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Biomedical subjects

A Eisen

Publications and source records attributed to A Eisen.

At least 19 recordsLinked to original sources
PubMed2006

Clinicopathological phenotype of ALS with a novel G72C SOD1 gene mutation mimicking a myopathy.

A 71-year-old woman with a family history of amyotrophic lateral sclerosis (ALS) was investigated for symmetrical, proximal limb and abdominal muscle weakness. Initial examination showed mild proximal muscle weakness in the arms and legs, slightly elevated serum creatine kinase (CK) level, and normal electromyographic (EMG) findings. A myopathy was the presumed diagnosis. Over the next year, weakness became severe and tendon reflexes became unelicitable; no upper motor signs were present. EMG then showed acute and chronic denervation and a muscle biopsy showed target fibers and grouped atrophy. DNA analysis revealed a G72C CuZn-superoxide dismutase (SOD1) mutation. Fasciculations were absent throughout the disease. The patient died 53 months after symptom onset and autopsy revealed loss of lower motor neurons (LMN) and SOD1-positive inclusions. This case expands the phenotypic spectrum of ALS associated with SOD1 mutations to include presenting features that mimic a myopathy.

Aged↗
PubMed2005

Pharmacogenomic assessment of treatment options in gestational diabetes.

Gene expression profiles offer a multidimensional view of metabolic diseases, typically characterized by a single parameter, and can provide a basis for choosing between therapies yielding a common clinical end point. We applied such an approach in gestational diabetes mellitus (GDM). Gene expression was examined in four maternal tissues and placentas from normal patients and euglycemic GDM patients, undergoing elective Cesarean sections at term, treated either by diet or diet plus insulin. Deviations from normal were 11-fold greater for the patients treated by diet, alone, than for patients treated by diet plus insulin. Assuming the achievement of a "normal" gene expression profile, in addition to euglycemia, is a desirable outcome of treatment, insulin treatment appears to have a beneficial effect in the treatment of GDM. Subsequently, we utilized the expression data to identify serum biomarkers that provide ways to monitor the benefits of insulin treatment in GDM.

Adipose Tissue↗
PubMed2003

Scleromyxoedema: treatment of cutaneous and systemic manifestations with high-dose intravenous immunoglobulin.

Scleromyxoedema is a rare disease characterized by cutaneous sclerosis, mucin deposition and paraproteinaemia. Internal disease is common, particularly musculoskeletal, gastrointestinal and central nervous system involvement. We report a series of three consecutive patients with scleromyxoedema treated with high-dose intravenous immunoglobulin (hdIVIg). Each of the three patients had relatively low levels of a highly basic IgG-lambda paraprotein, and each has demonstrated a sustained response of both their cutaneous and extracutaneous disease to hdIVIg. As all patients had perioral skin involvement and microstomia, one measure of cutaneous improvement was the increase in intraincisor distance. Extracutaneous manifestations of scleromyxoedema that improved included ureteral stricture, vocal strength and dysphagia.

Aged↗
PubMed2001

Electromyography of respiratory muscles in amyotrophic lateral sclerosis.

We reviewed the records of 52 amyotrophic lateral sclerosis (ALS) patients examined between 1995 and 2000 who had needle electromyography (EMG) of their respiratory muscles, including the diaphragm, at or near the time of their diagnosis. With respiratory function testing, patients with abnormal diaphragmatic EMG at diagnosis (Group 1, n=23) had significantly lower forced vital capacity (FVC), lower daytime arterial PO(2) and higher PCO(2) measurements (p<0.05) than patients with normal diaphragmatic EMG (Group 2, n=29). Twenty-eight percent of the patients without symptoms or signs of respiratory insufficiency at the time they were examined had an abnormal diaphragm EMG. Mean survival of Groups 1 and 2 were similar. However, sub-analysis of patients within each group, comparing those treated with non-invasive positive pressure ventilation (NIPPV) with those not treated, showed that treated patients in Group 1 (abnormal diaphragm EMG) survived significantly longer (p<0.05) than untreated patients. They also started NIPPV earlier than treated patients in Group 2. We conclude that respiratory muscle EMG was simply and safely performed on ALS patients at or around the time of diagnosis. The procedure can detect sub-clinical respiratory muscle dysfunction. The technique used for EMG of the respiratory muscles, its pitfalls and contraindications are also reviewed.

