Involvement of APOE in Incidence of Revascularization in Patients Affected by Peripheral Arterial Disease: A Prospective Study from Southern Italy.

INTRODUCTION: Atherosclerosis is a complex multifactorial disease and apolipoprotein E (APOE) polymorphism has been associated with cardiovascular events. The APOE gene, located on chromosome 19q13.2, has an important role in lipid metabolism, in particular on circulating cholesterol levels, implying further pleiotropic effects; from its polymorphism are derived three alleles (ε2, ε3 and ε4), which induce different phenotypes, while its impact on carotid and femoral atherosclerosis is still controversial. OBJECTIVES: The aim of the study is to investigate the relationship between APOE genotypes and peripheral revascularization in a cohort of patients affected by advanced peripheral arterial disease (PAD) at a prolonged follow-up. MATERIALS AND METHODS: Some 332 patients (259 males and 73 females; mean age 70.86 ± 7.95 years) with severe PAD were enrolled in a longitudinal study, with a 90.75 ± 32.25 month follow-up, assessing major adverse cardiovascular events (MACE). RESULTS: As compared with ε3/ε3, in ε4 patients we observed a significant higher incidence of carotid (13.2% vs. 5.6%; HR = 2.485, 95% CI 1.062-5.814; p = 0.036) and lower limb (11.8% vs. 4.3%; HR = 2.765, 95% CI 1.091-7.008; p = 0.032) revascularizations and, accordingly, a higher incidence of total peripheral revascularizations (13.5% vs. 9.5%; HR = 2.705, 95% CI 1.420-5.151; p = 0.002). HR remained statistically significant even when adjusted for classic cardiovascular risk factors. CONCLUSIONS: In our observational study, we confirm that the ε4 allele is associated with higher total peripheral revascularization in patients with advanced atherosclerotic vascular disease at prolonged follow-up.

Italian Case Report with a Double Mutation in PSEN1 (K311R and E318G).

Alzheimer's disease (AD) is the most common cause of dementia worldwide. The clinical spectrum of suspected AD has been extended from mild cognitive impairment (MCI) to preclinical AD which includes people who have typical cognitive function but harbor the underlying biological features of AD. We report the first case of an Italian patient affected by MCI (MMSE 24\30), characterized by a double mutation p.Lys311Arg (K311R) and p.Glu318Gly (E318G) in Presenilin-1 but with the absence of abnormal accumulation of amyloid beta.

Pharmacogenetics in the clinical analysis laboratory: clinical practice, research, and drug development pipeline.

Introduction: Over the last decade, the spread of next-generation sequencing technology along with the rising cost in health management in national health systems has led to widespread use/abuse of pharmacogenetic tests (PGx) in the practice of many clinical disciplines. However, given their clinical significance, it is important to standardize these tests for having an interaction with the clinical analysis laboratory (CAL), in which a PGx service can meet these requirements. Areas covered: A diagnostic test must meet the criteria of reproducibility and validity for its utility in the clinical routine. This present review mainly describes the utility of introducing PGx tests in the CAL routine to produce correct results useful for setting up personalized drug treatments. Expert opinion: With a PGx service, CALs can provide the right tool to help clinicians to make better choices about different categories of drugs and their dosage and to manage the economic impact both in hospital-based settings and in National Health Services, throughout electronic health records. Advances in PGx also allow a new approach for pharmaceutical companies in order to improve drug development and clinical trials. As a result, CALs can achieve a powerful source of epidemiological, clinical, and research findings from PGx tests.

Hydroxytryptamine transporter gene-linked polymorphic region (5HTTLPR) is associated with delusions in Alzheimer's disease.

