The dynamics of soluble Fas/APO 1 apoptotic biochemical marker in acute ischemic stroke patients.

PURPOSE: Until recently, neuronal death in ischemic stroke infarction was ascribed exclusively to necrotic process. However, experimental animal models of cerebral ischemia suggest apoptosis to play a role in the pathogenesis of cerebral infarction. The aim of this study was to determine the level and monitor the dynamics of soluble Fas/APO 1 (sFas/APO 1) in serum and cerebrospinal fluid of acute ischemic stroke patients. MATERIAL AND METHODS: This prospective study included 23 patients with first ever, computed tomography verified acute ischemic stroke and 20 control subjects with other functional neurologic disorders. Serum and cerebrospinal fluid sFas/APO 1 levels were determined on several occasions. Blood samples were obtained on day 1, 3 and 12, and lumbar puncture on day 3 and 12 of disease onset. Quantitative sandwich ELISA method was used on sFas/APO 1 determination. RESULTS: On day 1 of disease onset, serum and cerebrospinal fluid sFas/APO 1 levels were significantly higher in stroke patients as compared to control subjects, and then gradually declined during the period of monitoring. CONCLUSION: Study results confirmed the dynamic pattern of sFas/APO 1 in serum and cerebrospinal fluid of patients with acute ischemic stroke, suggesting the possible role of apoptosis in the pathogenesis of cerebral infarction.

Comparison of the growth hormone, IGF-1 and insulin in cerebrospinal fluid and serum between patients with motor neuron disease and healthy controls.

Neurotrophic effects of the growth hormone (GH), insulin-like growth factor-1 (IGF-1) and insulin on the central nervous system have become more apparent in the past decade. In this study, we measured serum and cerebrospinal fluid (CSF) concentrations of GH, IGF-1 and insulin in 35 patients with motor neuron disease (MND) [24 patients with definite amyotrophic lateral sclerosis (ALS) and 11 patients with progressive bulbar palsy] and in 40 healthy controls. Levels of serum concentrations of GH and IGF-1 did not significantly differ between the MND patient group and the healthy controls, while the level of insulin was significantly decreased (P = 0.0033) in the MND patient group. However, levels of all three examined parameters in CSF were significantly lower in the MND group than in the healthy controls with the statistical significance for IGF-1 and insulin of P < 0.001. This finding has not been reported previously, and further investigations into its association with ALS should establish whether it can be used as an early marker of the disease, or whether it merely represents a consequence of ALS development.

Clinical variability of CMS-EA (congenital myasthenic syndrome with episodic apnea) due to identical CHAT mutations in two infants.

Congenital myasthenic syndromes (CMS) result from mutations in various synapse-associated genes. Mutations in the choline acetyltransferase (CHAT) gene cause a presynaptic CMS associated with episodic apnea (CMS-EA). We present two unrelated Croatian children affected by CMS-EA. Beside other clinical findings characteristic for CMS, both patients manifested intermittent apneas since early infancy. Whereas the course of disease is mild in the female patient (patient 2), the male patient (patient 1) experienced recurrent and severe episodes of apnea despite adequate treatment with AChE-inhibitors and shows a global developmental delay with delayed myelination and signs of hypoxic-ischemic injury in brain imaging. Interestingly, sequencing of the CHAT gene revealed identical, compound heterozygous mutations S694C and T354M in both children. These findings are in line with a remarkable clinical heterogeneity observed in patients with CHAT mutations and emphasize the potential role of apneic crises for the development of secondary hypoxic brain damage and psychomotor retardation.

The carcinostatic and proapoptotic potential of 4-hydroxynonenal in HeLa cells is associated with its conjugation to cellular proteins.