Aged↗
PubMed2001

The physiological basis of conduction slowing in ALS patients homozygous for the D90A CuZn-SOD mutation.

Familial amyotrophic lateral sclerosis (ALS) with the autosomal-recessively inherited D90A CuZn-superoxide dismutase (CuZn-SOD) mutation is characterized by a stereotypic slowly progressive, distinctive phenotype and very slow central motor conduction. To determine the basis of this slowing, we assessed corticomotoneuronal function using peristimulus time histograms (PSTHs) in 8 ALS patients homozygous for the D90A CuZn-SOD mutation. The results were compared with findings in 10 patients with multiple sclerosis (MS), in which slowing of central motor conduction is common, and 11 healthy subjects. PSTHs were constructed from 3-7 different, voluntarily recruited motor units recorded in each patient from the extensor digitorum communis muscle (EDC). In D90A and MS patients, the stimulus threshold, onset latency, number of excess bins, duration, amplitude, and synchrony of the primary peak differed significantly from controls (P < 0.0004). The mean onset latency of the primary peak in D90A patients was 35.3 ms, compared to 23.6 ms for MS patients and 19.3 ms for normal subjects (P < 0.0001). In the D90A patients, the onset latencies of the primary peak had a bimodal distribution, whereas in MS the distribution showed a continuum. Loss of synchrony was similar in D90A and MS patients, but the threshold, number of excess bins, and duration differed significantly (P < 0.0057), which suggests that either axonal loss or demyelination can result in delayed and desynchronized primary peaks. We propose that conduction slowing in the D90A homozygotes results from selective loss of fast-conducting large pyramidal cells with preservation of slow-conducting mono- or polysynaptic corticomotoneuronal connections.

Adult↗
PubMed2001

The motor cortex and amyotrophic lateral sclerosis.

On theoretical grounds, abnormalities of the motor cortex in patients with amyotrophic lateral sclerosis (ALS) could lead to anterograde ("dying-forward") transneuronal degeneration of the anterior horn cells as suggested by Charcot. Conversely, retrograde ("dying-back") degeneration of the corticospinal tracts could affect the motor cortex. Evidence derived from clinical, neuropathological, static, and functional imaging, and physiological studies, favors the occurrence of anterograde degeneration. It is hypothesized that transneuronal degeneration in ALS is an active excitotoxic process in which live but dysfunctional corticomotoneurons, originating in the primary motor cortex, drive the anterior horn cell into metabolic deficit. When this is marked, it will result in more rapid and widespread loss of lower motor neurons. In contrast, slow loss of corticomotoneurons, as occurs in primary lateral sclerosis (PLS), precludes excitotoxic drive and is incompatible with anterograde degeneration. Preservation of slow-conducting non-M1 direct pathways in PLS is not associated with excitotoxicity, and anterior horn cells survive for long periods of time.

Amyotrophic Lateral Sclerosis↗
PubMed2001

Clinical neurophysiology of ALS.

The neurophysiology of amyotrophic lateral sclerosis is important not only in relation to diagnosis, but also in the development of methods to follow progress, and the effects of putative therapies, in the disease. Quantitative techniques can be applied to the measurement of reinnervation using needle electromyogram. The methodology of motor unit number estimation may be useful in measuring loss of functioning motor units in groups of patients but variability in the measurement using current methods limits its sensitivity in the evaluation of individual patients. Conventional neurophysiological measurements, expressed as a multimetric index, may be useful in assessing progress. The cortical and upper motor neuron system can be assessed using transcortical magnetic stimulation protocols, and cortical excitability may be measured by the peristimulus histogram method. In this review the advantages, limitations and promise of these various methods is discussed, in order to indicate the direction for further neurophysiological studies in this disorder.