BACKGROUND: Serotoninergic pathways underlying delusion symptoms in Alzheimer's disease (AD) have not been fully clarified. 5-Hydroxytryptamine transporter gene-linked polymorphic region (5-HTTLPR) is a variable number tandem repeats in the promoter region of serotonin transporter encoding-gene affecting transcription. METHODS: We investigated the association of 5-HTTLPR with delusions in a total of 257 consecutive patients clinically diagnosed as AD according to the National Institute on Aging-Alzheimer's Association criteria. All participants underwent a comprehensive evaluation with a standardized comprehensive geriatric assessment and Neuropsychiatric Inventory. RESULTS: Delusion symptoms were observed in 171 patients (66.54%). In respect to AD patients without delusions, AD patients with delusions showed a low prevalence of S-plus carriers (5-HTTLPR-L/S + 5-HTTLPR-S/S genotypes) [p < 0.001; odds ratio (OR) = 0.240, 95% confidence interval (CI) = 0.121-0.471]. Logistic regression analysis adjusted for the apolipoprotein E polymorphism showed that in AD patients with delusions the presence of an 5-HTTLPR-S allele may reduce disease duration (p = 0.005; OR = 0.680, 95% CI = 0.522-0.886) and increase aberrant motor activity (p = 0.013; OR = 2.257, 95% CI = 1.195-4.260). The present findings suggested that 5-HTTLPR might be associated with delusions in AD. S-plus carriers might be associated with protective effect against delusions in AD. CONCLUSIONS: More studies on wider samples of high selected demented patients are needed to confirm our results. However, the present findings suggested that a genetic factor related to serotonin metabolism might exert a protective role on the clinical expression of neuropsychiatric clusters in AD with important implications regarding mechanisms underlying delusions and their possible treatment across the AD and dementia spectrum.

CYP2D6 genotypes in revolving door patients with bipolar disorders: A case series.

RATIONALE: In psychiatric disorders, interindividual differences in cytochrome P450 (CYP)2D6 (CYP2D6) enzymatic activity could be responsible of adverse drug reactions (ADRs) and therapeutic failures (TFs) for CYP2D6-metabolized drugs, contributing to the periodical hospital readmissions of the revolving door (RD) condition. PATIENT CONCERNS: We investigated CYP2D6 genotypes in a controlled series of 5 consecutive RD patients with Bipolar Disorder (BD). DIAGNOSES: Psychiatric patients affected by Bipolar Disorder. INTERVENTIONS: We defined TFs as a difference at the Brief Psychiatric Rating Scale score ΔBPRS < 25% at each 1-week of stable treatment, and ADRs as the onset of extrapyramidal symptoms and/or metabolic impairment with weight gain. OUTCOMES: At 3 months, a mean number of 2.75 ±â€Š1.26 ADR and a mean ΔBPRS score of 16.07 ±â€Š0.05% were observed. At 6 months of follow-up, compared to the only patient without BD (ΔBPRS < 32.10%), BD patients (n = 4) showed TFs (ΔBPRS < 25%). CYP2D6 genotyping revealed intermediate metabolizer phenotypes for BD patients and an extensive metabolizer phenotype for the patient without BD. In BD patients, the ratio of drugs maintained/discontinued for TFs or ADRs was 1.75 for non-CYP2D6 versus 0.33 for CYP2D6 interacting drugs, while the proportion of ADR:TF was 0:4 versus 6:3. LESSONS: Our findings may suggest that CYP2D6 clinically relevant genotypes may be involved in the unwanted outcomes observed in RD patients with BD.

Role of CLU, PICALM, and TNK1 Genotypes in Aging With and Without Alzheimer's Disease.

Healthy and impaired cognitive aging may be associated to different prevalences of single-nucleotide polymorphisms (SNPs). In a multicenter case-control association study, we studied the SNPs rs11136000 (clusterin, CLU), rs541458 (phosphatidylinositol binding clatrin assembly protein, PICALM), and rs1554948 (transcription factor A, and tyrosine kinase, non-receptor, 1, TNK1) according to the three age groups 50-65 years (group 1), 66-80 years (group 2), and 80+ years (group 3) in 569 older subjects without cognitive impairment (NoCI) and 520 Alzheimer's disease (AD) patients. In NoCI subjects, a regression analysis suggested a relationship between age and TNK1 genotypes, with the TNK1-A/A genotype frequency that increased with higher age, and resulting in a different distribution of the TNK1-A allele. In AD patients, a regression analysis suggested a relationship between age and PICALM genotypes and TNK1 genotypes, with the PICALM-T/C and TNK1-A/A genotype frequencies that decreased with increasing age. A resulting difference in the distribution of PICALM-C allele and TNK1-A allele was also observed. The TNK1-A allele was overrepresented in NoCI subjects than in AD patients in age groups 2 and 3. These results confirmed after adjustment for apolipoprotein E polymorphism, which suggested a different role of PICALM and TNK1 in healthy and impaired cognitive aging. More studies, however, are needed to confirm the observed associations.

