Cellular pathologies and genotoxic effects arising secondary to heavy metal exposure: A review.

Environmental pollution is significant and oftentimes hazardous in the areas, where mining, foundries and smelters and other metallurgical operations are located. Systematic research on the chronic effects of metals started during the past century; nevertheless, it is evident that even today, there are large gaps in knowledge regarding the assessment of the health effects caused by environmental and occupational exposures to these metals. Heavy metals induce the production of reactive oxygen species (ROS) causing oxidative stress, make several repair-inhibiting cellular changes and alter the DNA repair processes. They favour the 'false' repairing of double-strand breaks (DSBs), propagate DNA mutations and induce carcinogenesis. A detailed literature search was performed using the MedLine/PubMed database. Depending on the mechanism of action, arsenicals can act as genotoxins, non-genotoxic agents and carcinogens. Cadmium can bind to proteins, reduce DNA repair, activate protein degradation, up-regulate cytokines and proto-oncogenes (c-fos, c-jun and c-myc), induce the expression of metallothionein, haeme-oxygenases, glutathione transferases, heat-shock proteins, acute-phase reactants and DNA polymerase ß at lower concentrations. Inorganic mercury damages oxidative phosphorylation and electron transport pathways at the ubiquinone-cytochrome b5 locus and thus induces ROS production. Abandoned mining areas generate environmentally persistent waste. These specific sites urgently require maximally efficient and cheap remediation. This bears the need for methodologies employing green and sustainable remediation. Phytoremediation is important in that it is a prevalent in situ remediation technique. Its advantages include the use of solar energy, cost-effectiveness, easy operation, reduction in secondary contaminants, the use of biomass for biofuel production and low-cost adsorbents.

Cutaneous drug reactions to antiepileptic drugs and relation with HLA alleles in the Turkish population.

Summary: Background and objective. Many studies have shown associations between HLAB*15:02, HLA-A*31:01 and carbamazepine (CBZ)-induced delayed cutaneous hypersensitivity reactions. The aim of this study is to evaluate a possible association between delayed cutaneous reactions to antiepileptic drugs (AEDs) and certain HLA-A and HLA-B alleles in the Turkish population. Methods. The study consisted of 3 groups: Group I (reactive group) included the patients who had documented delayed cutaneous reactions to any antiepileptic drug. Group II (non-reactive group) included the patients who have been on antiepileptic treatment at least for three months without any adverse reactions. Group III consisted of healthy subjects. The HLA-A and B alleles were analyzed in all groups. Results. Forty patients (29 female) had experienced different hypersensitivity reactions due to AEDs: maculopapular exanthema (26 patients), Stevens-Johnson syndrome (6 patients), drug rash with eosinophilia and systemic symptoms (7 patients), toxic epidermal necrolysis (1 patient). Lamotrigine (11) and CBZ (10) were the most common culprit drugs involved in the reactions. The HLA-B*15:02 was not present in any of the study groups. However, HLA-B*35:02 was found in 4 patients from the reactive group, while it was not observed in non-reactive patients and was detected in only one healthy subject (p = 0.021). Conclusion. Although our preliminary results did not indicate a strong allele association with AED hypersensitivity, HLA-B*35:02 appears to be a candidate allele for MPE / DRESS / DIHSS induced by AED's in Turkish population. Further studies with a larger sample size may result in more comprehensive data about the genetic tendency for AED hypersensitivity in the Turkish population.

Decreased left ventricular torsion in patients with isolated mitral stenosis.

BACKGROUND: Left ventricular (LV) torsion is a sensitive indicator of myocardial contractility and cardiac structure, and has recently been recognized as a sensitive indicator of cardiac performance. The aim of our study was to assess the effect of isolated mitral stenosis on LV torsion. PATIENTS AND METHODS: We enrolled 19 patients with isolated mitral stenosis and 19 age- and gender-matched healthy subjects in the study. All patients had a normal sinus rhythm. All study subjects underwent two-dimensional echocardiography. Basal and apical LV rotations and LV torsion were evaluated using speckle-tracking echocardiography. RESULTS: Demographic characteristics, basic echocardiographic measures of LV ejection fraction, LV wall thickness, and LV mass index were similar between the two groups. The degrees of LV torsion (11.3 ± 4.7, 15.4 ± 4.9°, p=0.014) and LV basal rotation (- 3.7 ± 1.9, - 6.5 ± 2.1°, p< 0.001) were significantly decreased in the mitral stenosis group. There was a moderate positive correlation between mitral valve area and LV torsion (r=0.531, p=0.019). CONCLUSION: We showed significant reductions in LV torsion and LV basal rotation in patients with mitral valve stenosis. Structural and anatomical changes occurring during the progression of mitral stenosis may be responsible for these impaired movements.

