Web-Based Intervention Effects on Mild Cognitive Impairment Based on Apolipoprotein E Genotype: Quasi-Experimental Study.

BACKGROUND: Apolipoprotein E (APOE) ε4 allele is a major genetic risk factor for Alzheimer disease and mild cognitive impairment (MCI). Computer-based training programs can improve cognitive performance in elderly populations. However, the effects of computer-based interventions on MCI APOE ε4 carriers have never been studied before. OBJECTIVE: The effects of different web-based interventions and the APOE isoform-specific differences in training outcomes are investigated. METHODS: Using a quasi-experimental study design, 202 participants with MCI aged 60 years and older took part in three different intervention programs (physical and cognitive [Long-Lasting Memories, or LLM], cognitive [Active Control, or AC], or physical intervention [Physical Training Control, or PTC]) via an innovative information and communication technologies exergaming platform. Participants in each interventional group were subdivided into APOE ε4 carriers and non-APOE ε4 carriers. All participants underwent an extensive neuropsychological evaluation before and after the training, blood tests, and brain imaging. RESULTS: All interventions resulted in multiple statistically significant cognitive benefits after the intervention. Verbal learning (California Verbal Learning Test: immediate recall test score-LLM: P=.04; AC: P<.001), working memory (digit span forward and backward test scores-AC: P=.03; PTC: P=.02 and P=.006, respectively), and long-term memory (California Verbal Learning Test: delayed recall test score-LLM: P=.02; AC: P=.002; and PTC: P=.02) were improved. There was no statistically significant difference among the intervention effects. APOE ε4 presence moderates intervention effects as the LLM intervention improved only their task-switching processing speed (Trail Making Test, Part B: P=.03) and the PTC intervention improved only the working memory (digit span backward: P=.03). No significant performance alteration was noted for the APOE ε4+ cognitive AC training group. CONCLUSIONS: None of the applied interventions could be identified as the optimal one; it is suggested, however, that combined cognitive and physical training and physical training via exergaming may be more effective for the high-risk MCI ΑPOE ε4+ subgroup.

Olanzapine: evaluation of the in vivo cytogenetic effect.

BACKGROUND/AIMS: Olanzapine (OLZ), an atypical antipsychotic, is licensed for use in the treatment of schizophrenia and other psychiatric disorders. METHODS: OLZ cytogenetic effects were investigated by evaluating the frequency of Sister Chromatid Exchanges (SCEs) and Proliferation Rate Index (PRI) in cultured lymphocytes of schizophrenic patients who were under treatment of OLZ. SCE estimation is one of the most sensitive biomarkers of potential cytotoxicity, while PRI is used as a valuable marker of cytostatic activity. RESULTS: Our results showed a statistically significant increase of SCEs in the cultured lymphocytes of patients (p < 0,001) compared to the lymphocytes of healthy donors, a statistically significant increase of SCEs (p < 0.001) in the lymphocytes of smoker patients compared to those of non-smoker patients and a statistically significant increase of SCEs (p < 0.001) in the lymphocytes of chronic recipients of OLZ compared to those of the patients with recent initiation of treatment. We did not detect any statistically significant differences with respect to PRI between the various groups examined. CONCLUSIONS: Our results indicate a mild cytotoxic-but not cytostatic-effect of OLZ which was more prominent in smokers and in chronically treated patients. That effect should be taken into consideration by psychiatrists upon assessing the benefit/risk ratio of their prescriptions.

Cytogenetic effects of valproic acid and ziprasidone in human lymphocyte cultures.

BACKGROUND/AIMS: Valproic acid or valproate (VA) is an anticonvulsant and mood-stabilizing drug primarily used in the treatment of epilepsy and bipolar disorder. Ziprasidone (ZPN) is an atypical antipsychotic drug used mainly for the treatment of schizophrenia. METHODS: This study is a part of our investigation on the cytogenetic effects of psychotropic drugs. Lymphocytes of peripheral blood cultures from 3 healthy donors treated with VA, ZPN and combinations of these (at concentrations equivalent to the oral doses) were used for the estimation of sister chromatid exchanges (SCEs) and the proliferation rate index (PRI). As a biomarker of genotoxicity, we used SCEs, one of the most sensitive methods reflecting DNA damage and/or subsequent DNA repair, and as a marker of cytostaticity we estimated the PRI. RESULTS: All treated lymphocyte cultures showed a statistically significant increase in SCE frequency and a significant decrease in PRI values (p<0.001). The combined effect of the drugs induced similar or more intense results, without reaching levels indicating synergistic action. CONCLUSION: This in vitro study investigated the cytogenetic activity of monotherapy vs. combined chronic drug exposure, and could form a catalyst for further investigations aiming to develop more efficacious therapy with decreased cytogenetic damage.

