The Implications of Cytochrome P450 2D6/CYP2D6 Polymorphism in the Therapeutic Response of Atypical Antipsychotics in Adolescents with Psychosis-A Prospective Study.

BACKGROUND: The plasma level of antipsychotics and their metabolites depends on the activity of the cytochrome P450 (CYP) system in the liver. This research aims to test the individual response variability to atypical antipsychotic drugs, depending on the activity of the CYP2D6 enzyme. METHODS: In a prospective, noninterventional study, we included 56 adolescents, 51.79% male, diagnosed with schizophrenia. The patients underwent DNA sampling for genotyping SNP by RT-PCR and CYP* allelic variants using Applied Bio-systems™ TaqMan® Assays Foster City, CA, USA). and clinical and paraclinical assessments. The effectiveness of the therapy was evaluated with the PANSS scores at baseline and 3, 6, and 12 months after the initiation of an atypical antipsychotic treatment. RESULTS: Based on the genotyping results, the patients were divided into slow metabolizers (Group 1), extensive metabolizers (Group 2), and intermediate metabolizers (Group 3). The PANSS score showed a significant decrease in Group 2, compared to Group 3 after 3 (p = 0.02), 6 (p = 0.0009), and 12 months (p < 0.0001). The patients in Group 1 showed high PANSS scores, and those in Group 2 had fewer adverse reactions than the other groups. CONCLUSIONS: Assessing the CYP2D6 polymorphism may be useful in clinical pediatric psychiatric practice towards improving clinical results and patients' quality of life.

The Role of Circular RNA for Early Diagnosis and Improved Management of Patients with Cardiovascular Diseases.

Cardiovascular diseases (CVDs) are responsible for approximately 17.9 million deaths every year. There is growing evidence that circular RNAs (circRNAs) may play a significant role in the early diagnosis and treatment of cardiovascular diseases. As regulatory molecules, circular RNAs regulate gene expression, interact with proteins and miRNAs, and are translated into proteins that play a key role in a wide variety of biological processes, including the division and proliferation of cells, as well as the growth and development of individuals. An overview of the properties, expression profiles, classification, and functions of circRNAs is presented here, along with an explanation of their implications in cardiovascular diseases including heart failure, hypertension, ischemia/reperfusion injury, myocardial infarction, cardiomyopathies, atherosclerosis, and arrhythmia.

Genetic Characterization of Dilated Cardiomyopathy in Romanian Adult Patients.

Dilated cardiomyopathy (DCM) represents a group of disorders affecting the structure and function of the heart muscle, leading to a high risk of heart failure and sudden cardiac death (SCD). DCM frequently involves an underlying genetic etiology. Genetic testing is valuable for risk stratification, treatment decisions, and family screening. Romanian population data on the genetic etiology of DCM are lacking. We aimed to investigate the genetic causes for DCM among Romanian adult patients at tertiary referral centers across the country. Clinical and genetic investigations were performed on adult patients presenting to tertiary hospitals in Romania. The genetic investigations used next-generation sequencing panels of disease-associated DCM genes. A total of 122 patients with DCM underwent genetic testing. The mean age at DCM diagnosis was 41.6 ± 12.4 years. The genetic investigations identified pathogenic or likely pathogenic variants in 50.8% of participants, while 25.4% had variants of unknown significance. Disease-causing variants in 15 genes were identified in people with DCM, with 31 previously unreported variants. Variants in TTN, LMNA, and DSP explained 75% of genetic causes for DCM. In total, 52.4% of patients had a family history of DCM/SCD. Left ventricular ejection fraction of <35% was observed in 41.9% of patients with disease-causing variants and 55% with negative or uncertain findings. Further genotype-phenotype correlations were explored in this study population. The substantial percentage (50.8%) of disease-causing variants identified in patients with DCM acknowledges the importance of genetic investigations. This study highlights the genetic landscape in genes associated with DCM in the Romanian population.