Evaluation of corpus callosum morphometry in patients with mesial temporal lobe epilepsy with hippocampal sclerosis.

PURPOSE: The purpose of the study was to evaluate the effects of mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) on corpus callosum (CC) morphometry in large and pathologically proven MTLE-HS patients. METHODS: We measured certain CC dimensions in 103 patients and 33 healthy controls using in vivo magnetic resonance imaging. In particular, we compared the two groups in relation to the clinical (localization of the HS, duration of epilepsy, frequency of seizures and length of seizures) and demographical (age, gender, handedness) features. Students' t test, two-way ANOVA and Spearman test were used for statistical analysis. RESULTS: There was no significant difference between CC morphometry with respect to age and handedness among patients. The differences between the genders, however, were significant favouring longer diameters in males. We found significant decrease in the dimensions of the genu, body, isthmus and splenium of the CC in the MTLE-HS group, but there was no reduction in the size of the rostrum. CONCLUSIONS: This general reduction in the size of the CC except for the rostrum was thought to be the result of cortical atrophy secondary to the disease. Concerning the preserved rostral part of the CC, it was thought that the fibers of the frontal lobe pass through different pathways than the tracts in the rostrum.

Cell death and survival mechanisms are concomitantly active in the hippocampus of patients with mesial temporal sclerosis.

Mesial temporal lobe epilepsy (MTLE) is often characterized pathologically by severe neuronal loss in the hippocampus. In this study we investigated concomitant appearance of the pro-apoptotic and anti-apoptotic mechanisms in injured neurons in epileptic human hippocampi. Postsurgical hippocampal specimens of randomly selected 25 patients with MTLE were studied with standard immunohistochemical techniques to detect the below markers of cell death pathways: truncated Bid - tBid, mitochondrial translocation of Bax (markers of pro-apoptotic Bcl-2 protein activation) and nuclear translocation of AIF (caspase-independent pro-apoptotic pathway). For cell survival pathways, we investigated the expression of c-IAP1, c-IAP2 and Hsp70 (heat shock protein). Immunopositive cells were counted in different regions of the hippocampus. We also verified IAP (inhibitor of apoptosis) expression with Western blotting. The results were statistically compared with hippocampi from non-epileptic autopsy controls. In patient hippocampi, Bax and tBid immunoreactivity were significantly increased and Bax staining was consistent with mitochondrial translocation. AIF was not translocated to the nucleus. c-IAP1 and c-IAP2 were barely detectable in control hippocampi, whereas their expression was dramatically increased in the patients in all hippocampal subfields. Interestingly, these neurons were also positively co-labeled for tBid and translocated Bax. Hsp70 immunreactivity was significantly increased in all surviving neurons in patient hippocampi whereas degenerating neurons failed to express Hsp70. Our findings are consistent with both pro-apoptotic and anti-apoptotic mechanisms being active within the same hippocampal neurons of patients with MTLE, illustrating an ongoing struggle between cell death and survival mechanisms in neurons under stress.

Effect of patient sex on white matter alterations in unilateral medial temporal lobe epilepsy with hippocampal sclerosis assessed by diffusion tensor imaging.

BACKGROUND AND PURPOSE: Studies shows ictal behavior and symptoms are affected by patient sex in temporal lobe epilepsy. The purpose of our study was to determine whether alterations in the WM as assessed by DTI display different patterns in male and female patients with unilateral HS. MATERIALS AND METHODS: Patients with unilateral HS were categorized as women with right HS (n=12), men with right HS (n=10), women with left HS (n=12), and men with left HS (n=10). DTI of the brain along 64 noncollinear directions was obtained from 44 patients and 37 sex-matched control participants. We used TBSS to analyze whole-brain WM. Regions with significant changes of FA and MD, and their mean FA, MD, total number of significant voxels, and asymmetry indices were determined for each group. RESULTS: All groups showed bilateral and extensive reductions of FA and elevated MD in the WM, more prominent ipsilateral to the affected hippocampus. The total number of voxels with decreased FA in patients compared with that of control participants was higher in women with right HS (24,727 vs 5,459) and in men with left HS (27,332 vs 14,013) than in their counterparts. Changes in MD associated with right HS were more extensive in both men and women (right vs left HS, women: 16,926 vs 5,458; men: 5,389 vs 4,764) than in those with left HS. In patients with right HS, the ipsilateral cingulum, uncinate fasciculus, internal and external capsules, and right acoustic radiation were involved extensively in women. CONCLUSIONS: Women and men showed different patterns in extent of WM alterations associated with HS.

