The neuropathies of Waldenström's macroglobulinemia (WM) and IgM-MGUS.

BACKGROUND: Neuropathy is common in Waldenström's macroglobulinemia (WM, an IgM-associated lymphoplasmacytic lymphoma) and in IgM-monoclonal gammopathy of undetermined significance (IgM-MGUS). Paraneoplastic or paraimmune mechanisms are thought to be involved in the pathogenesis of these neuropathies. Attempts at distinguishing WM and IgM-MGUS neuropathies are lacking especially among bone marrow (BM) confirmed patients. METHODS: Retrospective analyses were performed on BM confirmed WM (N=30) and IgM-MGUS (N=73) neuropathy patients with neurologic assessments and hematologic features. RESULTS: The presence of anemia and quantity of IgM monoclonal protein were significantly greater in WM. Based on multiple neurologic assessments differences were not found for: 1) length of time from neurologic symptom onset to evaluation; 2) chief complaint of painless loss of feeling in the feet, Romberg's sign and tremor; and 3) clinical motor, sensory and reflex abnormalities. Autonomic testing was normal in both diseases. Using nerve conduction (NCS) criteria for demyelination, 62% of IgM-MGUS and 27% of WM met this criteria (p=0.013). IgM MGUS patients had greater terminal conduction slowing by ulnar residual latency calculation (<0.01). The degree of axonal loss as measured by summated compound muscle action potentials and available nerve biopsy was not significantly different between diseases. CONCLUSION: Although WM and IgM-MGUS must be distinguished for hematologic prognosis and treatment, clinical neuropathy presentations of WM and IgM-MGUS are similar and likely related to comparable axonal loss in both conditions. Despite these similarities, evidence of demyelination was found by electrophysiologic studies much more commonly in IgM-MGUS. This difference may reflect varied immune mechanism(s) in the two disorders.

Prehospital neurologic deterioration in patients with intracerebral hemorrhage.

OBJECTIVE: Early neurologic deterioration has been studied in patients with intracerebral hemorrhage during hospitalization, but rates and factors associated with prehospital neurologic deterioration (PND) are unknown. We sought to determine the prevalence of PND among patients with intracerebral hemorrhage during Emergency Medical Services transportation to the hospital. DESIGN: Historical cohort study. SETTINGS: U.S. acute care hospital from 2000 to 2004. PATIENTS: Hospitalized patients with a diagnosis of spontaneous intracerebral hemorrhage were identified by codes of the International Statistical Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). METHODS: The initial Glasgow Coma Scale score ascertained at the scene by the Emergency Medical Services was compared with the subsequent evaluation in the emergency department to identify neurologic deterioration (defined as a decrease in Glasgow Coma Scale of > or = 2 points). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 98 patients with acute intracerebral hemorrhage, 22 patients (22%) showed PND during Emergency Medical Services transport, with a mean decrease in the Glasgow Coma Scale score during transport of 6 points. The patients who demonstrated neurologic deterioration tended to have higher diastolic blood pressure at the scene (p = .045), greater rates of intraventricular extension (p < .0001), and radiologic signs of herniation (p < .0001) on initial computed tomographic scan. There was a statistically significant decrease in diastolic blood pressure between the evaluations of the Emergency Medical Services and the emergency department among both patients with and without PND. CONCLUSIONS: PND occurs in nearly one fifth of patients with intracerebral hemorrhage. Higher diastolic blood pressure at the scene, intraventricular extension, and radiologically evident herniation seem to be associated with PND. Prospective studies are needed to evaluate the efficacy of Emergency Medical Services interventions to reduce this early clinical deterioration.

Serum BAFF expression in patients with myasthenia gravis.

A B-cell activating factor of the tumor necrosis factor (TNF) family (BAFF) is an essential B-cell survival factor. Myasthenia gravis (MG) is one of the most typical antibody-mediated autoimmune disorders. To test whether serum BAFF levels are increased in MG patients, we compared the serum BAFF levels of 40 MG patients with those of 30 healthy controls. Serum BAFF levels of MG group were significantly higher than those of healthy group. These results suggested that the BAFF might play a role in the immunopathogenesis of MG and further study on B-cell and T-cell activation may be needed.

Prediction of Tensile Behavior of UHSFRC Considering the Flow Field in the Placing Dominated by Shear Flow.