BACKGROUND: Previous studies have shown that the lipid peroxidation product 4-hydroxynonenal (HNE) acts as a cell growth modulator if used at low, physiological concentrations being strongly cytotoxic at higher concentrations for a number of cells. These effects of HNE also appeared to be mutually dependent on the effects of serum growth factors. The aim of this investigation was to study the concentration-dependent response of human cervical carcinoma (HeLa) cells in vitro with respect to the intracellular uptake of exogenous HNE, the cellular energy metabolism, DNA synthesis, overall gene expression and susceptibility to apoptosis. MATERIALS AND METHODS: MTT assay was applied as an index of energy metabolism and the replicative activity was quantitated by the 3H-thymidine incorporation assay. The occurence and intracellular distribution was studied with monoclonal antibodies directed against HNE-protein conjugates. Binding of HNE to serum proteins was determined with the same antibodies by Western blotting. Differential gene expression was studied by differential display RT-PCR while a novel photometric assay, denoted Titer-TACS, was used for in situ detection and quantitation of apoptosis in monolayer cell cultures. RESULTS: A physiological concentration of HNE (1 microM) had hardly any effect on the parameters of the replicative activity and the energy metabolism. No morphological changes were observed and the number of HNE-positive cells was not significantly different when compared to the untreated control cells, while most of the aldehyde appeared to be bound to serum proteins (albumin fraction). A ten-fold higher concentration (10 microM) was found to be cytostatic. Spindle-shaped cells with a picnotic nucleus were observed occasionally, as well as membrane blebs, which were HNE-positive. The number of HNE-positive cells was significantly increased compared both to the control cells and cells treated with 1 microM HNE, but in the presence of serum the effects of 10 microM HNE were negated due to its binding to the serum proteins. Finally, 100 microM HNE was cytotoxic for the HeLa cells. Most of the cells were picnotic, together with a few spindle-shaped or oval cells. The staining for HNE was diffuse and strong (90% of the cells were HNE-positive) while even binding of the aldehyde to serum proteins did not prevent its cytotoxic effects. This concentration of HNE caused acute stress response of the cells resulting in the decreased expression of several as yet unidentified genes. The altered pattern of gene expression was followed by programmed cell death, i.e. an increased number of apoptotic cells after treatment with low (1 and 10 microM) concentrations of HNE. A rebound effect was observed, i.e. a decrease of apoptotic cells after 24 hours followed by an overshooting increase after 48 hours. CONCLUSIONS: For HeLa carcinoma cells there appears to be a concentration range of HNE where it does not cause necrosis but preferentially apoptosis. At this concentration range HNE is cytochemically detectable within the cells as a protein conjugate. It is proposed that a possible differential sensitivity of cancer cells and their normal counterparts to the cytostatic activity of HNE should be explored.

[Euthanasia]. / Eutanazija.

The paper gives a historical overview, and describes psychosociological constellation and tactics of the euthanasia movement. Further, medicosocial experiment and medicolegal engineering which preceded it and followed it are presented on the example of euthanasia in The Netherlands. Legal, ethical, formally logical and psychological arguments against euthanasia are presented. The article concludes with the opinion that it was the duty of the World Medical Association to protect medical profession with the procedure of demedicalization of euthanasia, and to appropriately punish the Royal Dutch Medical Society for breaking professional ethical codex in its essential part, which is the basis of the very identity of medical profession.

Clinical variability and molecular diagnosis in a four-generation family with X-linked Emery-Dreifuss muscular dystrophy.

AIM: To describe the clinical variability of X-linked Emery-Dreifuss muscular dystrophy (X-EDMD) with cardiac involvement in a four-generation family with a novel mutation in the STA gene. METHODS: Clinical data were provided for 4 affected males and a female carrier. The Western blot analysis of emerin was performed on lymphoblastoid cell lines and followed by sequencing of the emerin gene. RESULTS: A thymine insertion at nucleotide 417 in exon 2, resulting in a frameshift with a premature stop codon at position 62 and absence of functional protein, was found in one of the three available patients. In ten-year-old proband's dizygotic twin-nephews the intermittent first-degree A-V block, atrial and ventricular ectopy, atrial runs, and exit sinus block were found, although the echocardiographic findings were normal. One of the twins also had short episodes of atrial fibrillation, idioventricular rhythm, and junctional rhythm. CONCLUSION: Cardiac abnormalities in the proband's ten-year-old dizygotic twins without evident clinical features suggestive of EDMD were remarkable in contrast to the oldest patient in the family, who lived to the age of 63 without a pacemaker, and to the proband who had a very early onset of muscle wasting and weakness, and a pacemaker implantation at the age of 27. This striking intra-familial variability in cardiac involvement associated with specific null mutation (417 ins T) has practical early diagnostic and possibly preventive implications. It also points at genetic and environmental factors as causes of clinical features in X-EDMD.

Nervous system in the fibrillar theory of Giorgio Baglivi.