Mesial temporal lobe epilepsy with hippocampal sclerosis in two pairs of identical twins.

The most common pathology in adult patients with temporal lobe epilepsy is hippocampal sclerosis (HS), the etiology of which is not clear. There is a conflicting evidence in literature regarding whether HS is genetic or acquired. Twin studies can help to clarify the mechanisms of HS, but limited numbers of twins have been studied. We describe two monozygotic pairs, in whom the affected twin had mesial temporal lobe epilepsy and HS. The unaffected twin remained seizure free on long-term follow-up. HS was confirmed pathologically in one of the affected twins. Our data and other limited twin studies indicate that HS occurs as a consequence of prolonged repeated seizures or other events during childhood. In other words, some acquired factors may be more important than genetic ones in the etiology of HS (Fig. 2, Ref. 16).

A case with an asymptomatic malformation of cortical development diagnosed in eighth decade of life.

We report a patient newly diagnosed with cortical dysplasia upon magnetic resonance imaging (MRI) in his eighth decade of life after a recent syncopal attack. The neurological examination and laboratory findings were normal. His cranial MRI revealed a lesion giving a low signal on T1-weighted images, which was evaluated as focal cortical dysplasia. No treatment was given, and he did not have any further syncopal or epileptic attacks during the subsequent two-year follow up. No previous study has described such a case of malformations of cortical development (MCD) in patients older than 70. Especially in asymptomatic or clinically less severe patients, the underdiagnosis of MCD may result in a clinical spectrum that is too narrow to reflect the reality (Fig. 1, Ref. 6).

Serial analysis of gene expression in the hippocampus of patients with mesial temporal lobe epilepsy.

Hippocampal sclerosis constitutes the most frequent neuropathological finding in patients with medically intractable mesial temporal lobe epilepsy. Serial analysis of gene expression was used to get a global view of the gene profile in human hippocampus in control condition and in epileptic condition associated with hippocampal sclerosis. Libraries were generated from control hippocampus, obtained by rapid autopsy, and from hippocampal surgical specimens of patients with mesial temporal lobe epilepsy and the classical pattern of hippocampal sclerosis. More than 50,000 tags were analyzed (28,282, control hippocampus; 25,953, hippocampal sclerosis) resulting in 9206 (control hippocampus) and 9599 (hippocampal sclerosis) unique tags (genes), each representing a specific mRNA transcript. Comparison of the two libraries resulted in the identification of 143 transcripts that were differentially expressed. These genes belong to a variety of functional classes, including basic metabolism, transcription regulation, protein synthesis and degradation, signal transduction, structural proteins, regeneration and synaptic plasticity and genes of unknown identity of function. The database generated by this study provides an extensive inventory of genes expressed in human control hippocampus, identifies new high-abundant genes associated with altered hippocampal morphology in patients with mesial temporal lobe epilepsy and serves as a reference for future studies aimed at detecting hippocampal transcriptional responses under various pathological conditions.

Psychiatric morbidity, quality of life, and disability in mesial temporal lobe epilepsy patients before and after anterior temporal lobectomy.

Considerable interest has been focused on the psychiatric complications of medically refractory temporal lobe epilepsy (TLE) before and after epilepsy surgery. The aim of the present study was to evaluate the psychiatric status, quality of life, and level of disability in medically refractory mesial temporal lobe epilepsy (MTLE) patients, a homogenous subgroup of patients with TLE, before and after anterior temporal lobectomy (ATL). The study population consisted of 22 patients with medically refractory MTLE who were candidates for ATL. Patients were examined before surgery as well as in the third and sixth months of the postoperative period. Psychiatric diagnosis was determined by using SCID-I. To rate the severity of psychiatric disorders, BPRS, HDRS, and HARS were employed on each visit. WHO-DAS-II and WHOQOL-BREF were used to determine the level of disability and quality of life. Preoperatively, six patients had a psychiatric diagnosis. Three months after surgery, six of the patients had psychiatric diagnoses. Five of these six patients had not been previously diagnosed. There was no significant difference between preoperative and postoperative follow-up evaluations in terms of HDRS, HARS, and BPRS ratings. With respect to the total scores and domains of WHO-DAS-II, the change in pre- and postoperative evaluations was statistically significant only for the social life attendance domain. There was no significant difference in the mean scores on the WHOQOL-BREF domains or on the first question about general evaluation of quality of life. For the second question on the level of satisfaction with health, the difference between the three ratings was statistically significant. Preoperative and postoperative rates of psychiatric disorders in our sample were low. While social phobia was frequently seen preoperatively, the postoperative period was spearheaded by major depressive disorder. The decrease in disability in attendance to social life and improvement in the quality of health were in concordance with the literature, indicating the positive results of surgical treatment of epilepsy on quality of life. This study suggests that surgical intervention might be one of the causes of postoperative psychiatric disorders in patients with MTLE.