Erythrocyte Associated Amyloid-ß as Potential Biomarker to Diagnose Dementia.

BACKGROUND: Although it is known that Alzheimer's disease (AD) is associated with the progressive accumulation of amyloid ß-peptide (Aß) in the human brain, its pathogenic role has to be completely clarified. Aß moves from the bloodbrain barrier to the plasma and an increased Aß production in brain could be associated with higher Aß concentrations in blood. A recent study has evaluated Aß40 and Aß42 levels in human red blood cells (RBCs) with evidence of agedependent higher Aß concentration in RBCs. OBJECTIVE: The aim of the study was to investigate if erythrocyte associated Aß (iAß) levels could be different in subjects affected by dementia in comparison with controls and according to the patient's cognitive impairment or different dementia subtypes. METHOD: To answer these questions we assessed iAß40 and iAß42 levels in 116 patients: 32 healthy controls, 39 with diagnosis of vascular dementia (VaD), 14 mild cognitive impairment (MCI) and 31 AD. RESULTS: In this population we found significant differences in iAß42 between controls and cognitive impaired patients. Moreover, iAß42 significantly differed between dementia vs MCI. AD also showed different iAß42 levels as compared to VaD. Conversely, no differences were found for iAß40. All the analyses were adjusted for potential confounders like age, gender and Hb concentration. A direct correlation between increasing iAß42 concentration and the progression of the cognitive decline using the MMSE score as continuous variable was also found. CONCLUSION: Our findings support the evidence that iAß42 could be an instrument to early recognize dementia and predict cognitive impairment.

Psychotropic drugs and CYP2D6 in late-life psychiatric and neurological disorders. What do we know?

INTRODUCTION: Late-life psychiatric and neurological disorders (LLPND) are interesting models to understand the potential role of pharmacogenetics in drug management, since several pharmacological approaches for treating LLPND have proven to be ineffective or deleterious, thus resulting in therapeutic failures (TF) and adverse drug reactions (ADR). Common variants in the genes encoding the cytochrome P450 (CYP) enzyme system, the 'engine room' of drug metabolism, together with well-known age-related increased polypharmacy also contributed to the prevalence of TF and ADR observed in these patients, also rising number and time of hospital readmissions and rate of institutionalizations. Areas covered: The genetics of CYP and how it may be used for the management of the outcomes of the most frequent drugs (antidepressants, antipsychotics, anticholinesterase inhibitors, and anxiolytics) used in LLPND. Expert opinion: Tailored CYP-based pharmacological treatments of LLPND will reduce TFs and ADRs, improving patient's life, reducing number and dosage of administered drugs, and the number and duration of hospital readmissions, saving costs for clinical management of LLPND. Pharmacokinetic interactions are less predictable than pharmacodynamic ones and several requests are made to regulatory organisms for the pharmacological management of frail older patients affected by LLPND.

Role of the APOE polymorphism in carotid and lower limb revascularization: A prospective study from Southern Italy.

BACKGROUND: Atherosclerosis is a complex multifactorial disease and the apolipoprotein E (APOE) polymorphism has been associated to vascular complications of atherosclerosis. OBJECTIVES: To investigate the relationship between the APOE genotypes and advanced peripheral vascular disease. MATERIALS AND METHODS: 258 consecutive patients (201 males and 57 females, mean age 70.83 ± 7.89 years) with severe PVD were enrolled in a 42-months longitudinal study (mean 31.65 ± 21.11 months) for major adverse cardiovascular events. At follow-up genotypes of the APOE polymorphism were investigated in blinded fashion. RESULTS: As compared with ε3/ε3, in ε4-carriers a significant higher incidence of major adverse cardiovascular events (35.58% vs. 20.79%; p = 0.025) and total peripheral revascularization (22.64% vs. 5.06%; p < 0.001) was observed. Prospective analysis, showed that ε4-carriers have an increased hazard ratio for major adverse cardiovascular events (adjusted HR 1.829, 95% CI 1.017-3.287; p = 0.044) and total peripheral revascularization (adjusted HR = 5.916, 95% CI 2.405-14.554, p <0.001). CONCLUSIONS: The ε4 allele seems to be risk factor for major adverse cardiovascular events, and in particular for total peripheral revascularization in patients with advanced atherosclerotic vascular disease.

