Conduction block in immune-mediated neuropathy: paranodopathy versus axonopathy.

BACKGROUND AND PURPOSE: Conduction block is a pathognomonic feature of immune-mediated neuropathies. The aim of this study was to advance understanding of pathophysiology and conduction block in chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). METHODS: A multimodal approach was used, incorporating clinical phenotyping, neurophysiology, immunohistochemistry and structural assessments. RESULTS: Of 49 CIDP and 14 MMN patients, 25% and 79% had median nerve forearm block, respectively. Clinical scores were similar in CIDP patients with and without block. CIDP patients with median nerve block demonstrated markedly elevated thresholds and greater threshold changes in threshold electrotonus, whilst those without did not differ from healthy controls in electrotonus parameters. In contrast, MMN patients exhibited marked increases in superexcitability. Nerve size was similar in both CIDP groups at the site of axonal excitability. However, CIDP patients with block demonstrated more frequent paranodal serum binding to teased rat nerve fibres. In keeping with these findings, mathematical modelling of nerve excitability recordings in CIDP patients with block support the role of paranodal dysfunction and enhanced leakage of current between the node and internode. In contrast, changes in MMN probably resulted from a reduction in ion channel density along axons. CONCLUSIONS: The underlying pathologies in CIDP and MMN are distinct. Conduction block in CIDP is associated with paranodal dysfunction which may be antibody-mediated in a subset of patients. In contrast, MMN is characterized by channel dysfunction downstream from the site of block.

3 T MRI uterine peristalsis: comparison of symptomatic fibroid patients versus controls.

AIM: To compare uterine peristalsis between symptomatic fibroid patients and normal subjects and to determine the possible effect of fibroid characteristics on uterine peristalsis at high-field magnetic resonance imaging (MRI). MATERIALS AND METHODS: The present study included 20 symptomatic fibroid patients (age range 39-53 years) and 20 normal subjects (age range 19-46 years). MRI images were obtained during the peri-ovulatory phase using 3 T MRI using a sagittal T2 turbo spin-echo sequence and a half-Fourier acquisition single-shot turbo spin-echo sequence for display on cine mode. Two radiologists independently evaluated the images for the presence of uterine peristalsis by confidence level. In cases where peristalsis was present, the images were also evaluated for peristalsis frequency and direction. For fibroid patients, uterine and index fibroid volume, fibroid burden and index fibroid location were also recorded. RESULTS: Uterine peristalsis was significantly decreased in symptomatic fibroid patients compared with normal controls (p < 0.01). Peristalsis frequency in fibroid patients was also lower than in normal subjects. Direction of peristalsis was cervix-to-fundus for the majority of fibroid patients and controls. There was no significant relationship between fibroid characteristics, such as uterine volume, index fibroid volume, index fibroid location, and fibroid number in fibroid patients with, and fibroid patients without peristalsis. CONCLUSION: In women with symptomatic fibroids, the presence of uterine peristalsis is significantly decreased compared to normal controls on 3 T cine MRI. The presence of fibroids appears to disturb the normal conduction of uterine peristalsis and may interfere with fluid (e.g., menses, sperm) transport.

Late-onset neurological symptoms in thalidomide-exposed subjects: a study of an Australasian cohort.

BACKGROUND AND PURPOSE: Thalidomide was marketed for the treatment of morning sickness and resulted in foetal death and physical deformities. The exact mechanism of action of thalidomide in its teratogenicity is still actively debated in the literature. METHODS: This study reviewed 16 of the confirmed Australasian victims of in utero exposure to thalidomide who now presented with new-onset neurological symptoms in the fourth and fifth decades. RESULTS: Clinical neurological examination and neurophysiological investigations revealed that new symptoms were due in part to compressive neuropathies, often exacerbated by the adaptations made to accommodate the disability and poor mobility arising from the limb deformities. Other subjects were found to have musculoskeletal symptoms due to compensatory postures employed to perform tasks of daily living. CONCLUSIONS: The study provides no evidence of ongoing loss of neurons or late reactivated neural degeneration and no evidence of a generalized peripheral neuropathy. Rather, the development of new symptoms in subjects can be explained by compressive neuropathies and compensatory postures employed to perform tasks of daily living.

