Unsuccessful treatment of severe pyruvate carboxylase deficiency with triheptanoin.

UNLABELLED: Pyruvate carboxylase (PC) deficiency (OMIM 266150) is an autosomal recessive disorder that usually presents with lactic acidaemia and severe neurological dysfunction, leading to death in infancy. Because the enzyme is involved in gluconeogenesis and anaplerosis of the Krebs cycle, therapeutic strategies have included avoiding fasting and attempts to correct the defect of anaplerosis. Triheptanoin is a triglyceride of C7 fatty acids. The oxidation of odd chain fatty acids leads to the production not only of acetyl-CoA but also of propionyl-CoA, which is an anaplerotic substrate for the Krebs cycle. One infant with PC deficiency has previously been treated with triheptanoin as well as citrate and 2-chloropropionate. We report two further patients with PC deficiency, who were treated with triheptanoin, continuously from 11 and 21 days of age. They were also given citrate, aspartate and dichloroacetate. Triheptanoin did not lead to any clinical or biochemical improvement. The plasma and CSF lactate concentrations remained high with episodes of severe ketoacidosis and lactic acidosis. Both patients had severe hearing loss, roving eye movements, seizures and very limited neurodevelopmental progress; they died at the ages of 7 and 8 months. CONCLUSION: Though triheptanoin did not alter the clinical course in our patients, it was well tolerated. It remains possible that less severely affected patients might benefit from this form of therapy.

Novel and recurrent connexin 30.3 and connexin 31 mutations associated with erythrokeratoderma variabilis.

Erythrokeratoderma variabilis (EKV) is characterized by fixed hyperkeratotic plaques and transient erythema. Mutations in the genes GJB3 and GJB4, which encode connexin (Cx)31 and Cx30.3, are associated with EKV. We report one novel mutation in Cx31 and one recurrent mutation in Cx30.3 in two different families. One novel rare sequence variant of unknown clinical significance was also identified. This finding extends the spectrum of known EKV-associated mutations.

Premature mortality in refractory partial epilepsy: does surgical treatment make a difference?

BACKGROUND: Epilepsy carries an increased risk of premature death. For some people with intractable focal epilepsy, surgery offers hope for a seizure-free life. The authors aimed to see whether epilepsy surgery influenced mortality in people with intractable epilepsy. METHODS: The authors audited survival status in two cohorts (those who had surgery and those who had presurgical assessment but did not have surgery). RESULTS: There were 40 known deaths in the non-surgical group (3365 person years of follow-up) and 19 in the surgical group (3905 person-years of follow-up). Non-operated patients were 2.4 times (95% CI 1.4 to 4.2) as likely to die as those who had surgery. They were 4.5 times (95% CI 1.9 to 10.9) as likely to die a probable epilepsy-related death. In the surgical group, those with ongoing seizures 1 year after surgery were 4.0 (95% CI 1.2 to 13.7) times as likely to die as those who were seizure-free or who had only simple partial seizures. Time-dependent Cox analysis showed that the yearly outcome group did not significantly affect mortality (HR 1.3, 95% CI 0.9 to 1.8). CONCLUSION: Successful epilepsy surgery was associated with a reduced risk of premature mortality, compared with those with refractory focal epilepsy who did not have surgical treatment. To some extent, the reduced mortality is likely to be conferred by inducing freedom from seizures. It is not certain whether better survival is attributable only to surgery, as treatment decisions were not randomised, and there may be inherent differences between the groups.

Do alterations in inter-ictal heart rate variability predict sudden unexpected death in epilepsy?

Reduced heart rate variability (HRV) may predispose to sudden unexpected death in epilepsy (SUDEP). We ascertained whether HRV predicts SUDEP in chronic epilepsy using a case-control design and investigated parameters of inter-ictal HRV in 14 patients (7 had died from SUDEP). No HRV parameter was associated with SUDEP. Thus, although altered HRV might be involved in SUDEP, HRV parameters are not clear-cut predictors for SUDEP.

Human rabies therapy: lessons learned from experimental studies in mouse models.

