DESIGN AND METHODS

From 2006 to 2009, there were 32 type 2 diabetic patients (20 males and 12 females, aged 51.63 ± 10.93 years) with skin denervation and neuropathic pain. CHEPs were recorded with heat stimulations at the distal leg, where skin biopsy was performed.

RESULTS

CHEP amplitude was reduced in patients compared with age- and sex-matched control subjects (14.8 ± 15.6 vs. 33.7 ± 10.1 μV, P < 0.001). Abnormal CHEP patterns (reduced amplitude or prolonged latency) were noted in 81.3% of these patients. The CHEP amplitude was the most significant parameter correlated with IENF density (P = 0.003) and pain perception to contact heat stimuli (P = 0.019) on multiple linear regression models. An excitability index was derived by calculating the ratio of the CHEP amplitude over the IENF density. This excitability index was higher in diabetic patients than in control subjects (P = 0.023), indicating enhanced brain activities in neuropathic pain. Among different neuropathic pain symptoms, the subgroup with evoked pain had higher CHEP amplitudes than the subgroup without evoked pain (P = 0.011).

CONCLUSIONS

CHEP offers a noninvasive approach to evaluate the degeneration of thermonociceptive nerves in diabetic neuropathy by providing physiological correlates of skin denervation and neuropathic pain.Type 2 diabetic neuropathy is frequently complicated with neuropathic pain, suggesting the involvement of small-diameter thermonociceptive nerves (1). Two approaches have been developed for the diagnosis of small-fiber sensory neuropathy: psychophysical assessments by measuring thermal thresholds on quantitative sensory testing (2,3) and pathological evaluations by quantifying intra-epidermal nerve fiber (IENF) density in punch skin biopsies (4–6). These examinations provide psychophysical and neuropathological evidence of small-diameter thermonociceptive nerve degeneration and serve as the definition of small-fiber sensory neuropathy (7,8). These two tests are sensitive in detecting the negative symptoms of diabetic neuropathy, for example, the elevation of thermal thresholds (9). However, the neurophysiological correlates of these tests with positive symptoms such as neuropathic pain are limited, and the physiological consequences of thermonociceptive nerve involvements in diabetic neuropathy have rarely been explored.In recent years, several groups, including our own, have established contact heat–evoked potential (CHEP) as a clinically feasible approach to examine the physiology of thermonociceptive nerves (10,11). CHEP, by activating Aδ fibers, can be recorded at the vertex for clinical use (12). Thus, CHEPs provide a noninvasive technique to objectively evaluate the physiology of thermonociceptive nerve dysfunctions. This approach raises the possibility of whether CHEP can be a noninvasive diagnostic tool complementary to IENF density and thermal thresholds and whether CHEP parameters can reflect the neurophysiological correlates of reduced IENF density in diabetic neuropathy. Additionally, since the CHEP amplitude parallels the perceived intensity of heat pain in normal subjects (11,13), a further critical issue is whether CHEP could demonstrate positive symptoms or signs of neuropathic pain in diabetic neuropathy. These include the spontaneous forms, such as a burning sensation, and the evoked forms, such as hyperalgesia to thermal stimuli.To address the above issues, our study investigated the following: 1) the changes in CHEP and its diagnostic role in diabetic neuropathy, 2) the correlations of CHEP with the skin innervation and thermal thresholds, and 3) the relationship of CHEP and neuropathic pain in diabetic neuropathy.     

Detection and characterization of placental microRNAs in maternal plasma

BACKGROUND: The discovery of circulating fetal nucleic acids in maternal plasma has opened up new possibilities for noninvasive prenatal diagnosis. MicroRNAs (miRNAs), a class of small RNAs, have been intensely investigated recently because of their important regulatory role in gene expression. Because nucleic acids of placental origin are released into maternal plasma, we hypothesized that miRNAs produced by the placenta would also be released into maternal plasma. METHODS: We systematically searched for placental miRNAs in maternal plasma to identify miRNAs that were at high concentrations in placentas compared with maternal blood cells and then investigated the stability and filterability of this novel class of pregnancy-associated markers in maternal plasma. RESULTS: In a panel of TaqMan MicroRNA Assays available for 157 well-established miRNAs, 17 occurred at concentrations >10-fold higher in the placentas than in maternal blood cells and were undetectable in postdelivery maternal plasma. The 4 most abundant of these placental miRNAs (miR-141, miR-149, miR-299-5p, and miR-135b) were detectable in maternal plasma during pregnancy and showed reduced detection rates in postdelivery plasma. The plasma concentration of miR-141 increased as pregnancy progressed into the third trimester. Compared with mRNA encoded by CSH1 [chorionic somatomammotropin hormone 1 (placental lactogen)], miR-141 was even more stable in maternal plasma, and its concentration did not decrease after filtration. CONCLUSION: We have demonstrated the existence of placental miRNAs in maternal plasma and provide some information on their stability and physical nature. These findings open up a new class of molecular markers for pregnancy monitoring.     

Genetic analysis of the CYP2D6 locus in a Hong Kong Chinese population

BACKGROUND: The cytochrome P450 CYP2D6 enzyme debrisoquine 4-hydroxylase metabolizes many different classes of commonly used drugs, such as tricyclic antidepressants and neuroleptics. Genetic polymorphism of the CYP2D6 gene is responsible for pronounced interindividual and interracial differences in the metabolism of these drugs. The CYP2D6*10 allele and its variants are the most frequent alleles found in Orientals, and they are responsible for diminished debrisoquine 4-hydroxylase activity because of the presence of a C(188)-->T mutation in exon 1. METHODS: One hundred nineteen Hong Kong Chinese subjects were genotyped by means of allele-specific PCR, PCR, and restriction enzyme analysis for 10 CYP2D6 alleles (CYP2D6*1, *2, *4D, *5, *8/*14, *10A, *10B, *15, *16, and J9). RESULTS: CYP2D6*10B was the most prevalent allele, and CYP2D6*10/CYP2D6*10 was the most frequent genotype, representing 41.17% [corrected] of the population. CONCLUSIONS: There was no significant difference in the prevalence of the alleles analyzed between our study and the Chinese populations genotyped previously. This is the largest study in terms of the number of CYP2D6 alleles analyzed in an Oriental population and the first one conducted in a Hong Kong Chinese population.     