Chromosomal translocation involving the beta T cell receptor gene in acute leukemia.

DNA spanning a t(7;19) chromosomal translocation breakpoint was isolated from the human T cell line SUP-T7 established from an acute lymphoblastic leukemia. Nucleotide sequence analysis showed that the point of crossover on chromosome 7 occurred immediately adjacent to joining segment J beta 1.1 within the TCR-beta gene, suggesting that this translocation resulted from an error in TCR gene rearrangement. On chromosome 19, the translocation occurred within a previously uncharacterized transcriptional unit for which we propose the name lyl-1. An approximately 1.5-kb RNA is transcribed from this gene in a wide variety of hematolymphoid cell lines. The t(7;19) results in truncation of the lyl-1 gene and production of abnormal-sized RNAs, suggesting a role for lyl-1 in the pathogenesis of this leukemia.

Effect of leflunomide on the peripheral nerves in rheumatoid arthritis.

BACKGROUND: The objective of this study was to determine the neurophysiological effects of leflunomide on peripheral nerves in rheumatoid arthritis. METHODS: We conducted a prospective cohort trial of 32 patients with rheumatoid arthritis with 16 patients receiving leflunomide treatment and 16 receiving other disease-modifying anti-rheumatic drug therapies. Clinical, laboratory and neurophysiological measurements were used to determine the presence of a peripheral neuropathy in these patients at study entry and then after a further 3 and 6 months. RESULTS: Fifty-four per cent of the leflunomide group and 8% of the control group had an increase in their neuropathy symptom score 6 months into the study (P = 0.01). No correlation was found between the electrophysiological findings and the clinical symptoms. There was no significant difference between the two groups in upper and lower limb sensory and motor amplitudes and conduction velocities recorded at 3 and 6 months. One patient developed both clinical and neurophysiological evidence of a peripheral neuropathy 5 months into the study that improved after cessation of leflunomide therapy and cholestyramine washout. CONCLUSION: After 6 months of exposure we found that leflunomide was associated with an apparent increase in the clinical symptoms of peripheral neuropathy in patients with rheumatoid arthritis. These symptoms did not correlate with neurophysiological studies.

Autoantibody responses to nodal and paranodal antigens in chronic inflammatory neuropathies.

Autoantibodies to nodal/paranodal proteins have been reported in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). To determine the frequency of anti-paranodal antibodies in our cohort of CIDP patients and to validate the presence anti-nodal antibodies in MMN, sera were screened for IgG against human neurofascin 155, contactin-1, neurofascin 186 and gliomedin using ELISA. In CIDP patients, 7% were anti-NF155 IgG4 positive and 7% were anti-CNTN1 IgG4 positive. Positive results were confirmed using cell based assays and indirect immunofluorescence on teased nerve fibres. We did not detect IgG autoantibodies against these nodal/paranodal antigens in MMN patients.

The histopathology of cutaneous lesions of Kikuchi's disease (necrotizing lymphadenitis): a report of five cases.

Kikuchi's disease (KD) is an idiopathic, self-limited necrotizing lymphadenitis that can clinically and histologically mimic high-grade lymphoma, including Hodgkin's disease, or can be mistaken for the lymphadenitis of systemic lupus erythematosus (SLE). Involvement of extranodal sites is unusual but well documented, especially in Asia, where KD is more common than in North America or Europe. The successful distinction of KD from malignant lymphoma and SLE is imperative for the appropriate treatment of affected patients. We describe five patients with cutaneous involvement by KD, all of whom presented with fever, lymphadenopathy, and an eruption on the skin of the upper body, which in one case was clinically suspected to be due to SLE and in another, polymorphous light eruption. The patients ranged in age from 10 months to 42 years (median, 33 years) and included three females and two males. All five patients had negative serologic studies for collagen vascular disease. Each patient had a lymph node biopsy showing the typical necrotizing lymphadenitis of KD. Skin biopsies from all five patients shared a specific constellation of histologic features: vacuolar interface change with necrotic keratinocytes, a dense lymphohistiocytic superficial and deep perivascular and interstitial infiltrate, varying amounts of papillary dermal edema, and abundant karyorrhectic debris with a conspicuous absence of neutrophils and a paucity of plasma cells, paralleling the nodal histology in KD. CD68 immunohistochemistry on paraffin-embedded sections showed many histiocytes and plasmacytoid monocytes in all cases, whereas CD3, CD4, and CD8 showed highly variable staining among the cases. There was only rare staining with TIA-1 and CD30. We believe that the papular eruption of KD has recognizable histopathologic features and that a CD68 stain that marks many cells that initially seem to be lymphocytes can be performed to confirm the diagnosis.