Klotho Gene and Selective Serotonin Reuptake Inhibitors: Response to Treatment in Late-Life Major Depressive Disorder.

Klotho protein, encoded by the Klotho gene (KL) at locus 13q12, is an antiaging hormone-like protein playing a pivotal role in cell metabolism homeostasis and associated to longevity and age-related diseases. In particular, altered cell metabolism in central nervous system may influence the behavior of serotoninergic neurons. The role of KL in the response to treatment with selective serotonin reuptake inhibitors (SSRIs) in late-life depressive syndromes and late-life major depressive disorder (MDD) is unclear. We genotyped three single-nucleotide polymorphisms (SNPs) of KL in 329 older patients with diagnosis of late-life MDD, treated with SSRIs and evaluated with the Hamilton Rating Scale for Depression 21-items (HRSD-21) at baseline and after 6 months. A reduction ≥50 and <10 % in HDRS-21 score was considered as response or nonresponse to therapy, respectively, and the values of reduction between 10 and 49 % as poor responders. After 6 months of SSRI treatment, 176 patients responded, 54 patients did not respond and 99 patients showed a poor response. Ordinal logistic models showed a significant association between mutation of SNP rs1207568 and responders and, similarly, for each unitary risk allele increase overlapping results were found. Conversely, a significantly higher frequency of the minor genotype of SNP rs9536314 was found in nonresponders. Considering the pre-post differences of HRSD-21 scores as a continue variable, we confirmed a significant improvement of depressive symptoms after treatment in patients carrying at least one minor allele at rs1207568 and a worse response in patients homozygous for the minor allele at rs9536314. Our results were the first that suggested a possible role of KL in the complex pathway of SSRI response in late-life MDD.

Psychiatry meets pharmacogenetics for the treatment of revolving door patients with psychiatric disorders.

INTRODUCTION: Therapeutic failures (TFs) and adverse drug reactions (ADRs), together with the recurring nature of the clinical course of psychiatric disorders, mainly bipolar disorders (BDs), strongly contributed to the prevalence and frequency of hospital readmissions observed in these patients. This is the revolving door (RD) condition, dramatically rising costs for the management of these patients in psychiatric settings. Areas covered: We searched in the medical literature until May 2016 to review the role of functional variants in the cytochrome P450 (CYP) 2D6 gene on observed ADRs and TFs in RD patients with BDs, conferring a different capacity to metabolize psychotropic drugs. Expert commentary: CYP2D6 functional polymorphisms might directly contributed to the prevalence and frequency of the RD condition, commonly observed in BD patients. Although several environmental and socio-demographic/diagnostic variables such as alcohol/drug abuse, and medication non-compliance accounted for a significant proportion of the ability to predict RD prevalence and frequency, the pharmacogenetics of CYP, particularly CYP2D6, may help to identify BD patients at risk for ADRs and TFs. These patients may be addressed towards alternative treatments, thus improving their quality of life, and reducing RD prevalence and frequency and the overall costs for their management.

Role of CYP2D6 Polymorphisms in the Outcome of Postoperative Pain Treatment.