The drafts, epistles, headwords, and conceptual basis known as the fibrillar theory of Giorgio Baglivi, published in his book entitled De fibra motrice et morbosa, were analyzed in an attempt to re-evaluate Baglivi's contribution, generally considered quite modest, to the development of scientific thought on the nervous system functions. The analysis revealed Baglivi's identification of the reflex organization, vegetative nervous system function, and neural aspect of the vasomotor function to be surprisingly valuable. I believe that the lucidity and genuine contemporariness of Baglivi's standpoints arise the question of the historical precedence in the discovery of these functions (it is usually attributed to F.X. Bichat for vegetative nervous system, and to Claude Bernard for vasomotor nerves). In the light of these facts, the need of an expert revision of the history of discovering nervous system functions is suggested.

Role of the suprachiasmatic nucleus in the pathogenesis of migraine attacks.

Neuroanatomic, morphometric, immunocytochemical, neurobiochemical and clinical data support the hypothesis that the suprachiasmatic nucleus of the hypothalamus might be the initial site of migraine attacks. The prodromal phase of a migraine attack could be considered a syndrome of functional suprachiasmatic nucleus insufficiency, and other phases a reactive denervation hypersensitivity with the affection of the visual, nociceptive, antinociceptive and cranial vasomotor system.

Epileptic seizures as a symptom of various neurological diseases.

The authors evaluate the most frequent causes of seizures in 562 patients admitted at the emergency out-patient ward because of fits. 194 patients were admitted because of the first occurrence of seizures, in 12 of them the first manifestation was status epilepticus of the generalized (8), or focal type (4). The commonest causes of seizures were alcoholism (82), disturbances of the brain blood flow (74), posttraumatic states (20), brain tumor (4), or encephalopathies. In 11 patients the cause of seizures was not found. Besides the causes, the authors stressed the most frequent type of seizures, as well as therapeutic measures. They pointed out that in alcoholism generalized seizures, and grand mal status were the commonest expression of seizures. The same was found in patients with posttraumatic seizures, but they mostly suffered single attacks, and the same in encephalopathies. In patients with vascular lesions focal seizures were not rare. The antiepileptic therapy is not applied in the first occurrence of convulsions, therapy is causal, linked primarily to basic etiopathogenic mechanism responsible for triggering seizures.

Primary trigeminal neuralgia (algophoric deafferentation hypersensitivity syndrome).

In the article the author presents his theory of the pathogenesis of primary trigeminal neuralgia, explaining the occurrence of this mysterious disease by algophoric deafferentation hypersensitivity. Tooth extraction is the sole cause of algophoric deafferentation hypersensitivity, which, culminating in epileptiform discharges of the trigeminal nociceptive pathway neurons, leads to clinical features of characteristic neuralgic paroxysms. Trigger mechanism is explained by ephaptic transmission between the broken fibers for phasic pain of the tooth pulp and neighbouring fibers of epicritic and proprioceptive sensitivity. The typical occurrence of periods with remission of neuralgic paroxysms the author explains by his original theory of biorhythms neogenesis with the involvement of two antagonistic neural subsystems (nociceptive and antinociceptive system). The concept is based on indisputable clinical, anatomical, pathoanatomical, experimental and pharmacologic facts, which the author quotes as the contribution to his theory.

Intravenous chlormethiazole in the management of primary trigeminal neuralgia resistant to conventional therapy.

The therapeutic efficacy of 0.8% chlormethiazole, administered as 3-10 intravenous infusions each lasting 5-6 h on alternate days, was assessed in an uncontrolled study of 16 patients, aged 44-82 years, with primary trigeminal neuralgia. Prior to entry into the study, patients showed a high frequency of neuralgic paroxysms (20-70 attacks/day) which were refractory to high dosages (1600-2000 mg/day) of carbamazepine. After treatment with chlormethiazole neuralgic paroxysms no longer occurred in five patients, were considerably reduced in intensity and frequency (less than or equal to 5 attacks/day) in six patients, moderately improved in two patients, slightly improved in one patient and showed no change in two patients. The relatively small number of cases and short post-treatment follow-up period limit the conclusions which can be drawn. These results indicate, however, that infusion with chlormethiazole is effective in the treatment of primary trigeminal neuralgia in patients for whom conventional therapy has been unsuccessful.