Synergy between antibody and P2-reactive T cells in experimental allergic neuritis.

Studies were conducted in experimental allergic neuritis (EAN) to evaluate the possible interaction of cellular and humoral immune mechanisms in the demyelinating process. EAN was induced in Lewis rats by passive transfer of T cells reactive to P2 myelin protein or by active immunisation with whole myelin. Animals were then given systemic antimyelin antibody or control serum and assessed clinically, electrophysiologically and with semiquantitative histological studies. Animals given intraperitoneal (i.p.) P2-reactive T cells and systemic antimyelin antibody developed much more severe disease than those given i.p. T cells alone (P < 0.001). In actively immunised animals, the addition of systemic antimyelin antibody did not significantly alter disease severity. We believe the more severe disease in animals receiving T cells and antimyelin antibody reflects synergy between cellular and humoral immune mechanisms whereby neural antigen-specific T cells breach the blood-nerve barrier, allowing demyelinating antibody access to the endoneurium. In EAN induced by active immunisation with whole myelin it is likely that both B and T cell activation occurs and that the more severe demyelination characteristic of this disease reflects the involvement of both humoral and cellular immunity.

A rapid novel derivatization of amphetamine and methamphetamine using 2,2,2-trichloroethyl chloroformate for gas chromatography electron ionization and chemical ionization mass spectrometric analysis.

Amphetamine and methamphetamine are commonly abused central nervous system stimulants. We describe a rapid new derivatization of amphetamine and methamphetamine using 2,2,2-trichloroethyl chloroformate for gas chromatography-mass spectrometric analysis. Amphetamine and methamphetamine, along with N-propyl amphetamine (internal standard), were extracted from urine using 1-chlorobutane. The derivatization with 2,2,2-trichloroethyl chloroformate can be achieved at room temperature in 10 minutes. The electron ionization mass spectrum of amphetamine 2,2,2-trichloroethyl carbamate showed two weak molecular ions at m/z 309 and 311, but showed diagnostic strong peaks at m/z 218, 220, and 222. In contrast, chemical ionization of the mass spectrum of amphetamine 2,2,2-trichloroethyl carbamate showed strong (M + 1) ions at m/z 310 and 312 and other strong diagnostic peaks at m/z 274 and 276. The major advantages of this derivative are the presence of a diagnostic cluster of peaks due to the isotopic effect of three chlorine atoms (isotopes 35 and 37) in the derivatized molecule and the relative ease of its preparation. We also observed strong molecular ions for derivatized methamphetamine in the chemical ionization mass spectrum, but the molecular ions were very weak in the electron ionization mass spectrum. We used the scan mode of mass spectrometry in all analyses. When using a urine standard containing 1,000 ng/mL of amphetamine (a 7.4-micromol/L concentration) and methamphetamine (a 6.7-micromol/L concentration), the within-run precisions were 4.8% for amphetamine and 3.6% for methamphetamine. The corresponding between-run precisions were 5.3% for amphetamine and 6.7% for methamphetamine. The assay was linear for amphetamine and methamphetamine concentrations of 250 to 5,000 ng/mL (amphetamine, 1.9-37.0 micromol/L; methamphetamine, 1.7-33.6 micromol/L). The detection limit was 100 ng/mL (amphetamine, 0.74 micromol/L; methamphetamine, 0.67 micromol/L) using the scan mode of electron ionization mass spectrometry. We observed good a correlation between the concentrations of amphetamine and methamphetamine in five urine specimens positive for amphetamines using the more conventional pentafluoropropionyl derivative and our new derivative using 2,2,2-trichloroethyl chloroformate.