Changes in activities of caspase-8 and caspase-9 in human cervical malignancy.

INTRODUCTION: The apoptotic process of programmed cell death and its dysfunctions in a variety of human diseases, including cervical cancer, has become the focus of extensive scientific research. Caspases are considered key factors in the execution of apoptosis, although there are many aspects of their role to be elucidated. It has been found that disturbance of initiator caspase-8 and caspase-9 expression or function may contribute to cancer formation/progression, and inactivation of them could promote resistance to current treatment approaches. In our research, the activities of caspase-8 and caspase-9 have been estimated during the progression of human cervical malignancy. MATERIALS AND METHODS: The experimental material includes human cervical tissue samples (normal and pathological), in which enzyme activities have been measured colorimetrically. RESULTS: Activities of caspase-8 and caspase-9 presented the highest increase, compared to the controls, in the low-grade squamous intraepithelial lesion samples (statistically significant, P < 0.01 by t test). The activities diminished in the high-grade squamous intraepithelial lesion and even more in the cancer samples but remained higher than the controls. CONCLUSION: The observed changes in the activities of caspase-8 and caspase-9 could be attributed to their involvement in the cervical tissue's effort to resist malignancy progression.

Indication of participation of caspase-2 and caspase-5 in mechanisms of human cervical malignancy.

INTRODUCTION: When apoptosis is disrupted, the transformed cells can survive, proliferate, and evolve into a malignancy. The strictly conserved caspase genes and the reliable experimental data clearly show that some caspases play a crucial role in apoptosis even if some of them have no apoptotic activity and others exhibit both apoptotic and nonapoptotic properties. Although caspase-2 belongs to initiator caspases, its normal role remains unclear. Experimental studies have shown that it is primarily necessary for the execution of apoptosis in mutagenic cells. Human caspase-5 is classified as an inflammatory caspase, although its substrate has not been identified yet. In this research, the activities of caspase-2 and caspase-5 have been estimated during the progression of human cervical malignancy. METHODS: The experimental material includes human cervical tissue samples (normal and pathological) and blood serum samples of the corresponding tissue donors, where enzyme activities have been measured colorimetrically. RESULTS: Both caspases' activities showed the highest increase, statistically significant (P < 0.01, by t test) compared with the controls, in the low-grade squamous intraepithelial lesion tissues. Caspase-2 of all pathological tissues was proved more active than the controls. Serum caspases' activities were significantly lower than those of the tissues. Serum caspase-2's activity in patients with low-grade squamous intraepithelial lesion stage showed no statistically significant increase compared with the controls. Serum caspase-5's activity of all patients with malignancy stages was presented elevated, whereas that of the serum of patients with cervical cancer had the highest activity (P < 0.01, by t test). CONCLUSIONS: The changes of caspase-2 and caspase-5 activities could be indicative of their involvement in the cervical malignancy mechanisms.

A survey on smoking habits and attitudes among adolescents in Greece.

The objective of the present study was to investigate smoking habits among 699 secondary school students, along with their attitudes toward smoking and their perceptions on the consequences of tobacco use in their health. Our results indicate that Greek adolescents begin to smoke mainly due to curiosity and for stress reasons. Furthermore, having friends who smoke is highly associated with smoking and intention for smoking. Likewise, paternal smoking seems to reinforce students' intention for smoking. On the contrary, parental disapproval of smoking leads to anti-smoking behavior. Adolescents' attitudes toward smoking are also related to a series of similar factors such as parental educational status, parental smoking, and parental disapproval of smoking, friends who smoke, and, finally, adolescents' age, smoking behavior, and intention for smoking. The impact of tobacco use in human health seems to be understood better by older students. All these factors must be taken into account for a successful implementation of an anti-smoking intervention program.