Latent Tuberculosis in Psoriasis Patients on Biologic Therapies: Real-World Data from a Care Center in Romania.

Background and Objectives: Psoriasis is a chronic and inflammatory condition that has a huge impact on the patient's quality of life. Biological treatment improved psoriasis therapy, with impressive results seen in the evolution of the disease and the patient's quality of life. However, the risk of mycobacterium tuberculosis (MTB) infection reactivation is well-known to biological therapy, which raises problems especially in an endemic country. Materials and Methods: In this study, we followed moderate to severe psoriasis patients who had latent tuberculosis infection (LTBI) following treatment with a biological therapy approved in Romania. Results: The patients were evaluated at baseline and then followed-up with Mantoux tests and chest X-rays every year, resulting in 54 patients being diagnosed with LTBI. At the initial evaluation, 30 patients with LTBI were identified, and 24 more were identified during biological therapy. These patients were given prophylactic treatment. Out of the 97 participants in this retrospective study, 25 required association of methotrexate (MTX) alongside biological therapy. We compared the prevalence of positive Mantoux tests in patients with combined therapy with that of patients only on biological treatment, and the results were higher in the combined therapy group. Conclusion: All the patients in the study were vaccinated against tuberculosis (TB) after birth, and none were diagnosed with active tuberculosis (aTB) before or after the start of therapy according to the pulmonologist.

Primary Cutaneous B-Cell Lymphoma Co-Existing with Mycosis Fungoides-A Case Report and Overview of the Literature.

The existence of two sequential lymphomas, one localized and one systemic, either both with B or T lymphocytes, or one with B cells and one with T cells, with the same patient, is a known possibility. The second lymphoma is often induced by immunodepression or by the initial treatment. However, the existence of two cutaneous lymphomas with different cell lines, without systemic involvement, represents an uncommon situation. In this report, we describe the case of a 37-year-old man with an initial diagnosis of PMZBCL that over 10 months also developed a MF patch/plaque on the left leg.

Cardiofaciocutaneous syndrome - a longitudinal study of a case over 33 years: case report and review of the literature.

Cardiofaciocutaneous (CFC) syndrome [Online Mendelian Inheritance in Man (OMIM) #115150] is characterized by craniofacial dysmorphism, heart malformation, ectodermal abnormalities, neuromotor delay and intellectual disability. It is not a frequent disease, about 300 cases have been reported in the medical literature. We describe the case of a 34-year-old patient presenting with CFC syndrome phenotype, monitored since the age of 1 1∕2 years. Clinical findings included craniofacial dysmorphism, development delay, heart malformation and severe intellectual disability. The evolution was with progressive intellectual disability, hypogonadism, hypertrophic cardiomyopathy, wrinkled palms and soles. Molecular analysis showed a heterozygous variant in the B-Raf proto-oncogene, serine∕threonine kinase (BRAF) gene (7q34): NM_001354609.2:c.1502A>G, with pathogenic significance. We report this case, observed along a period of 33 years, for illustration of clinical evolutive particularities, and for difficulties in establishing the positive diagnosis.

Oral cancer histopathological subtypes in association with risk factors: a 5-year retrospective study.