Lafora disease due to EPM2B mutations: a clinical and genetic study.

OBJECTIVE: To study EPM2B gene mutations and genotype-phenotype correlations in patients with Lafora disease. METHODS: The authors performed a clinical and mutational analysis of 25 patients, from 23 families, diagnosed with Lafora disease who had not shown mutations in the EPM2A gene. RESULTS: The authors identified 18 mutations in EPM2B, including 12 novel mutations: 4 nonsense mutations (R265X, C26X, W219X, and E67X), a 6-base pair (bp) microdeletion resulting in a two amino acid deletion (V294_K295del), a 4-bp insertion resulting in a frameshift mutation (S339fs12), and 6 missense mutations (D308A, I198N, C68Y, E67Q, P264H, and D233A). In our data set of 77 families with Lafora disease, 54 (70.1%) tested probands have mutations in EPM2A, 21 (27.3%) in EPM2B, and 2 (2.6%) have no mutations in either gene. The course of the disease was longer in patients with EPM2B mutations vs patients with EPM2A mutations. CONCLUSIONS: Genetic allelic heterogeneity is present in Lafora disease associated with mutations in EPM2B. Patients with mutations in EPM2A and EPM2B express similar clinical manifestation, although patients with EPM2B-associated Lafora disease seem to have a slightly milder clinical course. The lack of mutations in EPM2A and EPM2B in two families could be because of the presence of mutations in noncoding, nontested regions or the existence of an additional gene associated with Lafora disease.

Neurotrophin receptor immunoreactivity in the hippocampus of patients with mesial temporal lobe epilepsy.

Recent evidence supports a critical role of neurotrophins in the regulation of both neuronal survival and synaptic transmission during epileptogenesis. We have examined the immunohistochemical expression of high- (tyrosine kinase receptors, trk) and low-affinity (p75) neurotrophin receptors (NTRs) in the hippocampal specimens from 18 patients with chronic temporal lobe epilepsy [TLE; 14 patients with hippocampal sclerosis (HS) and four with focal lesions (tumours) not involving the hippocampus proper]. Nonepileptic autopsy brains (n = 6) and surgical specimens from tumour patients without epilepsy (n = 3) were used as controls. Immunoreactivity (IR) for the trk receptors (trkA, trkB, trkC) was detected in normal human brain within the pyramidal neurones of hippocampal cornus ammoni (CA) regions and in the dentate gyrus. There were no detectable differences in the neuronal trk IR patterns in the hippocampus between control and TLE cases with HS, except for a decrease in neuronal density in regions where cell death had occurred (CA1, CA3 and CA4). In contrast, a consistent increase in trkA IR was observed in reactive astrocytes in CA1 and dentate gyrus. The low-affinity p75 neurotrophin receptor (p75(NTR)) was expressed in low levels in postnatal normal hippocampus. In contrast, neuronal p75(NTR) IR was detected in 10/14 cases of HS in spared neurones within the CA and hilar regions of the hippocampus. Double labelling revealed that p75(NTR)-positive neurones also contain trk receptor IR. In six cases with prominent glial activation strong p75(NTR) IR was observed in microglial cells within the sclerotic hippocampus. The present results indicate that changes in NTR expression are still detectable in the hippocampus of patients with chronic TLE and involve both glial and neuronal cells. Reactive astrocytes were immunoreactive for trkA, whereas activated microglia cells were reactive for p75(NTR), suggesting different functions for specific NTRs in the development of reactive gliosis. Moreover, the increased expression of p75(NTR) in hippocampal neurones of TLE patients may critically influence the neuronal survival during the epileptogenic process.

Determination of heavy metal contents in human colostrum samples by electrothermal atomic absorption spectrophotometry.