OBJECTIVE: To investigate the role of CYP2D6 phenotype in the outcome of postoperative (PO) pain (POP) treatment. DESIGN: Longitudinal cohort study. Open-label trial with post hoc analysis. SETTING: General Hospital Surgery and Recovery Units. PATIENTS: Ninety unrelated Caucasians submitted to abdominal/thoracic surgery. INTERVENTIONS: Standard multimodal POP treatment including opioids (tramadol) and nonsteroidal anti-inflammatory drugs (ketoprofen) at different dosages and infusion rates according to the predicted mild, moderate, or severe POP. OUTCOME MEASURES: Pain (Numeric Rating Scale-NRS) and sedation (Ramsay Sedation Scale-RSS) up to 24 hours after surgery. By genotyping 16 CYP2D6 alleles, the four CYP2D6 phenotypes poor metabolizer (PM), intermediate metabolizers (IM), extensive metabolizers (EM) and ultrarapid metabolizers (UM) were predicted. RESULTS: As compared with the CYP2D6-EM phenotype, in the early PO time (30 min) a higher RSS mean score in IM was observed (P = 0.035). A suggestion towards higher mean score in PM (P = 0.091) and a minor mean score in UM (P = 0.091) was also detected. No difference in the outcome of pain across the CYP2D6 phenotypes was observed. CONCLUSIONS: In respect to the normal CYP2D6 phenotype, our results suggested that slowly metabolizers (IMs and PMs) might have a major sedation, whereas more rapid metabolizers (UM) a minor sedation, in the early time after surgery. A minor role of CYP2D6 phenotype in PO analgesia may be suggested.

Role of the serotonin transporter gene locus in the response to SSRI treatment of major depressive disorder in late life.

It has been suggested that the serotonin or 5-hydroxytriptamine (5-HT) transporter (5-HTT) and its gene-linked polymorphic region (5-HTTLPR) are selective serotonin reuptake inhibitor (SSRI) response modulators in late-life depression (LLD), and particularly in late-life major depressive disorder (MDD). Previous studies differed in design and results. Our study aimed to investigate the solute carrier family 6 (neurotransmitter transporter and serotonin) member 4 (SLC6A4) gene locus, encoding 5-HTT and SSRI treatment response in late-life MDD. For a prospective cohort study, we enrolled 234 patients with late-life MDD to be treated with escitalopram, sertraline, paroxetine or citalopram for 6 months. The SLC6A4 polymorphisms rs4795541 (5-HTTLPR), rs140701 and rs3813034 genotypes spanning the SLC6A4 locus were investigated in blinded fashion. No placebo group was included. We assessed responder or non-responder phenotypes according to a reduction in the 21-item version of the Hamilton Depression Rating Scale (HDRS-21) score of ⩾ 50%. At follow-up, 30% of the late-life MDD patients were non-responders to SSRI treatment. No time-course of symptoms and responses was made. A poor response was associated with a higher baseline HDRS-21 score. We observed a significant over-representation of the rs4795541-S allele in the responder patients (0.436 versus 0.321; p = 0.023). The single S-allele dose-additive effect had OR = 1.74 (95% CI 1.12-2.69) in the additive regression model. Our findings suggested a possible influence of 5-HTTLPR on the SSRI response in patients with late-life MDD, which is potentially useful in identifying the subgroups of LLD patients whom need a different pharmacological approach.

FOXO1 locus and acetylcholinesterase inhibitors in elderly patients with Alzheimer's disease.

OBJECTIVE: Acetylcholinesterase inhibitors (AChEIs) may reduce the oxidative stress in brain of Alzheimer's disease (AD) patients. Forkhead box O1 (FOXO1) protein has been reported as the link between oxidative stress and AD. We evaluated a potential association between FOXO1 gene locus and the response to AChEI treatment in patients with sporadic AD. METHODS: In this prospective study, 109 Caucasian AD patients were treated with standard doses of donepezil, galantamine, or rivastigmine for 6 months. Functional and cognitive status were evaluated at baseline and after treatment. Response to therapy was defined according to the National Institute for Health and Clinical Excellence criteria. Genotype analyses, including the APOE polymorphism, were made in blinded fashion. RESULTS: A significantly higher frequency of FOXO1 rs7981045 G/G genotype was observed in nonresponders compared with responders (17.14% versus 2.70%, P=0.010). Age, sex, and APOE-adjusted logistic regression analysis confirmed that patients with the G/G genotype had a significantly higher risk of poor response to AChEI treatment (odds ratio =10.310; 95% confidence interval, 1.510-70.362). Haplotype analysis revealed significant differences in haplotype frequency distribution between these groups. CONCLUSION: FOXO1 may influence the clinical response to AChEIs in AD patients.