Action Potentials↗
PubMed2001

Clinical electrophysiology of the upper and lower motor neuron in amyotrophic lateral sclerosis.

Electrophysiology is important in amyotrophic lateral sclerosis (ALS). It helps in the assessment of disease severity and rate of progression, and it plays a role in evaluating the efficacy of therapeutic trials. Presently, electrophysiology is the only means of confirming suspected ALS, and this has been incorporated into the El Escorial criteria. Needle electromyography identifies disease in clinically "unaffected muscles" including bulbar musculature, confirms involvement of anterior horn cells, and can detect early involvement of respiratory muscles (intercostals and diaphragm). Conduction studies are imperative to rule out motor neuropathy with multifocal conduction block. Various techniques (cortical threshold, cortical silent period, double stimulation) employing transcranial magnetic stimulation have demonstrated that the motor cortex in ALS is hyperexcitable. Central motor conduction is normal in ALS but uniquely slow in the D9OA SOD1 mutation. Using peristimulus time histograms (PSTHs) it is possible to estimate the size of a unitary excitatory postsynaptic potential (EPSP). In ALS the EPSP is typically desynchronized. With time it becomes reduced in amplitude and a slow conducting component becomes recognizable in the primary peak of the PSTH. This reflects conduction through a slow motor pathway. Abnormalities of the PSTH are not seen in Kennedy's disease, implying that the changes seen in ALS are due to supraspinal mechanisms.

Amyotrophic Lateral Sclerosis↗
PubMed2001

Nonneurologic hand pain versus carpal tunnel syndrome: do psychological measures differentiate?

OBJECTIVE: To determine whether psychological measures would differentiate a group of patients with physician-diagnosed nonneurologic hand pain from patients with carpal tunnel syndrome (CTS). Many patients, who also displayed symptoms of psychological distress, were referred to an electrodiagnostic clinic with a diagnosis of possible CTS; they subsequently had normal nerve conduction studies. DESIGN: Sixty patients with hand pain were referred to either of two university clinics for electrophysiologic testing, were assigned to either the CTS or nonneurologic group, and were compared on a series of psychometric tests. RESULTS: The Beck Depression Inventory and McGill Pain Questionnaire showed that the physician-assigned nonneurologic patients have a greater degree of depression, use more affective adjectives, and choose more words on the McGill Pain Questionnaire than the physician-assigned CTS group. The nonneurologic group also scored higher on indices of self-reported disability on the Pain Disability Inventory in five of seven categories. Although the CTS group perceived more control over their pain, no differences were observed in the types of coping strategies used on the Coping Strategy Questionnaire. Finally, the nonneurologic group had more Workers' Compensation Board claims. CONCLUSION: Evidence of important psychological issues in some patients with hand pain suggests a need for greater awareness among treating physicians.

Adolescent↗
PubMed2001

Use of radiotherapy for control of sialorrhea in patients with amyotrophic lateral sclerosis.

Many patients with amyotrophic lateral sclerosis (ALS) develop progressive difficulty with swallowing secretions, and drooling becomes a significant problem. The production of saliva can be reduced with radiation of the submandibular and sublingual salivary gland tissue. This method has been used successfully in Europe and had limited use at Vancouver Hospital. This study was undertaken to determine the lowest effective dose of radiation necessary to control salivary production. Over a 3-year period, patients with ALS who developed significant problems with drooling were identified and treated with a predetermined dose of radiation. The first group received a single dose of 8 Gy in one fraction and the second received a total of 12.5 Gy in two fractions. They were followed over the next 6 months and were evaluated for effectiveness and side effects. Their saliva was measured pre- and postradiation treatment, and they were also asked to evaluate the change subjectively, using a questionnaire. The preliminary findings suggest that 8 Gy of radiation was effective in controlling drooling, and increasing the dose did not improve initial control. Long-term control was difficult to evaluate as the patients entered in the study were very ill and their life expectancy was very short. Radiation at this low dose resulted in very few side effects. Low-dose radiation can safely help control secretions in selected patients with ALS.