Effect of magnesium supplementation on the fractional intestinal absorption of 45CaCl2 in women with a low erythrocyte magnesium concentration.

The cosupplementation of magnesium with calcium has been suggested to be beneficial in the prevention of osteoporosis. We investigated the effect of magnesium supplementation on parameters of bone resorption and fractional 45Ca absorption. Twenty apparently healthy women with a mean age of 39.2 +/- 9.2 years and an erythrocyte magnesium concentration less than 1.97 mmol/L were recruited into a controlled magnesium supplementation trial. During weeks 1 to 4, they received a daily control preparation, potassium/sodium citrate malate (PSCM). During weeks 5 to 8, the subjects received magnesium citrate malate (MCM) equivalent to 250 mg magnesium per day. During the fourth and eighth weeks, blood was collected for measurement of the serum intact parathyroid hormone (PTH) concentration and serum and erythrocyte magnesium concentration. Urine was collected for measurement of calcium, magnesium, creatinine, and deoxypyridinoline excretion. On the final day of each treatment period, 5 microCi45CaCl2 was administered orally, and the isotope was traced in the blood and urine over 7 hours. Urinary calcium, 45Ca, and deoxypyridinoline excretion, as well as serum intact PTH levels, showed no statistically significant changes as a result of magnesium supplementation. However, urinary magnesium excretion increased by 31.1% (P < .005) while fractional 45Ca absorption decreased by 23.5% (P < .001) as a result of magnesium supplementation. It is concluded that magnesium supplementation does not result in changes in bone resorption, while the fractional intestinal absorption of 45Ca appears to decrease.

Uterine artery embolization for leiomyomata.

OBJECTIVE: To determine whether uterine artery embolization is safe and effective for treating uterine leiomyomata. METHODS: We analyzed 200 consecutive patients (61 reported previously) undergoing uterine artery embolization for the treatment of uterine leiomyomata at a single institution. After treatment, follow-up data were obtained by written questionnaire mailed to the patients at intervals of 2 weeks, 3 months, 6 months, and 12 months after treatment. Follow-up imaging was obtained at 3 months and 12 months after therapy. All complications and subsequent gynecologic interventions were recorded prospectively, obtained using the patient questionnaires and physician contact. The percentages and their 95% confidence intervals (CI) were calculated to compare the symptoms at follow-up. Proportional odds models for repeated ordinal responses were used to assess the stability of symptom improvement over time. RESULTS: The mean follow-up was 21 months (minimum 12). Heavy menstrual bleeding improved in 87% (95% CI 82%, 92%) of patients at 3 months and in 90% (95% CI 86%, 95%) at 1 year after therapy. Bulk symptoms improved in 93% of patients (95% CI 88%, 96%) at 3 months and in 91% (95% CI 86%, 95%) at 1 year after treatment. Only one major periprocedural complication occurred (pulmonary embolus), which resolved with anticoagulant therapy. Subsequent gynecologic interventions occurred in 10.5% of the patients (95% CI 7.0%, 15.0%) during the follow-up period. CONCLUSION: Uterine artery embolization is safe and controls the symptoms caused by leiomyomata in most patients.

Myasthenia gravis: options and timing of immunomodulatory treatment.

The autoimmune pathogenesis of myasthenia gravis is relatively well understood. The current options for treatment of this disease are acute and long term immunotherapies, acetylcholinesterase inhibitors and thymectomy. Many factors influence the timing of initiation of immunomodulatory therapy in myasthenia gravis and both disease factors, such as stage and severity, and patient factors, such as age, pregnancy and intercurrent illness, must be considered. Decisions regarding the choice of therapy can be difficult because of the limited number of randomised controlled trials that have been performed in myasthenic patients. In general, acetylcholinesterase inhibitors alone are used only in mild ocular disease, and in the majority of other patients immunomodulatory therapy is begun early. Corticosteroids are the most commonly used initial therapy, followed by azathioprine. In refractory cases, the available options include immunosuppressants such as cyclosporin, mycophenolate mofetil and cyclophosphamide. Plasmapheresis and intravenous immunoglobulin are important in the treatment of acute exacerbations and myasthenic crisis and in the perioperative setting. Despite many years of experience, the role of thymectomy in improving long term outcome in nonthymomatous myasthenia gravis remains controversial.