Correlación cito-colpo-histológica de lesiones causadas por el virus del papiloma humano (HPV) y la utilidad de la técnica de PCR para determinar la infección por HPV / Correlation of cyto-colpo-histology in human papillomaviruses (HPV) lesions and the use of PCR technique in determining HPV infection

Introducción: El cáncer de cuello uterino es una patología prevalente más aun en países sub-desarrollados y existe una relación causal entre la infección persistente con algún tipo oncogénico de HPV y el desarrollo de dicha neoplasia.Se cuenta con un estudio de screening mundialmente aceptado y que también previene el carcinoma cervical que es el Papanicolaou y colposcopia, y en los últimos años se han incorporado estudios de biología molecular para el estudio del ADN viral.Material y Métodos: Se estudiaron a 60 pacientes. Se tomo como método gold standard a la biopsia de cuello uterino y a 29 pacientes se les realizo PCR para identificar ADN-HPV. La edad promedio de las pacientes fue de 30,95 años con mayor cantidad de pacientes en el rango etareo de 21-25 años. Resultados: El 70% tuvo citología negativa y 48 pacientes tuvieron biopsia positiva, 16 con resultado positivo de PCR. Obtuvimos una alta especificidad el Papanicolaou con respecto a la biopsia (90%), no así en comparación con el test de PCR (S=56% E=50%) debido al número pequeño de pacientes que se sometieron a este estudio. Discusión: Las mujeres menores de 30 años son las que más chances tienen de contraer la infección, no así de desarrollar la enfermedad debido a la historia natural de la misma, por lo que aconsejamos continuar con el screening regular de Papanicolaou/colposcopia e introducir con lapsos de 3 años o más en mujeres mayores a 30 años los estudios de biología molecular.Conclusiones: Se espera poder contar con mayores estrategias que nos permitan usar los beneficios de los test ADN-HPV sin sobre tratar a mujeres que probablemente atraviesan por una infección transitoria.

Introduction: Cervical cancer is a prevalent pathology, especially in underdeveloped countries, and there is a causal relationship between persistent infection with some type of oncogenic HPVs and the development of said neoplasia. There are two universally-accepted screening studies which also prevent cervical cancer, i.e. Pap smear and colposcopy, and, in the last few years some molecular biology studies have been adopted for the study of viral DNA. Material and methods: 60 patients were studied. Cervical biopsy was the gold standard method used and 29 patients were tested using the PCR technique to identify HPV-DNA. Patients' average age was 30.95, most of whom belonged to the 21-25 years old age span. Results: 70% of patients had negative cytology test and 48 patients obtained positive biopsy results, 16 had positive results in the PCR test. The Pap smear specificity was higher as regards the biopsy (90%), unlike the PCR test (S=56% E=50%) due to the small number of patients that underwent this study. Discussion: Women younger than 30 years old have more chances of infection, but no of developing the disease considering its natural history. Therefore, we recommend continuing with the Pap smear/colposcopy regular screening and introducing molecular biology studies in women older than 30 years old, every 3 years or more.Conclusions: We hope to have more strategies available which enable the use of HPV-DNA test benefits, without overtreating patients who are probably suffering from a transitory infection.

Correlación cito-colpo-histológica de lesiones causadas por el virus del papiloma humano (HPV) y la utilidad de la técnica de PCR para determinar la infección por HPV / Correlation of cyto-colpo-histology in human papillomaviruses (HPV) lesions and the use of PCR technique in determining HPV infection