Sudden infant death syndrome due to long QT syndrome: a brief review of the genetic substrate and prevalence.

The pathophysiological mechanisms which lead to sudden infant death syndrome (SIDS) are not completely understood. Cardiac channelopathies are a well-established causative factor with long QT syndrome (LQTS) being the most frequent one, accounting for approximately 12% of SIDS cases. The genetic substrate of the above arrhythmogenic syndrome has been thoroughly described but only specific gene mutations or polymorphisms have been identified as SIDS causative. The review will focus on the prevalence of LQTS-induced SIDS or near-SIDS cases and the mutations held responsible. A literature search was performed in PubMed and Scopus electronic databases. Search terms used were: long QT syndrome, channelopathies, QT prolongation, cardiac ion channels. The above-mentioned search terms were always combined with the term: sudden infant death syndrome. Study types considered eligible were: case-control, family pedigree analysis, case reports. The prevalence of LQTS-induced SIDS according to six broad genetic studies ranges from 3.9 to 20.6%, with an average of 12%. Since LQTS can be effectively managed, LQTS-related SIDS cases could be prevented, provided that a screening method is efficient enough to detect all the affected infants.

One-pot microwave assisted synthesis of new 2-alkoxycarbonylmethylene-4-oxo-1,5-benzo-, naphtho-, and pyridodiazepines and assessment of their cytogenetic activity.

1,5-Benzo-, naphtho-, and pyridodiazepines 3 have been synthesized in excellent yields in one-step from the reaction of o-phenylenediamines with acetonedicarboxylates through microwave assisted acid catalysis. In order to ascertain their cytogenetic activity in vitro at doses equivalent to the per os doses of common 1,4-benzodiazepine drugs, Sister Chromatid Exchanges (SCEs) were employed, and for the determination of cytostaticity the Proliferation Rate Index (PRI) on lymphocytes of human whole blood cultures was estimated. It was found that benzodiazepines 3a, 3c, and 3e exhibit significant cytoprotection, but mild cytostatic effect (a statistically significant reduction of SCEs and a confined decrease of PRI values at similar concentrations). The most active compound was found to be 3e.

A comparative study on the cytogenetic activity of three benzodiazepines in vitro.

Even though benzodiazepines (BDZs) possess a leading place among drugs used as anxiolytics, sedatives, muscle relaxants, and anticonvulsants, their cytogenetic effects have not been widely studied in humans. Alprazolam (AZ), bromazepam (BZ), diazepam, and lorazepam (LZ) are some of the most commonly prescribed BDZs. Previous positive findings on diazepam's cytogenetic effects in human lymphocytes suggested additional investigation. In the present research, we explored the cytogenetic potential of AZ, BZ, and LZ in human lymphocyte cultures, using an expanded sample set, administering the under-investigation medications at final concentrations equivalent to oral dosage. As a biomarker of genotoxicity we used sister chromatid exchanges, one of the most sensitive methods reflecting DNA damage and/or subsequent DNA repair, and as a marker of cytostaticity we estimated the proliferation rate index. After 72 h of incubation in the cultures, all three BDZs caused a concentration-dependent, statistically significant increase of sister chromatid exchange frequency (p < 0.001) followed by a statistically significant decrease of proliferation rate index (p < 0.001) of lymphocytes. Our conclusive results suggest that AZ, BZ, and LZ, at concentrations equivalent to oral doses, exhibit statistically significant genotoxicity in human lymphocyte cultures.

Cytogenetic activity of newly synthesized 1,5-benzodiazepines in normal human lymphocyte cultures.