Determination of lead, cadmium, nickel, chromium, manganese and copper levels in colostrum samples (n = 30), collected from middle-class mothers, was carried out by electrothermal atomic absorption spectrophotometer (ETAAS) with Zeeman effect background correction using a tungsten-palladium-citric acid chemical modifier mixture. A wet-ashing procedure was applied to dissolve the samples and to remove the fat. The graphite furnace temperature programme for analytes determined by ETAAS was studied, and the optimum pyrolysis temperatures of Pb, Cd, Ni, Cr, Mn and Cu were determined in the presence of the modifier mixture. Detection limits of Pb, Cd, Cu, Mn and Cr were determined using a modifier mixture solution. Zinc and iron levels were determined by Zeeman flame atomic absorption spectrometer (F-AAS). Heavy metal levels (mean values) found in colostrum samples were 14.6 microg/l of Pb, 2.8 microg/l of Cd, 27.8 microg/l of Ni, 8.6 microg/l of Cr, 43.2 microg/l of Mn, 278 microg/l of Cu, 12.9 mg/l of Zn, and 3.5 mg/l of Fe. These metal levels were compared with results from other studies in different countries.

Epilepsia partialis continua: clinical and electrophysiological features of adult patients.

In this study we reviewed the clinical, electrophysiological and neuroimaging data of 21 patients with epilepsia partialis continua (EPC), which is a rare form of epilepsy with focal motor seizures persisting hours to years. We found infections, cerebrovascular events and tumors as the most common causes of EPC in adults. SSPE was also shown as a cause of EPC. EPC in SSPE patients was resistant to therapies and persisted more than 1 year. EPC is usually a predictor of poor outcome and 29% of patients died after EPC in this study. As prognosis is usually bad and as response to treatment is poor in patients who had EPC, early diagnosis and treatment of the underlying cause is important. Although the most common etiologies are infections, cerebrovascular events and tumors, if EPC persists several months SSPE should be kept in mind as a rare cause of EPC. MRI should be repeated in chronic cases to show dysplastic cortex, which was shown in 1 patient in this study.

Partial agenesis of the corpus callosum with partial seizures and bilateral congenital lacrimal duct atresia.

Patients with partial agenesis of the corpus callosum can be readily detected by magnetic resonance imaging.

Familial adult onset myoclonic epilepsy associated with migraine.

We report a new type of migraine associated epileptic syndrome in a family: adult onset myoclonic epilepsy with benign course and migraine. Affected members of the family had myoclonic and rare generalised tonic-clonic seizures. Most of the patients, but not all, had a history of migraine. Also, some cases of the family had only migraine. This family will be discussed because of two distinct features. Firstly, in this family a different type of epilepsy, adult onset myoclonic epilepsy was diagnosed that has not been classified in the ILAE 1989, classification(s), but was similar to that previously reported in Japanese families. Secondly, in most of the cases migraine was associated with the epilepsy.

The role of patient companions in long-term video-EEG monitoring.

In developing countries it is difficult to have full-time dedicated nurses in Epilepsy Monitoring Units (EMU). Our one-bed EMU is within the Neurology Service and is adequately staffed during daytime working hours only. So we created a new model where the patient's companion was asked to press a nurse call button, allowing the examination of the patient by the nurse. In this study we aimed to understand how patient companions behaved and which factors influenced their behaviour. Patients were allowed to choose a single companion who were educated by the specialist monitoring nurse according to a protocol. Only the first recorded seizures of the patients were included in the study. The seizures were reviewed from the video-cassette recordings and the behaviour of the companions was scored according to the results of the following three questions: (1) when was the seizure noticed?; (2) was the nurse call button pushed?; and (3) did the companion prevent the recording of the seizure by the camera? The companions were grouped according to the following criteria; age, sex, level of education, type of relationship. The scores were compared for each criterion separately. The behaviours of the 50 companions (34F, 16M; age: 25-72) were studied. When statistically compared for age, sex and level of education, there were no significant differences between different groups. However, the mean score of the 47 companions who were immediate family members (3.72) was greater than those three who were not (1.66) In one-bed EMUs, patient companions who are family members can help nurses in the early detection of seizures.

Circling seizures in a case with Wilson's disease.

We report a case of Wilson's disease with circling seizures. Because of the existence of other types of frontal automatism and the EEG focus on the frontal regions, circling seizures of the patient were thought to originate from the frontal lobe. Magnetic resonance imaging demonstrated large cavitary lesions on bilateral frontal lobes. The mechanisms of circling behavior are discussed in association with Wilson's disease.