A multiparametric MRI study of frontal lobe dementia in multiple sclerosis

Previous studies achieved conflicting results when correlating magnetic resonance imaging (MRI) abnormalities and cognitive impairment in multiple sclerosis (MS) patients. Recently, the estimation of MS lesion load on T1-weighted images and the analysis of magnetization transfer ratio (MTR) histograms, increased the degree of the correlation between physical disability and MRI findings in MS. We assessed the relationship of conventional and non-conventional MRI-derived measures with frontal lobe dementia in MS. Dual echo, T1-weighted and MT MRI scans of the brain were obtained in 11 MS patients with and in 11 without frontal lobe dementia, matched for age, sex, education and disability. Total (TLL) and frontal (FLL) lesion loads were assessed from T2- and T1-weighted scans. MTR histogram analysis was performed for the whole brain, the frontal lobe and the cerebellum. Median TLL and FLL were significantly higher in cognitively impaired patients on both T2- and T1-weighted scans. The MRI measure that better discriminated the two groups of patients was T1-weighted TLL (median values were 19.1 ml for demented and 1.9 ml for non-demented patients, P=0.006). Average MTR, peak height and location of overall brain and frontal lobe histograms were significantly lower for cognitively impaired than for cognitively intact patients (P values ranged from 0.0001 to 0.001). Cerebellar MTR histogram metrics did not significantly differ in patients with and without cognitive decline. The presence of cognitive decline in MS is associated with the extent and pathological severity of brain MRI abnormalities.     

Concentration-effect relationship of levodopa-benserazide dispersible formulation versus standard form in the treatment of complicated motor response fluctuations in Parkinson's disease

We compared the kinetic-dynamic profile of a postprandial dose of levodopa-benserazide dispersible formulation to that of the standard form in eight patients with parkinsonism presenting delayed or irregular patterns of after-meal levodopa dose effects. Patients were studied on two occasions, one week apart, according to an intra-subject randomized cross-over design. Thirty minutes after the consumption of a standard meal, patients received their usual levodopa-benserazide postprandial dose, on one occasion in the standard formulation and on the other one in the dispersible form. Blood venous samples for analysis of plasma levodopa concentrations were drawn at 15-minute intervals for the first 2 hours, then half-hourly until 5 hours after dosing. Motor response to the levodopa test dose was assessed by the finger tapping test at the same times as blood was sampled. The only statistically significant finding was a shorter time to peak plasma levodopa concentration with the levodopa-benserazide dispersible formulation compared with the standard form, whereas comparisons of levodopa pharmacodynamics showed little advantage of either formulation. Considering that liquid formulations of levodopa are less practical, we suggest reserving dispersible levodopa-benserazide tablets for selected patients and carefully monitoring drug dose motor response.     

Clinical pharmacokinetics of tacrolimus in heart transplant recipients

We report pharmacokinetic data on tacrolimus in 14 heart transplant patients (2 women, 12 men). The median age and the median body weight were 55.5 years (range, 23-61 years) and 67.0 kg (55-79 kg), respectively. All patients were maintained on a triple-drug protocol (tacrolimus, azathioprine, and prednisone), with a 7-day antithymocyte globuline induction. The first tacrolimus dose, administered orally 1 to 5 days posttransplant, ranged from 0.03 to 0.4 mg/kg (median = 0.052 mg/kg). The maintenance dose ranged from 0.03 to 0.13 mg/kg/day (administered in two equal doses) to achieve blood levels of 5 of 20 ng/ml, as determined by a microparticle enzyme immunoassay (MEIA). Whole blood samples were drawn just before, at 0.5 hour, and at 1, 2, 3, 4, 6, 8, 10, and 12 hours after the administration of the first dose; trough levels were measured thereafter.The mean oral clearance (CL/F) and apparent volume of distribution (Vd/F) averaged 0.21+/-0.08 L/hour/kg and 2.4+/-0.8 L/kg while the half-life averaged 8.7+/-3.5 hours. Tacrolimus accumulation index during chronic therapy (Rac = Cmin(steady state)/Cmin(first dose) normalized to the same dose) averaged 1.3. Eighty-eight percent of the trough blood levels measured in our patients were within 5 and 20 ng/ml. The incidence of rejection in the study population was extremely low: a prevalence of grade 2 rejection or more, of 0.4+/-0.8 episodes/ patient was observed after a follow-up period of 8.8+/-2.2 months. Only one patient experienced severe renal toxicity, probably because of his preoperative precarious hemodynamic status. Pharmacokinetic data suggest that maintenance tacrolimus daily dose should be equal to 0.1 mg/kg/day to obtain trough blood concentrations of approximately 10 ng/ml. Inter- and intra-patient variability of tacrolimus blood concentration should be expected and justify careful monitoring.     

