Neuropsychological Findings: Myoclonic Astatic Epilepsy (MAE) and Lennox-Gastaut Syndrome (LGS)

Summary:  Purpose: To identify a specific neuropsychological profile associated with myoclonic astatic epilepsy (MAE) and Lennox-Gastaut syndrome (LGS).
Methods: Seven patients diagnosed with MAE and four patients diagnosed with LGS were selected from patients referred to our Child Neurology Unit. The patients were assessed both clinically (awake, sleep, Holter EEG, seizures frequency, and semiology) and neuropsychologically (IQ, language, attention, visuospatial and visuomotor abilities, and behavior). One representative case of each syndrome is presented here.
Results: The clinical picture of the MAE patient resembled that of an MAE condition associated with transitory epileptic encephalopathy. The neuropsychological findings suggest that electroclinical anomalies can temporarily affect cognitive and behavioral functioning. Early effective antiepileptic drug (AED) treatment was found to improve cognitive outcome. In contrast, LGS was associated with mental retardation, which persisted after seizure control.
Conclusions: At present, it remains difficult to delineate a precise neuropsychological profile associated with MAE and LGS. The cognitive outcome of MAE is variable and depends on the clinical pattern. With regard to LGS, the hypothesis of a genetic predisposition underlying both the epilepsy and the mental retardation is still valid. Alternatively, exposure to subclinical electrophysiological anomalies during a critical period of cerebral development may be responsible for the mental retardation. At the time the clinical manifestations appear, drug treatment, even if effective, would have only limited impact on cognitive outcome. However, early multidisciplinary intervention may help to improve behavior and communicative abilities, enhancing the quality of life of these children and their families.     

Making clinical decisions for dental care: concepts to consider

Clinical decisions are often made with incomplete information, yet patient care decisions are made every day. Patients vary clinically, uncertainty exists in diagnostic and prognostic information, and many preventive and treatment alternatives have not been formally assessed for their effectiveness. Because scientific information will never answer all clinical questions, clinical decisions are partially based on probabilistic information.
This paper describes how to apply clinical decision making to diagnosing and managing dental caries and periodontal diseases. By using explicit information to quantify probabilities and outcomes, clinical decision making analyzes decisions made under uncertain conditions and the uncertain impact of clinical information.
Clinical decision making incorporates concepts for preventing, diagnosing and treating dental caries and periodontal diseases: risk assessment, evidence-based dentistry, and multiple oral health outcomes. This information can serve as a tool for clinicians to augment clinical judgment and expertise.     

Early, but not late therapy with a vasopressin V1a-antagonist ameliorates the development of renal damage after 5/6 nephrectomy.

INTRODUCTION: Vasopressin, mainly through the V1a-receptor, is thought to be a major player in the maintenance of hyperfiltration. Its inhibition could therefore lead to a decrease in progression of chronic renal failure. To this end, the effect of the vasopressin V1a-receptor-selective antagonist, YM218, was studied on proteinuria and focal glomerulosclerosis in early and late intervention after 5/6 nephrectomy in rats, and compared with an angiotensin-converting enzyme inhibitor (ACE-I). MATERIALS AND METHODS: After 5/6 nephrectomy, early intervention was performed between week 2 and 10 thereafter with the V1a-receptor-selective antagonist (VRA, 10 mg/kg/day, n=10), enalapril (ACE-I, 10 mg/kg/day, n=9), or vehicle (n=8). Late intervention was performed in another group between week 6 and 12 with VRA (10 mg/kg/day, n=7), lisinopril (ACE-I, 5 mg/kg/day, n=7), or vehicle (n=7). RESULTS: In early intervention, proteinuria and focal glomerulosclerosis were significantly decreased by VRA compared to vehicle (44+7% and 59+8% respectively). ACE-I significantly decreased proteinuria (67+7%) and a trend towards a decrease in focal glomerulosclerosis was observed (30+18%). In late intervention, VRA did not decrease proteinuria and focal glomerulosclerosis compared to vehicle (21+20% and 0%, respectively), ACE-I significantly lowered proteinuria (92+2%) and a focal glomerulosclerosis (69+1%) lowering trend was observed. CONCLUSION: These results indicate that VRA may protect against early progression of renal injury after 5/6 nephrectomy, whereas its effectiveness seems limited in established renal damage.     

Predictive value and limitations of animal models for human transplantation: do we need more models for facial transplantation?

Animal models have traditionally provided the basis for preliminary investigation of new techniques prior to trials taking place in human subjects. The timing of when to proceed with human trials is difficult, as the accuracy of preclinical models can only be determined with hindsight. This review outlines the progression from transplantation in animal models to man. Now that many transplant procedures are well established, it is possible to assess the predictive value and limitations of animal models. These results are of great importance in the current debate about composite tissue allotransplantation (CTA) and in particular facial transplantation. This progression of CTA from animal models to man is outlined and compared with early renal, cardiac, and liver transplants. There is some evidence to suggest that animal models may have been misleading in CTA and that this has effectively delayed the transition to humans. The role for animal models in facial transplantation, which is currently making the step to clinical trials, is discussed.     