Ketamine was one of the therapeutic agents used as a therapy for a human rabies survivor who did not receive rabies vaccine. Ketamine therapy is re-examined here in infected mouse primary neuron cultures and in adult ICR mice using the CVS strain with both intracerebral and peripheral routes of inoculation with ketamine vs. vehicle given intraperitoneally. No significant beneficial therapeutic effects of ketamine in the cultures or mouse model were observed. This team does not recommend further widespread clinical use of ketamine on human rabies patients until further experimental work demonstrates therapeutic efficacy. Because of the potential neuroprotective and anti-apoptotic properties of minocycline, minocycline therapy was assessed in infected primary neuron cultures and in neonatal ICR mice infected by peripheral inoculation with a highly attenuated rabies virus strain. No beneficial effect of minocycline was observed in the primary neuron cultures. In the mouse model, minocycline therapy aggravated the clinical neurological disease and resulted in higher mortality. An anti-apoptotic effect of minocycline was noted in the brains of infected mice, which may have very mildly increased viral spread. An anti-inflammatory effect was also noted in the brain using a CD3 T cell marker. These effects likely aggravated the disease. This team recommends that empirical therapy with minocycline be avoided in the management of rabies and viral encephalitis in humans until more information becomes available.

Treatment of inclusion body myositis with cyclosporin-A or tacrolimus: successful long-term management in patients with earlier active disease and concomitant autoimmune features.

OBJECTIVE: Sporadic inclusion body myositis (s-IBM) is a chronic, progressive, inflammatory myopathy of unknown aetiology, generally resistant to immunosuppressive therapy. Given that lymphocyte infiltrates in s-IBM muscle tissue are CD8+ T cells, targeting these cells may represent a valid approach. PATIENTS AND METHODS: Three patients with biopsy-proven s-IBM, high creatine kinase levels at diagnosis, two of whom with associated immune disorders, were treated with either cyclosporin-A (CyA) or tacrolimus, in combination with high doses of corticosteroids (CS), followed by rapid CS tapering. Clinical assessment and laboratory evaluation were performed every three months for the first year and then every six months for the second year. RESULTS: Based on muscle strength assessment and muscle enzyme serum levels, a major clinical response was observed at month +3 in two out of the three patients. A complete clinical response and major clinical response were obtained at month +6, in two and one patient, respectively. Normalization of serum muscle enzymes was observed in all. Steroids could be tapered to very low doses in all patients and were suspended early in one. Laboratory, but not clinical relapse occurred in one patient and was controlled by increasing the CyA dose. Treatment was well tolerated, with no serious adverse events occurring. All three patients are maintaining immunosuppressive therapy. CONCLUSION: Calcineurin inhibitors may represent a useful option for the long-term management of s-IBM, possibly in a subset characterized by a short duration with high disease activity or associated autoimmune manifestations.

Do seizures in patients with refractory epilepsy vary between wakefulness and sleep?

AIM: To determine the effects of sleep and wakefulness on seizures in patients with refractory epilepsy recorded while undergoing video-electroencephalography (EEG) telemetry. METHODS: The video-EEG data of patients who had two or more seizures during video-EEG telemetry (n = 270) were reviewed. Fifty seven patients who had seizures both in wakefulness and sleep were identified. The video and ictal EEG data were reviewed, paying specific attention to type of seizures, duration, semiology, lateralisation and number of seizures. RESULTS: Three hundred and sixty two seizures were recorded; 237 seizures while awake and 125 while sleeping. Secondary generalisation occurred more often in sleep than in wakefulness (p < 0.01). Overall, there was no significant effect of sleep on the duration of seizures or ictal EEG change. Sleep and awake seizures differed in only eight patients. CONCLUSION: Secondary generalisation occurred more often in sleep than in wakefulness, perhaps due to the facilitated spread of seizures during sleep. For the most part, however, seizures recorded during sleep did not differ from those recorded during wakefulness.

Application of SEBAL approach and MODIS time-series to map vegetation water use patterns in the data scarce Krishna river basin of India.

Evapotranspiration (ET) from irrigated land is one of the most useful indicators to explain whether the water is used as "intended". In this study, the Surface Energy Balance Algorithm for Land (SEBAL) was used to compute actual ET from a Landsat7 image of December 29, 2000 for diverse land use in the Krishna Basin in India. SEBAL ETa varies between 0 to 4.7 mm per day over the image and was quantified for identified land use classes. Seasonal/annual comparison of ETa from different land uses requires time series images, processed by SEBAL. In this study, the Landsat-derived snapshot SEBAL ETa result was interpreted using the cropping calendar and time series analysis of MODIS imagery. The wastewater irrigated area in the basin has the highest ETa in the image, partly due to its advanced growth stage compared to groundwater-irrigated rice. Shrub and forests in the senescence phase have similar ETa to vegetable/cash crops, and ETa from grasslands is a low 0.8 mm per day after the end of the monsoon. The results indicate that wastewater irrigation of fodder and rice is sufficient to meet crop water demand but there appears to be deficit irrigation of rice using groundwater.

Rituximab treatment for glomerulonephritis in HCV-associated mixed cryoglobulinaemia: efficacy and safety in the absence of steroids.