BACKGROUND: Oral cancer is a worldwide public health problem, being the sixth most common neoplasm. The high mortality rate of this type of cancer is due to a delayed diagnosis, a fast evolution and metastasis, no primary symptomatology, the multitude of risk factors and the lack of awareness among the population concerning oral malignancy. AIM: The aim of this 5-year retrospective study was to evaluate the incidence of oral cancer patients in the Clinic of Maxillo-Facial Surgery, Emergency County Hospital, Timisoara, Romania and quantify the histopathological (HP) subtypes, localization, age, gender, tumor staging and differentiation, positive loco-regional lymph nodes and risk factors. PATIENTS, MATERIALS AND METHODS: A number of 129 patients diagnosed with oral cancer were included in the study and their medical records were analyzed. A statistical analysis was performed that included the variables gender, age, tumor staging, differentiation grade, HP subtype, lymph nodes, localization, and risk factors. RESULTS: Our results outlined a high prevalence of oral cancer among males (65.9%), squamous cell carcinoma (SCC) being the most common HP subtype. Tumor staging revealed the fact that the majority of were T3 and T4 tumors with dissemination in the loco-regional lymph nodes. In 52% of the cases, tobacco was identified as a risk factor, and the association of tobacco and alcohol was present in 28.3% of the cases. CONCLUSIONS: The early diagnosis is crucial for the improvement of oral cancer survival rate. The oral cavity is permanently exposed to carcinogenic substances that associated with other risk factors have an influence upon the incidence of oral malignancies.

Synthesis and preliminary characterization of polyurethane nanoparticles with ginger extract as a possible cardiovascular protector.

Background and aim: The extract of ginger, obtained from the rhizome of Zingiber officinale, contains 6-gingerol, 6-shogaol, 8-gingerol, and 10-gingerol. It has many therapeutic effects such as being chemopreventive against stroke and heart diseases, malabsorption, bacterial infections, indigestion, and nausea, which have been observed since ancient times. The main aim of this study is to evaluate the polyurethane (PU) as a proper material for the hollow nanoparticles' preparation. Methods: The PU nanoparticles were obtained by a spontaneous emulsification, in the presence of a nonionic surfactant, combined with an interfacial polyaddition process between an aliphatic diisocyanate and different mixtures of etheric and esteric polyols. The synthesis was done without any PU additives, such as catalysts, blowing agents, chains promoters, cross-linking agents, and stabilizers. Results: The particles present almost neutral pH values and low water solubility. They are heat resistant up to 280°C. Decreased irritation level was found in the assay of PU nanoparticles loaded with pure ginger extract (GE) on the murine skin tests than the irritation level recorded for pure GE. Conclusion: This research shows the reduced noxiousness of these PU nanoparticles and consequently the possibility of their use as a possible cardiovascular protector.

Modern molecular study of weight gain related to antidepressant treatment: clinical implications of the pharmacogenetic testing.

Antidepressant medication influences cellular lipogenesis, being associated with metabolic side effects including weight gain. Due to the increasing use of antidepressants in children and adolescents, their metabolic and endocrine adverse effects are of particular concern, especially within this pediatric population that appears to be at greater risk. Genetic factors with a possible influence on antidepressant's adverse effects include CYP [cytochrome P450 (CYP450)] polymorphisms. We target to evaluate the efficacy of the pharmacogenetic testing, when prescribing antidepressants, in correlation with the occurrence of adverse events and weight gain. Our research was performed between the years 2010 and 2016, in the University Clinic of Child and Adolescent Psychiatry, Timisoara, Romania. We recruited 80 patients, children and adolescents with depressive disorders. Our study sample was divided in two groups: G1 - 40 patients took treatment after pharmacogenetic testing, and G2 - 40 patients without pharmacogenetic testing before the treatment election. Our results show statistically significant differences concerning the weight gain for groups G1 (with pharmacogenetic testing) and G2 (without pharmacogenetic testing). The CYP genotype and the pharmacogenetic testing, for choosing the personalized antidepressant therapy in children and adolescents with depressive disorders, proved to be good predictors for the response to antidepressants and the side effects registered, especially for weight gain. The significant correlations between the CYP polymorphisms for group G2 (without pharmacogenetic testing) and the weight gain/body mass index (BMI) increase, as major side effects induced by antidepressants, proved the fact that the pharmacogenetic screening is needed in the future clinical practice, allowing for individualized, tailored treatment, especially for at-risk pediatric categories.

Integrative clinico-biological, pharmacogenetic, neuroimagistic, neuroendocrinological and psychological correlations in depressive and anxiety disorders.

