Gabapentin therapy for amyotrophic lateral sclerosis: lack of improvement in neuronal integrity shown by MR spectroscopy

BACKGROUND AND PURPOSE: Proton MR spectroscopy has revealed impaired neuronal integrity in the motor cortex of patients with amyotrophic lateral sclerosis (ALS). We hypothesized that the N-acetylaspartate (NAA)-creatine (Cr) ratios in the motor cortex and adjacent brain could reflect the therapeutic effectiveness of gabapentin (GBP) treatment in ALS. METHODS: Eight patients with ALS underwent MR spectroscopy before and 26.5 days +/- 8.8 after starting GBP. In 10 patients with ALS who were not treated with GBP, paired spectra were obtained 21.4 days +/- 7.2 apart. Fourteen healthy subjects underwent a single MR spectroscopic examination. The NAA/Cr ratio was measured in the precentral gyrus, the postcentral gyrus, the superior parietal lobule, the supplementary motor area, and the premotor cortex. RESULTS: The NAA/Cr ratio was decreased in the precentral and postcentral gyri of patients with ALS compared with healthy controls. In those with ALS, the change in the NAA/Cr ratio was not different between treated patients and untreated patients in any of the regions studied. CONCLUSION: No improvement in neuronal integrity was detected in motor and nonmotor cerebral regions after GBP treatment. This result agrees with that of prior investigations showing the equivocal clinical effectiveness of GBP for ALS and supports the validity of the NAA/Cr ratio as a surrogate of therapeutic effectiveness.     

Kinematics of spinal motion during prolonged rowing

Low back pain is a common problem in rowers of all levels. Few studies have looked at the relationship between rowing technique, the forces generated during the rowing stroke and the kinematics of spinal motion. Of particular concern with respect to spinal injury and damage are the effects of fatigue during long rowing sessions. A technique has been developed using an electromagnetic motion system and strain gauge instrumented load cell to measure spinal and pelvic motion and force generated at the handle during rowing on an exercise rowing ergometer. Using this technique 13 elite national and international oarsmen (mean age 22.43 +/- 1.5 y) from local top squad rowing teams were investigated. The test protocol consisted of a one hour rowing piece. During this session rowing stroke profiles were quantified in terms of lumbopelvic kinematics and stroke force profiles. These profiles were sampled at the start of the session and at quarterly intervals during the hour piece. From this data we were able to quantify the motion of the lumbar spine and pelvis during rowing and relate this to the stroke force profile. The stroke profiles over the one hour piece were then compared to examine the effects of prolonged rowing. This revealed marked increases in the amount of spinal motion during the hour piece. The relevance of this with regard to low back pain requires further investigation.     

Inhibition of human liver microsomal (S)-nicotine oxidation by (-)-menthol and analogues

(-)-Menthol is a widely used flavoring ingredient present in mouthwash, foods, toothpaste, and cigarettes; yet, the pharmacological effects of menthol have not been widely studied. Mentholated cigarette smoking may increase the risk for lung cancer. Many African American smokers smoke mentholated cigarettes, and African Americans have a significantly higher incidence of lung cancer as compared with whites. There may be a relationship between the incidence of lung cancer and the type of cigarette smoked because the use of mentholated cigarettes by white smokers is significantly less and the incidence of lung cancer is less. The mechanism whereby (-)-menthol could increase the health risk of smoking is not known. The results of our in vitro studies herein show that (-)-menthol and synthetic congeners inhibit the microsomal oxidation of nicotine to cotinine and the P450 2A6-mediated 7-hydroxylation of coumarin. Replacement of the alcohol oxygen atom of menthol with other heteroatoms increased the potency of P450 2A6 inhibition. Thus, the K(i) value of (-)-menthol for inhibition of microsomal nicotine oxidation was 69.7 micro M but neomenthyl thiol possesses a K(i) value of 13.8 micro M. Menthylamine inhibited nicotine oxidation with a K(i) value of 49.8 micro M, but its hydroxylamine derivative gave an IC(50) value of 2.2 micro M. A series of 16 menthol derivatives and putative metabolites were procured or chemically synthesized and tested as inhibitors of P450 2A6. While highly potent inhibition of P450 2A6 was not observed for the menthol analogues examined, it is nevertheless possible that smoking mentholated cigarettes leads to inhibition of nicotine metabolism and allows the smoker to achieve a certain elevated dose of nicotine each day. This may be another example of self-medication to obtain the desired effect of nicotine.     