Thermodynamic stability of wild-type and mutant p53 core domain

Some 50% of human cancers are associated with mutations in the core domain of the tumor suppressor p53. Many mutations are thought just to destabilize the protein. To assess this and the possibility of rescue, we have set up a system to analyze the stability of the core domain and its mutants. The use of differential scanning calorimetry or spectroscopy to measure its melting temperature leads to irreversible denaturation and aggregation and so is useful as only a qualitative guide to stability. There are excellent two-state denaturation curves on the addition of urea that may be analyzed quantitatively. One Zn²⁺ ion remains tightly bound in the holo-form of p53 throughout the denaturation curve. The stability of wild type is 6.0 kcal (1 kcal = 4.18 kJ)/mol at 25°C and 9.8 kcal/mol at 10°C. The oncogenic mutants R175H, C242S, R248Q, R249S, and R273H are destabilized by 3.0, 2.9, 1.9, 1.9, and 0.4 kcal/mol, respectively. Under certain denaturing conditions, the wild-type domain forms an aggregate that is relatively highly fluorescent at 340 nm on excitation at 280 nm. The destabilized mutants give this fluorescence under milder denaturation conditions.     

The effect of oxygen free radicals on calcium current and dihydropyridine binding sites in guinea-pig ventricular myocytes.

1. We used electrophysiological and binding techniques to determine the effects of oxygen free radicals (OFRs) generated by dihydroxyfumaric acid (DHF, 5 mM) on calcium current and dihydropyridine binding sites in guinea-pig isolated ventricular myocytes. 2. Binding of [3H]-PN200-110 to isolated ventricular myocytes revealed one population of binding sites with a KD of 0.11 +/- 0.01 nM and Bmax of 139.1 +/- 6.9 fmol mg-1 protein (n = 24). After 15 min of exposure to DHF, the density, but not the affinity of [3H]-PN200-110 binding sites was significantly (P < 0.01) reduced to 35% of the control value (Bmax = 49.4 +/- 3.7 fmol mg-1 protein, KD = 0.11 +/- 0.01 nM, n = 15). In the presence of superoxide dismutase (SOD) and catalase (CAT) the reduction in [3H]-PN200-110 binding sites was almost completely prevented (Bmax = 120.5 +/- 7.4 in control, n = 4 and 98.8 +/- 7.4 fmol mg-1 protein in DHF plus SOD and CAT, n = 4). KD values were not modified (0.08 +/- 0.01 in control and 0.09 +/- 0.01 nM in DHF plus SOD and CAT). 3. The time-course of the reduction of [3H]-PN200-110 binding sites by OFRs was paralleled by the decrease in L-type calcium current (Ica,L) measured in patch-clamped guinea-pig ventricular myocytes either in the absence or in the presence of EGTA in the patch pipette. In the former conditions OFRs induced the appearance of calcium-dependent alterations, i.e. the transient inward current, within 10 min. After 30 min of incubation with DHF, [3H]-PN200-110 binding sites were reduced to 25% of the control value. 4. In myocytes incubated with the antilipoperoxidant agent, butylated hydroxytoluene (BHT, 50 microM), the decrease in [3H]-PN200-110 binding sites caused by DHF was partially prevented (Bmax values after 30 min exposure to DHF were 55.5 +/- 1.9 and 23.7 +/- 5.9 fmol mg-1 protein in the presence and in the absence of BHT respectively, P < 0.05). BHT did not affect the decrease in [3H]-PN200-110 binding sites during the first 15 min of exposure to DHF, but was able to prevent completely the further decrease occurring during the following 15 min of incubation with OFRs. 5. Our results demonstrate that the OFR-induced decrease in calcium current is associated with a reduction in DHP binding sites. The decrease in calcium current and in calcium channels may be implicated in the mechanical dysfunction associated with oxidative stress.     