OBJECTIVE: Rituximab, an anti-CD20 monoclonal antibody, has been used in lupus nephritis and membranous idiopathic nephropathy and has proved effective in non-renal manifestations of type II mixed cryoglobulinaemia (MC) syndrome. We investigated the possible efficacy and safety of rituximab in the treatment of cryoglobulinaemic nephritis. METHODS: Five patients with active, biopsy-proven, glomerulonephritis in hepatitis C virus (HCV)-related type II MC syndrome were treated with four weekly infusions of rituximab (375 mg/m2) in monotherapy, without steroids whenever possible. Rituximab was the first-line therapy in three cases. RESULTS: A rapid and sustained renal response was observed in all patients, in one of them without retreatment up to the last follow-up (month 21+). Renal biopsy was repeated after 6 months in one patient and histopathological improvement was documented. Three patients relapsed, at months +5, +7 and +12 of follow-up, respectively. Two of them were then retreated with rituximab and again presented a rapid improvement in renal function. Maintenance therapy with rituximab was performed in two patients: nephritis remission was maintained in both. Fc-gamma receptor 3a (FcgammaRIIIa) genotype characterization was consistent with the clinical response observed. Rituximab also proved effective against other active MC manifestations, when present. No major side-effects occurred and steroids were not required in the follow-up. CONCLUSIONS: Rituximab may provide effective and safe therapy in type II MC-related glomerulonephritis, possibly as first-line therapy, avoiding steroids and hazardous immunosuppressive treatment.

Magnetic correlations and the anisotropic Kondo effect in Ce1-xLaxAl3.

By combining the results of muon spin relaxation and inelastic neutron scattering in the heavy fermion compounds Ce1-xLaxAl3 (0.0

The midline thalamus: alterations and a potential role in limbic epilepsy.

PURPOSE: In limbic or mesial temporal lobe epilepsy, much attention has been given to specific regions or cell populations (e.g., the hippocampus or dentate granule cells). Epileptic seizures may involve broader changes in neural circuits, and evidence suggests that subcortical regions may play a role. In this study we examined the midline thalamic regions for involvement in limbic seizures, changes in anatomy and physiology, and the potential role for this region in limbic seizures and epilepsy. METHODS: Using two rat models for limbic epilepsy (hippocampal kindled and chronic spontaneous limbic epilepsy) we examined the midline thalamus for evidence of involvement in seizure activity, alterations in structure, changes in the basic in vitro physiology of the thalamic neurons. We also explored how this region may influence limbic seizures. RESULTS: The midline thalamus was consistently involved with seizure activity from the onset, and there was significant neuronal loss in the medial dorsal and reuniens/rhomboid nuclei. In addition, thalamic neurons had changes in synaptically mediated and voltage-gated responses. Infusion of lidocaine into the midline thalamus significantly shortened afterdischarge duration. CONCLUSIONS: These observations suggest that this thalamic region is part of the neural circuitry of limbic epilepsy and may play a significant role in seizure modulation. Local neuronal changes can enhance the excitability of the thalamolimbic circuits.

Spatio-temporal imaging of focal interictal epileptiform activity using EEG-triggered functional MRI.

EEG-triggered, blood oxygen level-dependent functional MRI (BOLD-fMRI) was used in 24 patients with localization-related epilepsy and frequent interictal epileptiform discharges (spikes) to identify those brain areas involved in generating the spikes, and to study the evolution of the BOLD signal change over time. The location of the fMRI activation was compared with the scalp EEG spike focus and the structural MR abnormality. Twelve patients (50%) had an fMRI activation concordant with the EEG focus and structural brain abnormalities where present (n = 7). In 2 other patients, the fMRI activation was non-concordant with electroclinical findings. The remaining 10 patients (41.7%) showed no significant fMRI activation. These patients had significantly lower mean spike amplitudes compared to those with positive fMRI results (p = 0.03). The time course of the BOLD response was studied in 3 patients and this revealed a maximum signal change 1.5 to 7.5 sec after the spike. In conclusion, EEG-triggered fMRI can directly identify the generators of interictal epileptiform activity, with high spatial resolution, in selected patients with frequent spikes. The superior spatial resolution obtainable through EEG-triggered fMRI may provide an additional non-invasive tool in the presurgical evaluation of patients with intractable focal seizures.

Ectoparasites of the island fox on Santa Cruz Island.