Introducción: El cáncer de cuello uterino es una patología prevalente más aun en países sub-desarrollados y existe una relación causal entre la infección persistente con algún tipo oncogénico de HPV y el desarrollo de dicha neoplasia.Se cuenta con un estudio de screening mundialmente aceptado y que también previene el carcinoma cervical que es el Papanicolaou y colposcopia, y en los últimos años se han incorporado estudios de biología molecular para el estudio del ADN viral.Material y Métodos: Se estudiaron a 60 pacientes. Se tomo como método gold standard a la biopsia de cuello uterino y a 29 pacientes se les realizo PCR para identificar ADN-HPV. La edad promedio de las pacientes fue de 30,95 años con mayor cantidad de pacientes en el rango etareo de 21-25 años. Resultados: El 70% tuvo citología negativa y 48 pacientes tuvieron biopsia positiva, 16 con resultado positivo de PCR. Obtuvimos una alta especificidad el Papanicolaou con respecto a la biopsia (90%), no así en comparación con el test de PCR (S=56% E=50%) debido al número pequeño de pacientes que se sometieron a este estudio. Discusión: Las mujeres menores de 30 años son las que más chances tienen de contraer la infección, no así de desarrollar la enfermedad debido a la historia natural de la misma, por lo que aconsejamos continuar con el screening regular de Papanicolaou/colposcopia e introducir con lapsos de 3 años o más en mujeres mayores a 30 años los estudios de biología molecular.Conclusiones: Se espera poder contar con mayores estrategias que nos permitan usar los beneficios de los test ADN-HPV sin sobre tratar a mujeres que probablemente atraviesan por una infección transitoria. (AU)

Introduction: Cervical cancer is a prevalent pathology, especially in underdeveloped countries, and there is a causal relationship between persistent infection with some type of oncogenic HPVs and the development of said neoplasia. There are two universally-accepted screening studies which also prevent cervical cancer, i.e. Pap smear and colposcopy, and, in the last few years some molecular biology studies have been adopted for the study of viral DNA. Material and methods: 60 patients were studied. Cervical biopsy was the gold standard method used and 29 patients were tested using the PCR technique to identify HPV-DNA. Patients average age was 30.95, most of whom belonged to the 21-25 years old age span. Results: 70% of patients had negative cytology test and 48 patients obtained positive biopsy results, 16 had positive results in the PCR test. The Pap smear specificity was higher as regards the biopsy (90%), unlike the PCR test (S=56% E=50%) due to the small number of patients that underwent this study. Discussion: Women younger than 30 years old have more chances of infection, but no of developing the disease considering its natural history. Therefore, we recommend continuing with the Pap smear/colposcopy regular screening and introducing molecular biology studies in women older than 30 years old, every 3 years or more.Conclusions: We hope to have more strategies available which enable the use of HPV-DNA test benefits, without overtreating patients who are probably suffering from a transitory infection. (AU)

TOMM40, APOE, and APOC1 in primary progressive aphasia and frontotemporal dementia.

The aim of this study was to investigate the apolipoprotein E (APOE) chromosomal region in frontotemporal lobar degeneration (FTLD), and in particular in primary progressive aphasia (PPA) and the behavioral variant frontotemporal dementia (bvFTD). To this aim, we selected three single-nucleotide polymorphisms (SNPs) rs2075650 and rs157590 (TOMM40), and rs1064725 (APOC1), representative of the linkage disequilibrium (LD) blocks at the 19q13-q13.2 chromosomal region. The SNPs rs429358 and rs7412 forming the APOE polymorphism were also included in the study. The analysis was made in 282 patients with a clinical diagnosis of sporadic FTLD, namely 207 bvFTD and 75 PPA, and 296 cognitively healthy control subjects. LD (r2 = 0.35) between TOMM40 (rs2075650) and APOC1 (rs1064725) was observed in PPA, but not in controls and in bvFTD. Inside this region of 26.9 kb, LD (r2 ≥ 0.50) between TOMM40 (rs2075650) and APOE (rs429358) was observed in bvFTD and in controls, but not in PPA. Inside this region of 16.3 kb, LD (r2 = 0.14) between TOMM40 (rs157590) and APOE (rs429358) was observed in PPA, but not in bvFTD and in controls. Although the genetics of PPA and bvFTD needs further investigation, our results suggested the presence of a different genetic background underlying PPA and bvFTD at the 19q13-q13.2 chromosomal region.

The APOE polymorphism in Alzheimer's disease patients with neuropsychiatric symptoms and syndromes.