Postural stability in Parkinson's disease: the effects of disease severity and acute levodopa dosing

We systematically assessed the potential effects of disease severity and acute levodopa dosing on body balance by a stable force measuring platform in 56 patients with Parkinson's disease, and compared them to 34 healthy volunteers. Postural sway variables were significantly higher in both patient groups without (Hoehn and Yahr 1-2) and with (Hoehn and Yahr 3-4) a clinically evident deficit of postural stability compared to controls. Levodopa dosing significantly increased postural sway 1 and 2 hours post-dose. The standardization of static posturography with respect to the clinical characteristics and drug schedule of patients may improve the sensitivity of the test, disclosing abnormalities of postural stance even at the early stages of the disease and revealing possible acute drug effects.     

Autonomic nervous system function in myotonic dystrophy

Symptoms suggestive of dysautonomia are often reported in Myotonic Dystrophy (MD) patients. 12 patients with MD underwent cardiovascular function testing with assay of plasma noradrenaline (NA) and adrenaline (A) in supine rest condition and after orthostatic and cold stimulus. Statistical analysis showed no differences between MD patients and an age and sex matched control group.

---

Sommario Nei pazienti affetti da Distrofia Miotonica si riscontrano spesso sintomi che suggeriscono un'alterata funzione del Sistema Nervoso Vegetativo. Abbiamo sottoposto a valutazione dei riflessi cardiovascolari e dei livelli ematici di catecolamine (adrenalina e noradrenalina) in condizioni basali, in psizione supina e dopo lo stimolo ortostatico e cold-pressor 12 pazienti affetti da Distrofia Miotonica. L'analisi statistica dei dati non ha mostrato differenze fra i pazienti e un gruppo di controllo comparabile per sesso ed età.

     

Electroencephalographic coherence analysis in multiple sclerosis: correlation with clinical, neuropsychological, and MRI findings

OBJECTIVE: To explore functional corticocortical connections in multiple sclerosis by means of coherence of the EEG, and to evaluate their correlations with the degree of cognitive impairment and with brain lesion load assessed by MRI. METHODS: EEG coherence was studied from 28 patients with clinically definite multiple sclerosis. Ten minutes of resting EEG were recorded with 20 scalp electrodes, with binaural reference. FFT power and coherence were calculated in artifact free epochs of 1 second and compared with values from 22 control subjects of comparable age and sex distribution. Patients also underwent MRI (n=27) and neuropsychological examination (n=21). RESULTS: Compared with controls, patients with multiple sclerosis showed increased theta power in the frontotemporal-central regions (p<0.005). theta Band coherence was decreased between homologous areas (p<0.02). alpha Band coherence was decreased both in the local and long distance connections (p<0.0005). These findings were most striking both in patients with high MRI subcortical lesion load and in patients with cognitive involvement. A significant correlation was found between interhemispheric theta (p=0.02) and alpha (p=0. 017) and anteroposterior alpha (p=0.013) coherence and subcortical MRI lesion load, but not with exclusively periventricular lesion load. CONCLUSIONS: These findings support the hypothesis that cognitive impairment in multiple sclerosis is mostly dependent on involvement of corticocortical connections related to demyelination and/or axonal loss within the white matter immediately underlying the cortex.     