Considering the case of fabricating a UHSFRC (ultra-high strength fiber-reinforced concrete) beam with the method of one end placing and self-flowing to the other end, it was intended to simulate the variation of the fiber orientation distribution according to the flow distance and the variation of the resultant tensile behaviors. Then the validity of the simulation approach was shown by comparing the simulated results with experimental ones. A three-point bending test with a notched beam was adopted for the experiment and a finite element analysis was performed to obtain the simulated results for the bending test considering the flow-dependent tensile behavior of the UHSFRC. From the simulation for the fiber orientation distribution according to the flow distance, it could be found that the major change in the fiber orientation distribution took place within a short flow distance and most of the fibers became nearly aligned to the flow direction. After some flow distance, there was a not-so-remarkable variation in the fiber orientation distribution that could influence the tensile behavior of the composite. For this flow region, the consistent flexural test results, regardless of flow distance, demonstrate the reliability of the simulation.

Case of mononeuritis multiplex onset with rituximab therapy for Waldenström's macroglobulinemia.

Waldenström's macroglobulinemia (WM) is a lymphoplasmacytic disorder with associated monoclonal gammopathy. A wide variety of neuropathies can be associated with WM, but most commonly it is a mild length-dependent sensory neuropathy of unclear etiology. Rituximab is a monoclonal antibody which suppresses mature B-cell populations. It has increasingly been used in wide applications including WM, especially in those cases with severe neuropathy. The highlighted case provides an example of rituximab treatment complication in a WM patient with mild sensory neuropathy that evolved to multiple mononeuropathies with features of systemic vasculitis and unusual conversion of type I to type II cryoglobulinemia.

The expression of BAFF in the muscles of patients with dermatomyositis.

A B-cell activating factor of the tumor necrosis factor (TNF) family (BAFF) plays a crucial role in B-cell survival and maturation. An elevated serum BAFF level has been linked to several autoimmune diseases such as Sjögren syndrome, systemic lupus erythematosus and rheumatoid arthritis. Dermatomyositis (DM), one of autoimmune inflammatory myopathies, is characterized by inflammatory cell infiltration (CD4(+) T cells and B cells) in skeletal muscle. Serum BAFF level was significantly high in DM, but the role of BAFF is not well understood. We investigated the role of BAFF in the immunopathogenesis of DM. To examine the transcriptional increase of BAFF gene expression, we performed RT-PCR analysis with skeletal muscle tissue that contained 4 controls and 9 patients with DM. Next, in order to detect BAFF expression and cellular localization in DM, we executed immunostaining in cryosection of biopsied muscle tissue with 4 controls and 8 patients and we adopted to double immunostaining to find which inflammatory cells expressed BAFF-receptor (BAFF-R). BAFF mRNA level was increased in DM patients compared with normal controls. BAFF expression was markedly increased at muscle fibers in the perifascicular area but not blood vessels. BAFF-R was expressed in inflammatory cells in skeletal muscle tissues of DM patients. We found that BAFF expression in muscle tissue may be associated with an increased number of CD4(+) T cells and CD19(+) B cells in DM. Our study results suggest that BAFF might play an important role in the pathogenesis of DM.

Insulin resistance is independently associated with peripheral and autonomic neuropathy in Korean type 2 diabetic patients.

In addition to chronic hyperglycemia, insulin resistance itself has been proposed to cause a diabetic neuropathy. We evaluated the role of insulin resistance in the pathogenesis of peripheral and autonomic neuropathy in patients with type 2 diabetes. Eighty-six patients with type 2 diabetes were evaluated for the anthropometric and biochemical profiles, and Kitt value was calculated from insulin tolerance test to assess the insulin resistance. Various autonomic function tests, nerve conduction velocity, and quantitative sensory tests were performed to assess autonomic and peripheral neuropathy. In univariate analysis, both autonomic and peripheral neuropathy were significantly associated with glycemic exposure index (GE index), HDL-cholesterol, duration of DM, and Kitt value. In stepwise linear regression analysis, GE index was an independent predictor of autonomic and peripheral neuropathy (ß = 0.643, P < 0.001; ß = 0.207, P = 0.013, respectively), and Kitt value was also an independent factor for the autonomic and peripheral neuropathy (ß = - 0.306, P < 0.001; ß = - 0.329, P < 0.001, respectively). Low HDL-cholesterol increased the odds ratio for peripheral neuropathy. Insulin resistance is independently associated with peripheral and autonomic neuropathy in Korean Type 2 diabetic patients along with hyperglycemia and HDL-cholesterol.