Amyotrophic Lateral Sclerosis↗
PubMed2000

Temporal dispersion of cortically evoked single motor unit potentials in ALS.

Peristimulus time histograms (PSTHs) can be used to investigate corticomotoneuronal dysfunction in amyotrophic lateral sclerosis (ALS). The most characteristic change is temporal dispersion of the primary peak. We recorded PSTHs in the extensor digitorum communis with voluntary motor units activation (standard PSTHs) or at rest (non-activated PSTHs). Standard PSTHs were recorded in 29 motor units of 12 healthy control subjects and 12 sporadic ALS patients. Double primary peaks were seen in three motor units of two healthy control subjects and 10 motor units from five ALS patients. The number of subpeaks was up to three in most of the normal motor units as well as in the earlier component of double primary peaks. The subpeaks were smaller and less discernible in the later component of double primary peaks. Non-activated PSTHs of ALS patients demonstrated similar decomposition of subpeaks in the motor units with significantly increased variability of latency. Similar findings in the standard PSTHs and non-activated PSTHs suggest that the abnormalities seen in ALS are independent of the membrane potential of the spinal motoneuron and therefore supraspinal in origin. The decomposed additional later component may indicate activation of slow conducting corticospinal tracts.

Amyotrophic Lateral Sclerosis↗
PubMed2000

The split hand in ALS has a cortical basis.

Loss of highly fractionated movement involving the thumb and index finger is an early characteristic of hand dysfunction in many ALS patients. These movements are largely subserved by the 'thenar complex' including the first dorsal interosseus muscle (FDI), whereas the 'hypothenar complex', innervated by the same myotome, has less ability to fractionate and is relatively spared. This suggests that in ALS, hand dysfunction and wasting is related to corticomotoneuronal representation and input. To determine whether corticomotoneuronal input to the thenar spinal pool is preferentially impaired compared to the hypothenar spinal pool in ALS, we studied 18 ALS patients and 11 normal subjects. Compound muscle action potentials (CMAPs) and motor evoked potentials (MEPs) of the thenar and hypothenar complexes were evoked by peripheral nerve stimulation and transcranial magnetic stimulation. In healthy control subjects the cortical/peripheral (MEP/CMAP) ratios were significantly larger for the thenar complex suggesting a stronger corticomotoneuronal input to this muscle complex (P<0.005). This was not the case in ALS patients. Comparing the ratios between control subjects and patients revealed a significant reduction for the thenar complex (P<0.02) in ALS patients but not for the hypothenar complex. We conclude that corticomotoneuronal input to the thenar complex is preferentially affected in ALS and that corticomotoneuronal disease may be the prime determinant of hand dysfunction and wasting.

Amyotrophic Lateral Sclerosis↗
PubMed2000

The yeast NuA4 and Drosophila MSL complexes contain homologous subunits important for transcription regulation.

In Drosophila, the MSL complex is required for the dosage compensation of X-linked genes in males and contains a histone acetyltransferase, MOF. A point mutation in the MOF acetyl-CoA-binding site results in male-specific lethality. Yeast Esa1p, a MOF homolog, is essential for cell cycle progression and is the catalytic subunit of the NuA4 acetyltransferase complex. Here we report that NuA4 purified from yeast with a point mutation in the acetyl-CoA-binding domain of Esa1p exhibits a strong decrease in histone acetyltransferase activity, yet has no effect on growth. We demonstrate that Eaf3p (Esa1p-associated factor-3 protein), a yeast protein homologous to the Drosophila dosage compensation protein MSL3, is also a stable component of the NuA4 complex. Unlike other subunits of the complex, it is not essential, and the deletion mutant has no growth phenotype. NuA4 purified from the mutant strain has a decreased apparent molecular mass, but retains wild-type levels of histone H4 acetyltransferase activity. The EAF3 deletion and the ESA1 mutation lead to a decrease in PHO5 gene expression; the EAF3 deletion also significantly reduces HIS4 and TRP4 expressions. These results, together with those previously obtained with both the MSL and NuA4 complexes, underscore the importance of targeted histone H4 acetylation for the gene-specific activation of transcription.