We approach the theme of modern treatment strategies, based on clinico-biological, pharmacogenetic, neuroimagistic, neuroendocrinological and psychological integrative correlations in the management of depressive and comorbid anxiety disorders. We target to evaluate the efficacy of the pharmacogenetic testing and the evolution, functioning of patients in correlation with specific neurobiological, neuroimagistic and neuroendocrinological markers. Our research was conducted between 2010-2016 on 80 children and adolescents with depressive and comorbid anxiety disorders - 40 children (G1 group), who benefited in choosing the pharmacotherapy from pharmacogenetic testing and 40 children without testing (G2 group). Also, the patients were evaluated through magnetic resonance (MR) spectroscopy at baseline and after pharmacotherapy. The efficacy of the chosen therapy in correlation with the pharmacogenetic testing was evaluated through the mean change in the CDRS (Children's Depression Rating Scale) total scores, in the CGI-S÷I (Clinical Global Impression - Severity÷Improvement), CGAS (Children's Global Assessment Scale) and through the change of the relevant neurobiological markers and MR spectroscopy metabolites. We evaluated the side effects through the PAERS (Pediatric Adverse Events Rating Scale)-Clinician. Our results show statistically significant differences of the clinical scores between the studied groups: for those subjects who benefited of pharmacogenetic testing, the CDRS, the global functioning scores prove a higher clinical improvement, a better compliance and lower PAERS side effects scores and also improvement concerning the MR spectroscopy dosed metabolites values. Our research was a proof sustaining the use of the pharmacogenetic testing in clinical practice and the value of investigating relevant neurobiological, neuroimagistic and neuroendocrinological markers for a personalized therapy in depressive disorders.

The prognostic and clinical significance of neuroimagistic and neurobiological vulnerability markers in correlation with the molecular pharmacogenetic testing in psychoses and ultra high-risk categories.

We approach an integrated, multidisciplinary, innovative research-action model in children and adolescents with psychosis and ultra high-risk categories. Our main focus was: to investigate the prognostic and clinical significance of neuroimagistic and neurobiological vulnerability markers in correlation with the molecular pharmacogenetic testing in psychoses and ultra high-risk categories; the dynamic evaluation of the clinical evolution for the studied groups in correlation with specific neurobiological and neuroimagistic variables and markers. Our research was conducted in the period 2009-2015 on 87 patients, children and adolescents with psychosis (42 took treatment after pharmacogenetic testing, 45 without) and 65 children with ultra high-risk (UHR) for psychosis - 32 benefited of pharmacotherapy after pharmacogenetic testing and 33 without. Also, the patients were evaluated through magnetic resonance (MR) spectroscopy at baseline and after pharmacotherapy. The efficacy of the chosen therapy in correlation with the pharmacogenetic testing was evaluated through the mean change in the Positive and Negative Syndrome Scale (PANSS) total scores, in the Clinical Global Impression of Severity and Improvement (CGI-S÷I), Children's Global Assessment Scale (CGAS) and through the change registered for the relevant neurobiological markers and MR spectroscopy metabolites, from baseline until endpoint in different timepoints. Our results, showed statistically significant differences of the clinical scores between the studied groups. Our research was a proof, sustaining the use of the pharmacogenetic testing in clinical practice and the value of investigating relevant neurobiological and neuroimagistic markers for a personalized, tailored therapy for psychotic patients and neuro-psychiatric UHR categories, as a fruitful pathway of intervention and care.

Assessment of chromosomal aneuploidies in sperm of infertile males by using FISH technique.