INTRODUCTION: Many different types of benzodiazepine medications exist to treat a wide array of psychological and physical diseases based on dosage and implications. Benzodiazepines are generally considered as safe and effective drugs in short term; however, cognitive impairments and paradoxical effects occasionally occur. Our recent studies have shown that some 1,4-benzodiazepines exhibit cytogenetic activity (alprazolam, diazepam, and lorazepam) in normal human lymphocyte cultures. 1,5-Benzodiazepine derivatives are used in the synthesis of fused ring compounds, to study the chemical structure-pharmacological activity correlation. We synthesized four compounds of this category with small structural differences. AIM: The aim of this study was to investigate their cytogenetic activity in vitro at doses equivalent to the per os doses of the used 1,4-benzodiazepines. Sister chromatid exchanges (SCEs), proliferation rate index, and mitotic index were evaluated in lymphocytes of peripheral blood cultures from two healthy donors. RESULTS: Three of the newly synthesized compounds exhibited positive cytogenetic activity (statistically significant reduction of SCEs, p < 0.01, t-test), without showing cytostatic properties. CONCLUSION: The observed reduction of the lymphocytes' SCEs because of 1,5-benzodiazepines' activity is remarkable and requires further investigation to improve pharmacological effects.

Cytogenetic effects of recombinant interferon-gamma on lymphocytes cultures from patients with non-small cell lung cancer.

Therapeutic effects of human interferons (IFN) on malignancies and infectious diseases have been demonstrated in several clinical trials. The effects of IFN alone or combined with other treatment modalities (radiotherapy and chemotherapy) in lung cancer are under investigation. Experimental data suggest that some cytokines, such as IFN-alpha and IFN-gamma, exhibit cytogenetic properties in human normal lymphocytes from peripheral blood, but the mechanisms are not clear. The aim of the present study was to investigate the in vivo cytotoxic and cytostatic activity of IFN-gamma. Patients with certain cases of non-small cell lung cancer not eligible for chemotherapy or chemoradiotherapy were treated with thoracic radiotherapy. After tumor relapse, local treatment with instillations of IFN-gamma through the fiberoptic bronchoscope followed. To clarify the cytogenetic activity of IFN-gamma, sister chromatid exchange (SCE) and proliferation rate index (PRI) were evaluated in lymphocyte cultures from these patients' peripheral blood samples immediately after diagnosis (baseline), 30 days after radiotherapy, and after the fifth instillation of IFN-gamma. Our results show a decrease in SCE frequency and PRI values in lymphocytes after treatment with IFN-gamma, suggesting that IFN-gamma does not have cytotoxic activity but, in contrast, may induce repair mechanisms, as shown in earlier studies in other biologic models.

Investigation of the genotoxic effect of pesticides on greenhouse workers' lymphocytes.

In the present study, the genotoxic effects of commonly applied pesticides were evaluated using the alkaline comet assay (pH > 13). The amount of DNA damage (% DNA in tail) in peripheral lymphocytes of 49 male agricultural workers from Southern Poland were measured and compared to 50 men from the same area who had no previous occupational exposure to pesticides. No statistically significant differences in basal DNA damage were found between the study groups. In addition, exposure of peripheral blood lymphocytes to hydrogen peroxide (100 and 150 microM) or gamma-irradiation (2.5 or 4.2 Gy) led to a similar degree of additional DNA damage and subsequent repair (for 2 hr) for all studied populations. In conclusion, our results indicate that the greenhouse workers who participated in this study had no detectable increased DNA damage or alteration in their cellular response to DNA damage in comparison to our control population.

Cytogenetic activity of diazepam in normal human lymphocyte cultures.

INTRODUCTION: Diazepam (DZ) belongs to benzodiazepines, a group of drugs used for sedation, for the relief of anxiety, and in the treatment of epilepsy. It has been found that DZ influences cytotoxic activity and diminishes antiviral and antitumor reactions in human natural killer cells in vitro. It has also been demonstrated that DZ causes a significant increase in the frequency of chromosomal aberrations in human lymphocytes in vitro. MATERIALS AND METHODS: In the present research the cytogenetic effects of DZ have been studied in normal human lymphocyte cultures of peripheral blood at 17.6-211.2 microM (final concentrations). Sister chromatid exchanges (SCEs), one of the most sensitive methods reflecting instability in DNA or a deficiency in DNA repair mechanisms, and proliferation rate index (PRI), a valuable indicator for cytostatic activity, have been evaluated. RESULTS: After 72-h incubation, DZ was found to cause a dose-dependent, statistically significant increase of SCE frequency (p < 0.001), followed by an equally significant decrease of PRI (p < 0.001). CONCLUSION: Our results suggest that DZ's administration presents cytogenetic effects in normal human lymphocyte cultures.