A controlled study of medial arterial calcification of legs: implications for diabetic polyneuropathy.

BACKGROUND: Diabetes mellitus (DM) is associated with an increased prevalence of peripheral arterial disease and medial arterial calcification (MAC), possibly related to prevalence and severity of diabetic polyneuropathy (DPN). OBJECTIVE: To assess the prevalence, risk covariates, and implication of MAC in a controlled study of healthy subjects and patients with DM. DESIGN: Masked evaluation of radiographs. SETTING: Olmsted County, Minnesota. PATIENTS: Ambulatory volunteers with DM from the Rochester Diabetic Neuropathy Study cohort (n = 260) and matched healthy subjects from the Rochester Diabetic Neuropathy Study-Healthy Subject cohort (n = 221). METHODS: Patients and controls underwent standard radiographs of distal legs and feet from January 1, 1995, through December 31, 2002. The radiographs were independently read by masked, experienced radiologists for vessel calcification. Medial arterial calcification prevalence, risk covariates, correlation with peripheral arterial disease, and implication for distal, length-dependent sensorimotor polyneuropathy (DSPN) were studied. RESULTS: Of 481 study participants, MAC was found in 66 (13.7%): 55 of 260 (21.2%) in patients with DM and 11 of 221 (5.0%) in healthy subjects (P < .001). Interrater agreement of MAC was 94.1% (κ coefficient of 0.7). Medial arterial calcification was significantly associated with DSPN (P < .001). In stepwise logistic regression analysis, the significant risk covariates for MAC were advancing age, male sex, DM, and stage of microvessel disease (retinopathy). CONCLUSIONS: Medial arterial calcification of legs was approximately 4 times as prevalent in population-representative ambulatory persons with DM as in healthy subjects. Advancing age, male sex, DM, and retinopathy were the significant risk covariates for MAC of legs. Medial arterial calcification of legs, although significantly associated with DSPN, was not a useful surrogate marker of DSPN. Also, MAC was not shown to be a risk covariate for late worsening of DSPN, although other lines of evidence suggest that peripheral arterial disease may worsen DSPN.

Successful compensation for dystrophin deficiency by a helper-dependent adenovirus expressing full-length utrophin.

Helper-dependent adenovirus vector (AdV)-mediated full-length dystrophin expression leads to significant mitigation of the dystrophic phenotype of the mdx mouse. However, dystrophin, as a neoantigen, elicits antibody formation. As an alternative approach, we evaluated gene transfer of full-length murine utrophin, a functional homologue of dystrophin that is normally present only at the neuromuscular junction. A single injection in the tibialis anterior (TA) muscle of the helper-dependent adenovirus vector encoding utrophin provided very good transduction, with 58% of fibers demonstrating sarcolemmal utrophin expression in the neonates, and 35% utrophin-positive (Utr(+)) fibers in adults. The presence of utrophin prevented extensive necrosis in the neonates, halted further necrosis in the adults, and led to restoration of sarcolemmal expression of dystrophin-associated proteins up to 1 year after injection. Marked physiological improvement was observed in both neonates and adults. Neither increased humoral responses nor cellular immune responses were evident. However, there was a time-related decline of the initial high utrophin expression. Although viral DNA persisted in animals that were injected in the neonatal stage, viral DNA levels decreased in muscles of adult mice. These results demonstrate that although utrophin gene transfer leads to amelioration of the dystrophic phenotype, the effects are not sustained upon loss of utrophin expression.

Guillain-Barré syndrome triggered by influenza vaccination in a recipient of liver transplant on FK506.

Guillain-Barré syndrome (GBS) has been rarely reported after liver transplantation and generally has good outcome. We report a liver transplant patient on FK506 (tacrolimus) who developed GBS 6 months after liver transplantation. There was no evidence of liver rejection or active infection. Despite treatment with intravenous immunoglobulin, the patient expired. GBS occurred despite downregulation of T cells by FK506, suggesting that humoral dysfunction might be the predominant mechanism of GBS in this report.