Underdiagnosis of obesity at a community health center

BACKGROUND: Obesity is at epidemic proportions. This study examined the extent to which obesity is being diagnosed at a community health center residency-training site. Results were examined by provider type. Characteristics of patients with obesity diagnosed by primary care providers were compared with characteristics of patients determined to be obese by body mass index (BMI) calculation exclusively. METHODS: A cross-sectional design was used. Medical records of 465 adult patients were audited. Data collected included diagnosis of obesity, height and weight, demographics, and comorbidity. RESULTS: Of the 465 patients' charts audited, 83 contained a provider diagnosis of obesity, and 74 additional patients were determined to be obese by BMI calculation exclusively. Significant underdiagnosis occurred among all provider types (P = .036). Patients with a diagnosis of obesity had significantly higher BMI scores (38.4 vs 34.4, P = .002). Obesity was more likely to be diagnosed in female than in male patients (P = .001). Differences related to age, insurance coverage, and comorbidity were not significant. CONCLUSIONS: Obesity was found to be an underdiagnosed condition among all provider types. As evidenced by significantly higher BMI scores for provider-diagnosed obesity, the data suggest that the obesity diagnosis is made by appearance. The importance of teaching and modeling the use of BMI to diagnose obesity is underscored.     

Allergic reaction to nanocolloid during lymphoscintigraphy for sentinel lymph node biopsy

Editor—We read with interest the case report by Stefanuttoand colleagues,¹ concerning an anaphylactic reaction to isosulphanblue dye during routine sentinel lymph node biopsy for breastsurgery. We agree that anaesthetists must be aware of the potentialserious risks of anaphylaxis in this group of patients. However,this is not a new finding; anaphylaxis to the blue     

Electrocochleography and gentamicin therapy for Ménière's disease: a preliminary report

OBJECTIVE: It is widely held that an enlarged summating potential (SP) relative to the eighth nerve action potential (AP) is a reflection of endolymphatic hydrops. Aminoglycosides are an accepted treatment for incapacitating Ménière's disease and are known to affect both sensory and secretory cells of the inner ear. The intent of this study was to determine whether this effect on secretory cells could be objectively confirmed by virtue of changes in the electrocochleogram (ECoG) of patients receiving gentamicin therapy for Ménière's disease. STUDY DESIGN: This was a prospective longitudinal study of repeated ECoG measures in three groups of subjects. Ménière's patients undergoing gentamicin treatment were compared with two control groups: individuals with stable Ménière's disease and normal-hearing control subjects. SETTING: The study was conducted at a tertiary referral center. PATIENTS: The sample included 21 normal-hearing subjects, 15 patients with stable unilateral Ménière's disease, and 12 with disabling unilateral Ménière's disease. INTERVENTIONS: For patients with disabling Ménière's disease, gentamicin was administered transtympanically. Audiograms, impedance tests, and ECoG were performed twice for all subjects. MAIN OUTCOME MEASURES: The SP and AP amplitudes, AP latency, and SP/AP ratio of the EcoG were measured. RESULTS: A statistically significant reduction in the SP/AP ratio was observed after gentamicin administration (analysis of variance interaction effect: F2 = 5.64; p = 0.0065). CONCLUSIONS: The significant reduction in the SP/AP ratio in the gentamicin-treated Ménière's group supports the hypothesis that gentamicin improves the electrophysiologic function of the cochlea, possibly by reducing the severity of the associated endolymphatic hydrops.     

ROLE OF EPIDURAL MEDICATION IN LUMBOSCIATIC SYNDROME

Role of epidural medication through caudal route was studied in 109 patients having lumbago with or without sciatica to highlight the value of this mode of treatment which relieved symptoms in more than 70% of cases without hospitalisation and without being off work for long periods as in usual methods of conservative treatment.KEY WORDS: Epidural medication, Backache, Lumbago, Sciatica     

Differential and synergistic effects of human granulocyte-macrophage colony-stimulating factor and human granulocyte colony-stimulating factor on hematopoiesis in human long-term marrow cultures.