Feline mammary carcinomas as a model for human breast cancer. I. Sensitivity of mammary tumor cells in culture to cytostatic drugs. A preliminary investigation of a predictive test.

Feline mammary carcinomas were found to maintain well in short-term cultures. Principally the same types of nuclear DNA frequency distribution histograms were recognized in feline mammary carcinomas as in human mammary carcinomas. However, the more abnormal histograms are less frequent in feline than in human mammary carcinomas. Feline mammary carcinomas appeared, at least in vitro, most sensitive to Doxorubicin and 5-fluorouracil. Preliminary, thymidine incorporation studies indicate both cytotoxic and cytostatic effects of Doxorubicin and 5-FU. Methotrexate was found to stimulate thymidine incorporation.

Validated method for quantitation of biomarkers for benzene and its alkylated analogues in urine.

A validated gas chromatography-mass spectrometric method for the analysis of the metabolites of benzene and its alkylated analogues in urine is reported. A number of metabolites, as required by authorities for biomonitoring of industrial exposure to aromatic vapour, were analysed simultaneously with preservation of quantitative information concerning positional isomers. The use of this method replaces a combination of analytical methods required for the analysis of all these metabolites. Urine samples were subjected to acidic deconjugation followed by a derivatization step. Phenol, ortho-, meta-, para-cresol, mandelic acid, and ortho-, meta-, para-methylhippuric acid were analysed as their corresponding ethoxycarbonyl derivatives, with single ion monitoring. The mass-to-charge ratios (m/z) of the ions used for quantitation by single ion monitoring of the metabolites were: phenol, 94 m/z; cresols, 108 m/z; mandelic acid, 206 m/z; hippuric acid, 105 m/z; methylhippuric acids, 119 m/z. The mass-to-charge ratios for the internal standards were: [(2)H(6)]phenol, 99 m/z; p-chlorophenol, 128 m/z and 3-chloro-4-hydroxyphenyl acetic acid, 214 m/z. The limits of detection for phenol and the cresols were below 0.4 micromol/l and below 0.05 micromol/l for mandelic acid and the hippuric acids. Within-run precision for mandelic acid was 6.2%, for hippuric acid was 7.32% and was below 5% for the rest of the analytes.

Cerebrovascular regulation in the postural orthostatic tachycardia syndrome (POTS).

Patients with the postural orthostatic tachycardia syndrome (POTS) have symptoms of orthostatic intolerance despite having a normal orthostatic blood pressure (BP), which suggests some impairment of cerebrovascular regulation. Cerebrovascular autoregulation refers to the maintenance of normal cerebral blood flow in spite of changing BP. Mechanisms of autoregulation include myogenic, metabolic and neurogenic vasoregulation. Beat-to-beat recording of blood-flow velocity (BFV) is possible using transcranial Doppler imaging. It is possible to evaluate autoregulation by regressing deltaBFV to deltaBP during head-up tilt. A number of dynamic methods, relating deltaBFV to deltaBP during sudden induced changes in BP by occluding then releasing peripheral arterial flow or by the Valsalva maneuver. The deltaBFV to deltaBP provides an index of autoregulation. In orthostatic hypotension, the autoregulated range is typically expanded. In contrast, paradoxical vasoconstriction occurs in POTS because of an increased depth of respiration, resulting in hypocapnic cerebrovascular constriction, and impaired autoregulation.

Tuberculous cranial pachymeningitis.

We describe two immunocompetent patients with tuberculous cranial pachymeningitis. Both patients underwent biopsy after focal dural thickening was identified on MRI. Histopathologic examination of tissue revealed necrotizing granulomatous inflammation. PCR for Mycobacterium tuberculosis DNA was negative on CSF but positive on tissue. Both patients responded to antituberculous therapy. Although uncommon as a cause of cranial pachymeningitis, tuberculosis should be considered, since it responds well to treatment.