Use of totally implantable central venous access ports for high-dose chemotherapy and peripheral blood stem cell transplantation: results of a monocentre series of 376 patients.

BACKGROUND: The complication rate of central venous totally implantable access ports (TIAP), used for high-dose chemotherapy with autologous stem cell transplantation support, has not been fully investigated to date, due to the almost exclusive use of externalised, tunnelled devices in this clinical setting. PATIENTS AND METHODS: During a 66-month period (from 1 January 1997 to 30 June 2002), 376 patients suffering from breast cancer, ovarian cancer, lymphoma or multiple myeloma were treated with high-dose chemotherapy and autologous stem cell transplantation at the European Institute of Oncology (Milan, Italy). A single type of port was used, constructed from titanium and silicone rubber, connected to a 7.8 F polyurethane catheter (Port-A-Cath; SIMS Deltec, Inc., St Paul, MN, USA) inserted into the subclavian vein. They were followed prospectively for device-related complications until the device was removed, the patient died or the study was closed (30 June 2002). RESULTS: No TIAP-related deaths were observed in this series. Seven pneumothoraxes (1.8%) occurred as a complication of TIAP placement, one patient only (0.2%) requiring a tube thoracostomy. Port pocket infection occurred twice in this series (0.53%, 0.01 episodes/1000 days of use), whereas three patients suffered from port-related bacteraemia (0.8%, 0.016/1000 days of use). Infections were successfully treated with antibiotics; all three cases had the ports removed at programme completion. Four cases of deep vein thrombosis were detected (1.06%, 0.022/1000 days of use); low molecular weight heparin was given, followed by oral anticoagulants. Finally, one case of extravasation occurred (0.26%, 0.005/1000 days of use), requiring port removal and local medical therapy. CONCLUSIONS: The use of TIAPs has resulted in a safe and effective option for high-dose chemotherapy deliverance and stem cell transplantation, in spite of inducing severe neutropenia and increasing the risk of sepsis in this category of oncology patient.     

Stroma cells: a novel target of herceptin activity.

PURPOSE: Stroma cells play a relevant role in tumor development and progression. We investigated the activity of herceptin (HER), a humanized monoclonal antibody widely used for the treatment of HER2-overexpressing epithelial cancer, toward stroma cell lines L87/4 and L88/5. EXPERIMENTAL DESIGN: We studied the antiproliferative potential of HER and role of human serum in HER activity. We also investigated the ability of HER to alter ancillary functions of L87/4 and L88/5, such as support to long-term hematopoiesis, growth factor production, breast cancer cell adhesion, and proliferation. RESULTS: Flow cytometry showed that HER2 membrane expression in L87/4 and L88/5 stroma cells was intermediate between the expression in HER2-negative/dim MCF-7 breast cancer cells and HER2-bright SK-BC3 breast cancer cells. HER2 gene amplification was not detected by fluorescence in situ hybridization in either stromal cell lines. HER significantly inhibited L87/4 and L88/5 proliferation. Mean ID(50)s were found to be 2000 and 1700 micro g/ml for L87/4 and L88/5, respectively, after 3-day exposure and 800 micro g/ml for both cell lines after 9-day exposure. The presence of 10% human serum in the culture increased HER inhibitory activity. IC(50) of stroma cells was found to be intermediate between HER2-bright breast cancer cells (SK-BC3) and HER2-negative/dim breast cancer cells (MCF-7). The drug did not significantly affect the ability of stroma cells to support long-term hematopoiesis in the cobblestone area forming cell assay. In contrast, in coculture assay, MCF7 cells demonstrated a worse adhesion and growth capability on HER-treated stroma layers when compared with untreated stroma. Moreover, HER significantly reduced vascular endothelial growth factor production by L88/5 cells. CONCLUSIONS: Our data support the novel finding that HER may have a relevant activity against stroma cells.