The ectoparasite fauna for island foxes (Urocyon littoralis) on Santa Cruz Island (California, USA) in April (wet season) and September (dry season) 1998 was evaluated. Three taxa of ectoparasites were identified. These were fleas (Pulex irritans), lice (Neotrichodectes mephitidis), and ticks (Ixodes pacificus). Ectoparasite abundances varied seasonally. Typical of insular endemic species, island foxes may be especially vulnerable to the introduction of novel disease organisms and their vectors.

Modeling pollutant release from a surface source during rainfall runoff.

Though runoff from manure spread fields is recognized as an important mode of nonpoint-source pollution, there are no models that mechanistically describe transport from a field-spread manure-type source. A mechanistic, physically based model for pollutant release from a surface source, such as field-spread manure, was hypothesized, laboratory tested, and field-applied. The primary objective of this study was to demonstrate the potential applicability of a mechanistic model to pollutant release from surface sources. The laboratory investigation used stable sources and a conservative "pollutant" (KCl) so that the dynamic effects of source dissolution and chemical transformations could be ignored and transport processes isolated. The field investigation used runoff and soluble reactive phosphorus (SP) data collected from a dairy-manure-spread field in the Cannonsville watershed in the Catskills region of New York State. The model predictions corroborated well with observations of runoff and pollutant delivery in both the laboratory and the field. "Pollutant" release from surface sources was generally predicted within 11% of laboratory KCl measurements and field SP observations. Laboratory flume runoff predictions with 15 and 26% errors for 25 and 15 mm h(-1) simulated rainfall intensity experiments, respectively, represented root mean square errors of less than 0.2 mLs(-1). A 26% error was calculated for overland flow predictions in the field, which translated into approximately a 39 mLs(-1) error. Results suggest that the hypothesized model satisfactorily represents the primary mechanisms in pollutant release from surface sources.

Transurethral radiofrequency thermal ablation of prostatic tissue: a feasibility study in humans.

OBJECTIVES: To evaluate the feasibility and efficacy of ablating prostatic tissue by inducing thermal lesions using radiofrequency (RF) energy delivered transurethrally through electrodes mounted on a Foley-like catheter. METHODS: Twenty male patients, candidates for radical cystoprostatectomy to treat bladder carcinoma, underwent RF prostate ablation 1 to 8 days before surgery (mean 2.8). Stainless steel, internally cooled, 2-cm-long electrodes mounted on a Foley-like catheter were used to deliver RF energy to the prostatic tissue. Semicircular electrodes were used in 10 patients (group A) and circular electrodes were used in the remaining 10 patients (group B). The urethral, rectal, and prostatic tissue temperatures were recorded. Histologic step sections were performed on whole mounts of the prostates to define the volume of the thermal lesions. RESULTS: The mean RF energy delivered was 36.5 kJ (range 26.4 to 53.1) in group A and 82.3 kJ (range 38 to 149) in group B. The intraprostatic temperatures were between 44 degrees C and 80 degrees C in group A and between 60 degrees C and 119 degrees C in group B. The urethral and rectal temperatures never exceeded 42 degrees C. No major complications occurred. After the RF procedure, 5 patients who received more than 75 kJ of energy could not void and required catheterization. The mean prostate volume was 11.54 cm(3) for group A and 24.02 cm(3) for group B. The mean volumes of the thermal lesions and their relative percentages in relation to the whole prostate in groups A and B were, respectively, 1.69 cm(3) and 15% and 6.91 cm(3) and 29% (P = 0.049). Analysis of variance showed a significant correlation between the thermal lesion volume and the energy delivered, regardless of the electrode shape (P = 0.001). CONCLUSIONS: Satisfactory thermal ablation of prostatic tissue can be achieved using RF electrodes mounted on a Foley-like catheter. The procedure is effective, simple, and safe and, therefore, can be used in pilot clinical studies on patients with benign prostatic hyperplasia.

Serum iron indices as a measure of iron deposits in chronic hepatitis C.

Serum iron indices are believed to be elevated in patients with hepatitis C virus (HCV) infection in connection to the presence of hepatic inflammation, though this hypothesis has never been formally tested. We studied 69 consecutive, unselected anti HCV antibody positive patients, aged 14 to 70 years. Iron, transferrin saturation and ferritin were measured in fasting serum samples. Histologically detectable iron (HDI) as well as histologic grading and staging were estimated semiquantitatively in liver biopsy samples. The median values for serum iron, transferrin saturation and serum ferritin were 24 micromol/l (range, 8-61), 29 percent (range, 6-77) and 170 microg/l (range, 1-954), respectively. At univariate analysis, all three serum iron indices were positively correlated with grading and staging scores, as well as with HDI in the liver; only serum iron was positively correlated with transaminases. At multivariate analysis, independent associations were found between serum iron and the grading score; ferritin and sinusoidal and portal HDI; transferrin saturation and total hepatic HDI. In conclusion, in hepatitis C, serum iron reflects the degree of current hepatic inflammation and necrosis, whereas the extent of progressive deposition of iron in sites of fibrosis is best reflected by serum ferritin. Transferrin saturation is the best predictor of the status of hepatic iron deposits.