The ability of granulocyte-macrophage colony-stimulating factor (GM-CSF) and G-CSF to influence hematopoiesis in long-term cultures (LTC) of human marrow was studied by cocultivating light density normal human marrow cells with human marrow fibroblast feeders engineered by retroviral infection to constitutively produce one of these growth factors. Feeders producing stable levels of 4 ng/mL GM-CSF or 20 ng/mL G-CSF doubled the output of mature nonadherent cells. The numbers of both colony forming unit-GM (CFU-GM) and erythroid burst forming unit (BFU-E) in the G-CSF LTC were also increased (twofold and fourfold, respectively, after 5 weeks in culture), but this effect was not seen with the GM-CSF feeders. At the time of the weekly half medium change 3H-thymidine suicide assays showed primitive adherent layer progenitors in LTC to be quiescent in both the control and GM-CSF cultures. In contrast, in the G-CSF cultures, a high proportion of primitive progenitors were in S-phase. A single addition of either recombinant GM-CSF or G-CSF to LTC in doses as high as 80 ng/mL and 150 ng/mL, respectively, failed to induce primitive progenitor cycling. However, three sequential daily additions of 150 ng/mL G-CSF did stimulate primitive progenitors to enter S-phase and a single addition of 5 or 12.5 ng/mL of G-CSF together with 10 ng/mL GM-CSF was able to elicit the same effect. Thus, selective elevation of G-CSF in human LTC stimulates proliferation of primitive clonogenic progenitors, which may then proceed through to the terminal stages of granulopoiesis. In contrast, the effects of GM-CSF in this system appear limited to terminally differentiating granulopoietic cells. However, when both GM-CSF and G-CSF are provided together, otherwise biologically inactive doses show strong stimulatory activity. These findings suggest that the production of both of these growth factors by normal stromal cells may contribute to the support and proliferation of hematopoietic cells, not only in LTC, but also in the microenvironment of the marrow in vivo.     

Regulators of human stem cell proliferation and engraftment

Transplantable human hematopoietic stem cells can be routinely detected by their ability to engraft sublethally irradiated immunodeficient mice with both lymphoid and myeloid progeny for periods of at least 6-8 weeks [1]. These cells include subsets with both short-term and longterm reconstituting activity, the former being responsible for most of the human cells seen in fully immunodeficient mice (eg, NOD/SCID-β2microglobulin^?/? mice) in the first 8 weeks and the latter being responsible for the lower levels of engraftment seen after the same period of time in less compromised (eg, NOD/SCID) mice [2]. Interestingly, human cells with short- and longterm hematopoietic reconstituting potential show further differences in the regulation of their ability to engraft when they are activated into cycle short-term reconstituting cells being unaffected whereas longterm reconstituting cells lose their transplantability when they transit S/G₂/M [2,3]. A closely related population of primitive human hematopoietic cells (referred to as longterm culture-initiating cells or LTC-ICs) are detected by virtue of their ability to generate intermediate types of progenitor cells for at least 5 weeks when co-cultured with stromal cell feeder layers, the intermediate progenitors being those that produce colonies of granulocytes and macrophages and/or erythroblasts in 2-week semi-solid cultures [4]. The proliferative status of these various stages of primitive human hematopoietic cells is regulated by their exposure to distinct types of both positively acting (mitogenic) and negatively acting (cytostatic) cytokines. We have recently discovered that stromal-derived growth factor 1 (SDF-1) belongs to a group of chemokines that act as inhibitors of primitive human progenitor cycling and is unique in its ability to force the entry of human LTC-ICs into G_o. SDF-1 can similarly act on proliferating human cells with longterm hematopoietic reconstituting ability in NOD/SCID mice. These cells can be shown to be actively proliferating at early times post-transplant in primary NOD/SCID mice by their high sensitivity to treatment with 5-fluorouracil in vivo or with high specific activity³H-thymidine in vitro as revealed when they are subsequently assayed in secondary NOD/SCID mice. Prior SDF-1 treatment in the primary mice abrogates this sensitivity. Importantly, this exposure to SDF-1 in vivo also causes a marked increase in the number of reconstituting cells that can be detected in the secondary mice even without exposure to a cycle-active drug - consistent with the restoration of engraftment potential by cycling longterm reconstituting stem cells forced to re-enter G_o. A similar, albeit less marked effect has also been achieved by SDF-1 treatment of human stem cells stimulated to proliferate in vitro. These findings demonstrate that cell cycle activation is a major but reversible constraint to the use of proliferating stem cells for transplantation therapies and suggest a novel approach to overcoming this limitation.