Acetyltransferases↗
PubMed2000

Effect of radiotherapy after breast-conserving treatment in women with breast cancer and germline BRCA1/2 mutations.

PURPOSE: Recent laboratory data suggest a role for BRCA1/2 in the cellular response to DNA damage. There is a paucity of clinical data, however, examining the effect of radiotherapy (RT), which causes double-strand breaks, on breast tissue from BRCA1/2 mutation carriers. Thus the goals of this study were to compare rates of radiation-associated complications, in-breast tumor recurrence, and distant relapse in women with BRCA1/2 mutations treated with breast-conserving therapy (BCT) using RT with rates observed in sporadic disease. PATIENTS AND METHODS: Seventy-one women with a BRCA1/2 mutation and stage I or II breast cancer treated with BCT were matched 1:3 with 213 women with sporadic breast cancer. Conditional logistic regression models were used to compare matched cohorts for rates of complications and recurrence. RESULTS: Tumors from women in the genetic cohort were associated with high histologic (P =.0004) and nuclear (P =.009) grade and negative estrogen (P=.0001) and progesterone (P=.002) receptors compared with tumors from the sporadic cohort. Using Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicity scoring, there were no significant differences in acute or chronic morbidity in skin, subcutaneous tissue, lung, or bone. The 5-year actuarial overall survival, relapse-free survival, and rates of tumor control in the treated breast for the patients in the genetic cohort were 86%, 78%, and 98%, respectively, compared with 91%, 80%, and 96%, respectively, for the sporadic cohort (P = not significant). CONCLUSION: There was no evidence of increased radiation sensitivity or sequelae in breast tissue heterozygous for a BRCA1/2 germline mutation compared with controls, and rates of tumor control in the breast and survival were comparable between BRCA1/2 carriers and controls at 5 years. Although additional follow-up is needed, these data may help in discussing treatment options in the management of early-stage hereditary breast cancer and should provide reassurance regarding the safety of administering RT to carriers of a germline BRCA1/2 mutation.

Adult↗
PubMed2000

Complex fasciculations and their origin in amyotrophic lateral sclerosis and Kennedy's disease.

Complex fasciculations are common in patients with amyotrophic lateral sclerosis (ALS). Combined fasciculations, defined as a complex fasciculation consisting of two or more components that occur independently but also in combination with another component, also occur in ALS. To test the hypothesis that combined fasciculations originate at the supraspinal level, we analyzed 2681 fasciculation potentials from 17 patients with definite or probable ALS by the El Escorial criteria. Results were compared with 304 fasciculation potentials recorded from 6 patients with Kennedy's disease, in which the upper motoneurons are spared. The mean firing frequency of the fasciculations was 24.4 +/- 25.6 per minute in ALS, significantly higher than the 2.9 +/- 3.4 per minute found in Kennedy's disease (P < 0.0001). In ALS, the mean combination ratio (the number of times that a combined fasciculation occurred divided by the total number of fasciculations) was 4.6 +/- 8.3% (range 0-33). Fourteen of 17 ALS patients had combined fasciculations, but only one combined fasciculation was found in a patient with Kennedy's disease. Combined fasciculations are distinctive in ALS, and we hypothesize that they are triggered by a supraspinal mechanism reflecting dysfunction of descending motor pathways.

Electromyography↗