Poisoning due to Pyrethroids

The first pyrethroid pesticide, allethrin, was identified in 1949. Allethrin and other pyrethroids with a basic cyclopropane carboxylic ester structure are type I pyrethroids. The insecticidal activity of these synthetic pyrethroids was enhanced further by the addition of a cyano group to give α-cyano (type II) pyrethroids, such as cypermethrin. The finding of insecticidal activity in a group of phenylacetic 3-phenoxybenzyl esters, which lacked the cyclopropane ring but contained the α-cyano group (and hence were type II pyrethroids) led to the development of fenvalerate and related compounds. All pyrethroids can exist as at least four stereoisomers, each with different biological activities. They are marketed as racemic mixtures or as single isomers. In commercial formulations, the activity of pyrethroids is usually enhanced by the addition of a synergist such as piperonyl butoxide, which inhibits metabolic degradation of the active ingredient. Pyrethroids are used widely as insecticides both in the home and commercially, and in medicine for the topical treatment of scabies and headlice. In tropical countries mosquito nets are commonly soaked in solutions of deltamethrin as part of antimalarial strategies. Pyrethroids are some 2250 times more toxic to insects than mammals because insects have increased sodium channel sensitivity, smaller body size and lower body temperature. In addition, mammals are protected by poor dermal absorption and rapid metabolism to non-toxic metabolites. The mechanisms by which pyrethroids alone are toxic are complex and become more complicated when they are co-formulated with either piperonyl butoxide or an organophosphorus insecticide, or both, as these compounds inhibit pyrethroid metabolism. The main effects of pyrethroids are on sodium and chloride channels. Pyrethroids modify the gating characteristics of voltage-sensitive sodium channels to delay their closure. A protracted sodium influx (referred to as a sodium ‘tail current’) ensues which, if it is sufficiently large and/or long, lowers the action potential threshold and causes repetitive firing; this may be the mechanism causing paraesthesiae. At high pyrethroid concentrations, the sodium tail current may be sufficiently great to prevent further action potential generation and ‘conduction block’ ensues. Only low pyrethroid concentrations are necessary to modify sensory neurone function. Type II pyrethroids also decrease chloride currents through voltage-dependent chloride channels and this action probably contributes the most to the features of poisoning with type II pyrethroids. At relatively high concentrations, pyrethroids can also act on GABA-gated chloride channels, which may be responsible for the seizures seen with severe type II poisoning. Despite their extensive world-wide use, there are relatively few reports of human pyrethroid poisoning. Less than ten deaths have been reported from ingestion or following occupational exposure. Occupationally, the main route of pyrethroid absorption is through the skin. Inhalation is much less important but increases when pyrethroids are used in confined spaces. The main adverse effect of dermal exposure is paraesthesiae, presumably due to hyperactivity of cutaneous sensory nerve fibres. The face is affected most commonly and the paraesthesiae are exacerbated by sensory stimulation such as heat, sunlight, scratching, sweating or the application of water. Pyrethroid ingestion gives rise within minutes to a sore throat, nausea, vomiting and abdominal pain. There may be mouth ulceration, increased secretions and/or dysphagia. Systemic effects occur 4–8 hours after exposure. Dizziness, headache and fatigue are common, and palpitations, chest tightness and blurred vision less frequent. Coma and convulsions are the principal life-threatening features. Most patients recover within 6 days, although there were seven fatalities among 573 cases in one series and one among 48 cases in another. Management is supportive. As paraesthesiae usually resolve in 12–24 hours, specific treatment is not generally required, although topical application of dl-α tocopherol acetate (vitamin E) may reduce their severity.     

Effect of ionenes on structure and catalytic activity of cobaltphthalocyanine, 1. Visible light spectroscopic investigations

The structural behaviour of cobalt(II)phthalocyanine-tetrasodium sulfonate (CoPc(NaSO₃)₄) ( 1 ), a catalyst used in thiol oxidation, was investigated in the presence of ionenes (poly-quaternary ammonium salts), ( 2 ) using visible light spectroscopy. It was observed that ionenes, which have been shown to promote the catalytic activity, strongly enhance the aggregation of the cobalt complex. No cobalt site isolation occurred up to N⁺/Co = 10⁵. Furthermore, a stoichiometric CoPc(NaSO₃)₄/ionene complex appeared to be formed with an N⁺/Co-ratio of 4:1. This ratio was found to hold for ionenes with M?_n varying from 6 100 to 22 000 and charge densities from 0,8 to 1,5. As the charge density was increased, the observed CoPc(NaSO₃)₄ spectrum was more affected. Experiments with oxygen in alkaline solution revealed that the complex was resistant toward oxygen adduct formation in the presence of ionenes. This phenomenon is discussed in relation to the catalytic activity of the system.     

The 5-Step family intervention in primary care: II. The views of primary healthcare professionals

Background: This is the second of two papers using qualitative methods from a study of an intervention for family members affected by close relatives' substance misuse problems.

Participants: 168 primary healthcare professionals (PHCPs: GPs, practice nurses and health visitors) working in general practices in two areas of England, and who took part in the study.

Data sources: Recruitment and post-session forms completed by PHCPs; telephone interviews with each PHCP 12 weeks after recruitment of a family member; interviews with PHCPs at the end of the study.

Results: At the end of the project PHCPs were overwhelmingly positive about the family member intervention and about primary care as the appropriate site. Difficulties were encountered, however, in identifying and engaging affected family members, who were often excluded on grounds of the complexity of their problems or the level of their distress. Shortage of PHCP time and other practice-related factors added to the difficulty. Active work by a PHCP was often necessary in order to make the link between presenting symptoms of physical or mental ill-health and the existence of a family substance misuse problem. When family members were identified and recruited, PHCPs were usually positive about what was achieved. Nearly all were in favour of an approach that combined giving a self-help manual with some follow-up contact with a family member as needed.

Conclusions: Taken in conjunction with statistical outcome findings of significant reductions in symptoms and changes in ways of coping, plus qualitative analysis of the views of family members, the present results encourage the view that a flexible form of this intervention should be developed for use in primary healthcare, and that further work should build on existing strengths and attempt to overcome weaknesses identified.