Recent advances in the pathophysiology, diagnosis and treatment of hereditary hemochromatosis and other iron overload syndromes.

Recent years have witnessed tremendous advances in the fields of pathophysiology, diagnosis and management of hereditary hemochromatosis (HH) and other iron overload syndromes, the dreadful consequences of which are fully preventable by early diagnosis and treatment. Missense mutations in HFE, a newly discovered gene encoding for a major histocompatibility class-I like molecule, have been found to be strictly associated with most cases of HH. The mechanisms by which a dysfunctional HFE molecule determines increased absorption of iron in HH are on the way to be fully clarified, due to the availability of a knockout mouse model. Epidemiologic studies have shown that HH is one of the most common human hereditary disorders. The possibility to identify HFE heterozygotes by means of a simple genetic test have prompted studies on the association between HFE mutations and iron overload syndromes different from HH. In the era of the historic completion of the human genome projects, genetic testing for HH may soon qualify for being adopted in universal population screening policies. In the present paper, the recent advances in the fields of genetics and pathophysiology of HH and other iron overload syndromes will be summarized. Furthermore, its clinical features, pathology and treatment will be reviewed, and the emerging issues of cost-effective diagnosis and of possible population screening strategies will be succintly discussed.

Aberrant neuronal physiology in the basal nucleus of the amygdala in a model of chronic limbic epilepsy.

Limbic epilepsy is a chronic condition associated with a broad zone of seizure onset and pathology. Studies have focused mainly on the hippocampus, but there are indications that changes occur in other regions of the limbic system. This study used in vitro intracellular recording and histology to examine alterations to the physiology and anatomy of the basal nucleus of the amygdala in a rat model of chronic limbic epilepsy characterized by spontaneously recurring seizures. Epileptic pyramidal neuron responses evoked by stria terminalis stimulation revealed hyperexcitability characterized by multiple action potential bursts and no evident inhibitory potentials. In contrast, no hyperexcitability was observed in amygdalar neurons from kindled (included as a control for seizure activity) or control rats. Blockade of ionotropic glutamate receptors unmasked inhibitory postsynaptic potentials in epileptic pyramidal neurons. Control, kindled and epileptic inhibitory potentials were predominantly biphasic, with fast and slow components, but a few cells exhibited only the fast component (2/12 in controls, 0/3 in kindled, 3/10 in epileptic). Epileptic fast inhibitory potentials had a more rapid onset and shorter duration than control and kindled. Approximately 40% of control neurons exhibited spontaneous inhibitory potentials; no spontaneous inhibitory potentials were observed in neurons from kindled or epileptic rats. A preliminary histological examination revealed no gross alterations in the basal amygdala from epileptic animals. These results extend previous findings from this laboratory that hyperexcitability is found in multiple epileptic limbic regions and may be secondary to multiple alterations in excitatory and inhibitory efficacy. Because there were no differences between control and kindled animals, the changes observed in the epileptic animals are unlikely to be secondary to recurrent seizures.

Design of an intensive epilepsy monitoring unit.

Video-electroencephalography (EEG) telemetry is a crucial component in the comprehensive evaluation of patients with epilepsy. The reasons for patients needing to be monitored fall broadly into three groups: presurgical assessment (36% of our patients), diagnostic assessment (52%), and sleep disorders (12%). Video EEG can be used to differentiate unusual epilepsies from pseudo seizures or other causes of paroxysmal neurological events. The design of a unit depends on the case mix of patients expected to be referred. The key elements to a successful unit are a reliable, flexible, easy-to-use recording system and a team of dedicated, experienced staff, both nursing and technical. The unit at the National Hospital is a six-bed ward with 7 nurses to provide 24-hour coverage, 5 technicians working in shifts, and physics support. A minimum of two staff are on duty at all times. It operates on a five-day week with a throughput of approximately 500 patients per year. It is vital that investigations are performed as efficiently and effectively as possible, and the patient's safety and wellbeing is paramount at all times. Drug reduction is likely to be used to precipitate seizures, especially in those being considered for epilepsy surgery, and this poses a risk of provoked secondary generalized seizures. Continuous supervision of patients, and the ability to respond rapidly to a seizure, are therefore essential. We adopt a standardized easy-to-follow drug-reduction protocol, similar to that used by other centers.