Reproductive failure is one of the most important issues for the population at age of procreation and approximately 15% of the couples who try to conceive a baby encounter reproductive difficulties. In this study, we used multicolor fluorescent in situ hybridization (FISH) probes for chromosomes 13, 18, 21, X and Y to evaluate the aneuploidy incidence in sperm cells. The study group included 35 males with infertility and oligoasthenoteratozoospermia (OAT) and 20 males with normal fertility and normal semen characteristics for which the conventional cytogenetic investigation using peripheral blood revealed a normal karyotype. The overall chromosome disomy and nulisomy in OAT group was higher than the one identified in the control group. By comparing the incidence of the disomy in the OAT group, the highest incidence was the sex chromosome disomy, followed by the disomy of chromosomes 13, 21 (equal values) and then 18. The nulisomy incidence in the OAT group was higher for sex chromosomes, followed by the nulisomy of autosomes 13, then 21 and 18. As in these days, for patients with OAT, intra-cytoplasmic sperm injection (ICSI) is frequently used, it is important to inform the patients if they might have an increased risk of aneuploidies in embryos.

-759C÷T polymorphism of the HTR2C gene is not correlated with atypical antipsychotics-induced weight gain, among Romanian psychotic patients.

We aim to investigate whether the -759C÷T polymorphism in 5-HTR2C gene was associated with weight change and hyperinsulinemia in Romanian pediatric patients with schizophrenia and bipolar disorders. The patients under investigation were enrolled between 2009 and 2014. A total of 81 schizophrenic and bipolar-disorder patients, aged between nine to 20 years (median age 15.74±4 years), who were following an atypical antipsychotic treatment (Risperidone, Aripiprazole, Olanzapine), were enrolled from University Hospital for Child and Adolescent Psychiatry and Neurology from Timisoara, Romania. The outcomes that we measured were the changes in Body Mass Index (BMI) from baseline to different time points: three months, six months, 12 months and 18 months, and the change in insulinemia over time, after atypical antipsychotic treatment. After carrying out the 5-HTR2C 759C÷T polymorphism identification, we found that 22 patients presented the -759C÷T polymorphism in 5-HTR2C gene. Between the patients exhibiting the 5-HTR2C -759C÷T polymorphism and the patients having the wild type alleles, there was no significant statistical difference in changes of BMI from baseline to endpoints that indicates the lack of the protective effect of the T allele against atypical antipsychotics-induced weight gain. Interestingly, we found a statistically significant association between insulinemia and T alleles' carriers, after 18 months of treatment with the above-mentioned antipsychotics. Taking into consideration that atypical antipsychotics have been associated with elevated insulin levels and insulin resistance, maybe in the future the -759C÷T polymorphism would find a role in the development of a more complex algorithm for prediction of diabetes mellitus risk, in patients taking atypical antipsychotics.

Intrapartum diagnostic of Roberts syndrome - case presentation.

Roberts syndrome is a rare disease, with multiple limb and skeletal abnormalities (called "pseudothalidomide disease"). There are only around 150 cases described in literature. We present a case of Roberts syndrome, diagnosed in moment of delivery, after a pregnancy without prenatal follow-up. The stillborn baby was naturally delivered by a 17-year-old primiparous woman at 38 weeks of amenorrhea. The pregnancy was not followed due to socioeconomic and family situation, and no prenatal ultrasound was performed. The male baby has 2650 g and presented several morphological abnormalities and tight double umbilical abdominal loop. The macroscopic evaluation showed: dolichocephaly, hypoplastic inferior maxilla with micrognathia, antimongoloid palpebral slant, pterygium colli, abnormal and lower implanted ears, superior limbs phocomelia, syndactyly at lower left limb and tetradactyly in all limbs, bilateral cryptorchidism, pancreatic aplasia. Roberts syndrome is a rare genetic disease with recessive autosomal transmission generated by mutations in ESCO2 gene, located on chromosome 8. The disease should be easy to diagnose by antenatal ultrasound examination, but in our case, the lack of prenatal follow-up determined the diagnostic at term. We believe consider this case is an argument towards introducing ultrasound-screening compulsory to all pregnancies. To identify a possible genetic mutation, further investigations of the parents are in progress, but classically the disease has a recessive autosomal transmission.