BACKGROUND: Neuropsychiatric symptoms (NPS) are a common feature of Alzheimer's disease (AD), resulting in particular AD endophenotypes. The common AD genetic risk factor apolipoprotein E (APOE) has been suggested underlying these AD endophenotypes. METHODS: APOE genotyping, a comprehensive geriatric assessment (CGA), and Neuropsychiatric Inventory were performed on 322 consecutive older patients. Patients were divided into three groups: AD with NPS (N = 93), AD without NPS (N = 108), and, as a control group, patients with no cognitive impairment (NoCI: N = 121). Patients with NPS were further sub-divided in four groups according to the European Alzheimer's Disease Consortium (EADC) classification of neuropsychiatric syndromes in AD: hyperactive, psychotic, affective, and apathetic. RESULTS: AD patients with NPS showed a significantly higher grade of cognitive impairment, more severity stage of dementia, more disability in the activities of daily living (ADL), and the instrumental ADL than AD patients without NPS. As expected, an higher frequency of APOE ε3/ε4 genotype was observed in patients with AD, both with and without NPS, than patients with NoCI. No difference in the distribution of APOE genotypes was found between AD patients with vs. without NPS. However, in AD patients APOE ε4-carriers, there was an increased risk of affective [odds ratio (OR): 2.34, 95% confidence interval (CI): 1.19-4.58) and apathetic (OR: 2.24,95%CI: 1.19-4.22) syndromes. CONCLUSIONS: These findings did not suggest a significant association between APOE polymorphism and presence of NPS in AD patients. In AD patients with NPS, however, APOE ε4-carrier status was associated with an increased risk of affective and apathetic syndromes.

Angiotensin-converting enzyme (ACE) genotypes and disability in hospitalized older patients.

The association between angiotensin-converting enzyme (ACE) genotypes and functional decline in older adults remains controversial. To assess if ACE gene variations influences functional abilities at older age, the present study explored the association between the common ACE insertion/deletion (I/D) polymorphism and disability measured with activities of daily living (ADL) in hospitalized older patients. We analyzed the frequency of the ACE genotypes (I/I, I/D, and D/D) in a population of 2,128 hospitalized older patients divided according to presence or absence of ADL disability. Logistic regression analysis adjusted for possible confounding factors, identified an association between the I/I genotype with ADL disability (OR=1.54, 95% CI 1.04-2.29). This association was significant in men (OR=2.01, 95% CI 1.07-3.78), but not in women (OR=1.36, 95% CI 0.82-2.25). These results suggested a possible role of the ACE polymorphism as a genetic marker for ADL disability in hospitalized older patients.

Apolipoprotein E-related all-cause mortality in hospitalized elderly patients.

The most common apolipoprotein E (APOE) allelic variation is implicated in many age-related diseases and human longevity with controversial findings. We investigated the effect of APOE gene polymorphism on all-cause mortality in elderly patients taking into consideration the functional disability, cognitive impairment, malnutrition, and the occurrence of common age-related diseases. APOE genotypes were determined in 2,124 geriatric hospitalized patients (46.5% men and 53.5% women; mean age, 78.2 +/- 7.1 years; range, 65-100 years). At hospital admission, all patients underwent a comprehensive geriatric assessment to evaluate functional disability, cognitive status, nutritional status, and comorbidity. The main and secondary diagnoses at hospital discharge were also recorded. Mortality status was evaluated in all patients after a maximum follow-up of 5 years (range, from 1.26 to 5.23 years; median, 2.86 years). During the study period, 671 patients died (32.0%). At hospital admission, these patients showed a significant higher prevalence of cardiovascular diseases (56.3% vs 53.4%; p = 0.007), neoplasias (32.3% vs 13.7%; p < 0.001), and lower prevalence of neurodegenerative diseases (17.7% vs 20.7%; p < 0.001) than survived patients. Moreover, they also showed an higher prevalence of disability (52.0% vs 25.6%; p < 0.001), cognitive impairment (31.0% vs 18.8%; p < 0.001), and malnutrition (74.0% vs 46.1%; p < 0.001) than survived patients. In the overall study population, the APOE epsilon2 allele was significantly associated to neurodegenerative diseases (odds ratio = 0.59; 95% confidence interval (CI), 0.37-0.94). No significant association between the APOE polymorphism and disability, malnutrition, co-morbidity status, and with all-cause mortality was observed. In patients with cardiovascular diseases, however, a decreased risk of all-cause mortality was found in the epsilon2 allele carriers (hazard ratio = 0.56; 95% CI, 0.36-0.88). In this population, APOE allele variants might play a role on cardiovascular disease-related mortality.