Early involvement of the spinal cord in diabetic peripheral neuropathy

OBJECTIVE: The pathogenesis of diabetic peripheral neuropathy (DPN) is poorly understood. We have recently reported a significant reduction in spinal cord cross-sectional area at the stage of clinically detectable DPN. In this study, we investigated whether spinal cord atrophy occurs in early (subclinical) DPN. RESEARCH DESIGN AND METHODS: Eighty-one male type 1 diabetic subjects, 24 nondiabetic control subjects, and 8 subjects with hereditary sensory motor neuropathy (HSMN) type 1A underwent detailed clinical and neurophysiological assessments. Diabetic subjects were subsequently divided into three groups based on neuropathy severity (19 with no DPN, 23 with subclinical DPN, and 39 with clinically detectable DPN). All subjects underwent magnetic resonance imaging of the cervical spine and cord area measurements at disc level C2/C3. RESULTS: Mean corrected spinal cord area index (SCAI) (corrected for age, height, and weight) was 67.5 mm [95% CI 64.1-70.9] in diabetic subjects without DPN. Those with subclinical (62.4 mm [59.5-65.3]) and clinically detectable DPN (57.2 mm [54.9-59.6]) had lower mean SCAIs compared with subjects with no DPN (P = 0.03 and P < 0.001, respectively). No significant difference was found between diabetic subjects without DPN and nondiabetic control subjects (69.2 mm [66.3-72.0], P = 0.47). Mean SCAIs in subjects with HSMN type 1A (71.07 mm [65.3-76.9]) were not significantly different from those for nondiabetic control subjects and diabetic subjects without DPN. Among diabetic subjects, SCAI was significantly related to sural sensory conduction velocities and the Neuropathy Composite and Symptom Scores. CONCLUSIONS: Spinal cord involvement occurs early in DPN. There is also a significant relation between reduction in SCAI and neurophysiological assessments of DPN.     

Binding and activation of human and mouse complement by Cryptosporidium parvum (Apicomplexa) and susceptibility of C1q- and MBL-deficient mice to infection

Cryptosporidium parvum is a protozoan parasite (Apicomplexa) that causes gastrointestinal disease in animals and humans. Whereas immunocompetent hosts can limit the infection within 1 or 2 weeks, immunocompromised individuals develop a chronic, life-threatening disease. The importance of the adaptive cellular immune response, with CD4+ T-lymphocytes being the major players, has been clearly demonstrated. Several non-adaptive immune mechanisms have been suggested to contribute to the host defence, such as interferon-gamma (IFN-gamma) from NK cells, certain chemokines, beta-defensins and pro-inflammatory cytokines, but the influence of the complement systems has been less well studied. We analysed the in vitro binding and activation of the human and mouse complement systems and tested the susceptibility to infection in complement-deficient mouse strains. We found that C. parvum can activate both the classical and lectin pathways, leading to the deposition of C3b on the parasite. Using real-time PCR, parasite development could be demonstrated in adult mice lacking mannan-binding lectin (MBL-A/C-/-) but not in mice lacking complement factor C1q (C1qA-/-) or in wild type C57BL/6 mice. The contribution of the complement system and the lectin pathway in particular to the host defence against cryptosporidiosis may become apparent in situations of immunodeficiency such as HIV infections or in early childhood.     

Vascular factors in diabetic neuropathy

Summary Despite considerable research we still do not have a comprehensive explanation for the pathogenesis of diabetic neuropathy. Although chronic hyperglycaemia is almost certainly involved, it is not known whether the primary pathology is metabolic, microvascular, or an interaction between the two. Hyperglycaemia-induced polyol pathway hyperactivity associated with nerve sorbitol accumulation and myo-inositol depletion may play a part in the genesis of diabetic neuropathy. The case for microvascular disease in diabetic neuropathy is now strong. Fibre loss in human sural nerve is multifocal, suggesting ischaemia. The degree of vessel disease has been related to the severity of neuropathy. People with chronic obstructive pulmonary disease develop the so called hypoxic neuropathy in which similar microvascular changes occur as in diabetic neuropathy. In rats with experimental diabetic neuropathy nerve blood flow is reduced and oxygen supplementation or vasodilator treatment improved the deterioration in conduction velocity and nerve blood flow. Similarly, in human diabetic neuropathy, there is impaired nerve blood flow, epineurial arterio-venous shunting and a reduction in sural nerve oxygen tension. At what stage during the development of nerve damage these changes occur is yet to be determined.Abbreviations RICF resistance to ischaemic conduction failure     