Use of individual surgeon versus surgical team approach: surgical outcomes of laparoscopic Roux-en-Y gastric bypass in an Asian Medical Center

BackgroundLaparoscopic Roux-en-Y gastric bypass (LRYGB) has been shown to improve both the health and the quality of life of morbidly obese patients. We compared the efficacy and safety of using a team approach to LRYGB versus an individual surgeon at a medical center.MethodsData were collected from 200 consecutive patients undergoing LRYGB for morbid obesity from August 2005 to February 2008. Groups 1 and 2 included 50 patients each who underwent surgery and were cared for by the same surgeon. Group 3 included the next 100 consecutive patients, who underwent LRYGB by the same surgeon but who were cared for by a dedicated bariatric team.ResultsFor the 76 men (38%) and 124 women (62%) in the study, the excess weight loss at 1 and 3 months of follow-up did not differ; however, it was significantly different at 6 and 12 months. At the mean follow-up period, 30% of group 1, 6% of group 2, and 8% of group 3 had experienced complications. Most complications in group 1 occurred early and were related to the surgical technique; however, in groups 2 and 3, the complications related to the technique were markedly reduced. Men were 4.57 times as likely as women to experience complications related to bariatric surgery.ConclusionA team-based approach is a better option for patients undergoing LRYGB than care by a single surgeon. With an experienced bariatric surgeon, the team approach resulted in shorter operative times and shorter hospital stays, with the same rate of complications.     

Mycobacterium chelonae infection after total knee arthroplasty: a case report

We present a case of Mycobacterium chelonae infection after total knee arthroplasty in a 70-year-old woman. The patient underwent implant removal, drainage, debridement, and insertion of a gentamycin-load cement spacer. After 4 months, the second-stage surgery was performed. Intravenous amikacin (6 weeks) and oral clarithromycin (12 weeks) were given. At the 12-month follow-up, the patient achieved 90 degrees of flexion and could walk with a stick for up to 15 minutes. She was not taking any analgesics.     

Rictor-dependent AKT activation and inhibition of urothelial carcinoma by rapamycin

ObjectiveWe previously reported a very high cumulative incidence of urothelial carcinoma in Taiwanese kidney transplant recipients. Rapamycin, the inhibitor of mTOR Complex 1, provides alternative immunosuppressive therapy after kidney transplantation with less neoplastic potential. We examined the in vivo and in vitro effects of rapamycin on urothelial carcinoma.Materials and methodsThe rat model of urothelial carcinoma was induced by 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in Fischer F344 rats. The anti-tumor effect of rapamycin was assessed grossly, microscopically, and by Western blot analysis. The mechanism of rapamycin's attenuation of urothelial carcinoma was also evaluated by T24 cells.ResultsRapamycin significantly reduced urinary bladder tumor growth in the rat model of 0.05% BBN-induced urothelial carcinoma (P < 0.001). The blood trough levels of rapamycin were correlated with the occurrence of urothelial carcinoma. In vitro, rapamycin also inhibited the cell proliferation, migration, and invasion, as well as the protein expression of vascular endothelial growth factor-A of T24 urothelial carcinoma cells, whereas rapamycin did not induce significant apoptosis in T24 cells. Rapamycin decreased the expression of phospho-mTOR, phospho-S6K, cyclin D1, and VEGF-A. Rapamycin also activated AKT in T24 cells in the rat model of urothelial carcinoma. The rapamycin-associated activation of AKT was inhibited by rictor siRNA, but not raptor siRNA.ConclusionsThis study provides in vitro and in vivo evidence that rapamycin may inhibit the development of urothelial carcinoma. The present findings also suggest rictor-dependent AKT activation as a consequence of mTORC1 inhibition.     

Factors contributing to hospital readmission in a Hong Kong regional hospital: a case-controlled study

BACKGROUND: As many as 50% of total hospital admissions are readmissions. Because the factors contributing to hospital readmission are multiple, and research findings are not conclusive, it is important for clinicians to gain an understanding of the key factors that contribute to readmission. OBJECTIVES:This study explores the factors contributing to hospital readmission and derives an explanatory model that can best identify characteristics of patients at high risk for hospital readmission. METHODS: This research was a case-controlled study with readmitted patients (n = 168) as the readmitted group and non-readmitted patients (n = 98) as the control group. The variables included demographic data, health assessment data, medical diagnosis, frequency of admissions, severity of illness, intensity of service and improvement of condition. The study sample was also interviewed to explore the patients' views on their repeated hospitalization. RESULTS: In the bivariate analysis significant differences between the study and control groups were multiple and generally consistent with findings in other studies. Using multiple logistic regression, however, the final model shows that only three factors best predict readmissions: frequency (3-4 times) of readmissions (OR = 9.96, p < .0001) and frequency (more than 5 times) of readmissions (OR = 15.73, p < .0001), financial assistance (OR = 5.03, p < .001), and severity of illness (OR = 3.12, p < .01). Our interview data suggest that the readmitted patients required assistance to accomplish daily living activities upon discharge and often returned to the hospital for the same health reason. CONCLUSION: The study findings suggest that patients who are frequently readmitted to the hospital are severely ill; are on public assistance; and may need special attention when discharged in order to attenuate repeated hospital readmission.