Improved Stability of Proline-Derived Direct Thrombin Inhibitors through Hydroxyl to Heterocycle Replacement

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Validity of the Patient-Reported Clinical Global Impression of Change as a Measure of Treatment Response in Men with Premature Ejaculation

IntroductionThe Clinical Global Impression of Change (CGIC) measures have high utility in clinical practice. However, it is unknown whether the CGIC is valued for assessing premature ejaculation (PE) symptoms and/or the relationship between CGIC and other validated PE patient-reported measures.AimThe study aims to assess the validity of the patient-reported CGIC measure in men with PE and to examine the relationship between CGIC ratings and assessments of control, satisfaction, personal distress, and interpersonal difficulty.MethodsData from a randomized, double-blind, 24-week phase 3 trial in 1,162 men with PE who received dapoxetine (30 mg or 60 mg) or placebo on demand provided the basis for the analysis. Patients were ≥18 years, in a stable monogamous relationship for ≥6 months, met the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition-Text Revision criteria for PE for ≥6 months, and had an intravaginal ejaculatory latency time (IELT) ≤2 minutes in ≥75% of intercourse episodes.Main Outcome MeasuresThe CGIC asked patients to rate improvement or worsening of their PE compared with the start of the study using a 7-point response scale; other patient-reported measures were control over ejaculation, satisfaction with sexual intercourse, interpersonal difficulty, and personal distress related to ejaculation. Stopwatch-measured IELT was recorded. Associations between CGIC and change in other measures at study end point were assessed.ResultsThe magnitude of IELT increased for each category of improvement on the CGIC: 1.63, 4.03, and 7.15 minutes for slightly better, better, and much better, respectively. Higher CGIC ratings were correlated with greater improvement in control (r = 0.73), satisfaction (r = 0.62), greater reduction in distress (r = ?0.52), and interpersonal difficulty (r = ?0.39). Total variance accounted for was 57.4%: control (48.7%), satisfaction (4.5%), IELT (2.8%), and distress (1.15%).ConclusionsThe analyses support the validity of the CGIC measure in men with PE. The CGIC can provide clinicians in practice with a valid and brief outcome assessment of their patient's condition. Althof SE, Brock GB, Rosen RC, Rowland DL, Aquilina JW, Rothman M, Tesfaye F, and Bull S. Validity of the patient-reported clinical global impression of change as a measure of treatment response in men with premature ejaculation.     

Kinetics of sedimentation rate, viral load and TNF-alpha in relation to HIV co-infection in tuberculosis

The kinetics of potential surrogate markers in HIV-positive (HIV+) and HIV-negative (HIV-), smear-positive tuberculosis (Tb+) patients in Gondar, Ethiopia (n = 60) was investigated. Clinical symptoms, sputum conversion, sedimentation rate (SR), HIV viral load and serum levels of TNF-alpha were determined before and 8 weeks after treatment initiation. The co-infection rate of HIV was 45%. There were significantly higher initial levels of SR and TNF-alpha in HIV+/Tb+ patients (79 +/- 29 mm/h and 13.5 +/- 7.6 pg/ml), than in HIV-/Tb+ patients (60 +/- 23 mm/h and 6.8 +/- 5.9 pg/ml, P<0.001). In HIV-/Tb+ patients, there was a marked decrease in SR compared with co-infected patients (46% [33 +/- 24 mm/h at week 8] vs. 24% [61 +/- 27 mm/h at week 8]). The HIV viral load (4.99 [range 3.70-5.92] to 4.90 [range 3.96-5.78] log10 copies/ml from week 0 to 8) and TNF-alpha (13.5 +/- 7.6 to 12.0 +/- 6.0 pg/ml) remained high in HIV+/Tb+ patients. In Tb patients, SR was significantly increased in HIV+ compared with HIV- patients. Additionally, TNF-alpha and HIV viral load remained elevated in HIV+/Tb+ patients following treatment despite clinical improvement comparable to HIV-/Tb+ patients.