Bioinformatics Accelerates the Major Tetrad: A Real Boost for the Pharmaceutical Industry.

With advanced technology and its development, bioinformatics is one of the avant-garde fields that has managed to make amazing progress in the pharmaceutical-medical field by modeling the infrastructural dimensions of healthcare and integrating computing tools in drug innovation, facilitating prevention, detection/more accurate diagnosis, and treatment of disorders, while saving time and money. By association, bioinformatics and pharmacovigilance promoted both sample analyzes and interpretation of drug side effects, also focusing on drug discovery and development (DDD), in which systems biology, a personalized approach, and drug repositioning were considered together with translational medicine. The role of bioinformatics has been highlighted in DDD, proteomics, genetics, modeling, miRNA discovery and assessment, and clinical genome sequencing. The authors have collated significant data from the most known online databases and publishers, also narrowing the diversified applications, in order to target four major areas (tetrad): DDD, anti-microbial research, genomic sequencing, and miRNA research and its significance in the management of current pandemic context. Our analysis aims to provide optimal data in the field by stratification of the information related to the published data in key sectors and to capture the attention of researchers interested in bioinformatics, a field that has succeeded in advancing the healthcare paradigm by introducing developing techniques and multiple database platforms, addressed in the manuscript.

Polyphenols Targeting MAPK Mediated Oxidative Stress and Inflammation in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disorder, predominantly symmetric, which causes joint inflammation, cartilage degeneration and bone erosion, resulting in deformity and the loss of physical function. Although the management of RA has steadily improved, the pathophysiological mechanism is incompletely elucidated, and therapeutic options are still limited. Due to shortcomings in the efficacy or safety profiles of conventional RA therapies, therapeutic alternatives have been considered. Therefore, natural extracts containing polyphenolic compounds can become promising adjuvant agents for RA global management, due to their antioxidant, anti-inflammatory and apoptotic properties. Polyphenols can regulate intracellular signaling pathways in RA and can generate different immune responses through some key factors (i.e., MAPK, interleukins (ILs 1 and 6), tumor necrosis factor (TNF), nuclear factor light k chain promoter of activated receptor (NF-κB), and c-Jun N-terminal kinases (JNK)). The critical function of the Toll like-receptor (TLR)-dependent mitogen-activating protein kinase (MAPK) signaling pathway in mediating the pathogenic characteristics of RA has been briefly discussed. Oxidative stress can trigger a change in transcription factors, which leads to the different expression of some genes involved in the inflammatory process. This review aims to provide a comprehensive perspective on the efficacy of polyphenols in mitigating RA by inhibiting signaling pathways, suggesting future research perspectives in order to validate their use.

The Use of Xpert MTB/RIF Ultra Testing for Early Diagnosis of Tuberculosis: A Retrospective Study from a Single-Center Database.

Tuberculosis (TB) is a multisystemic contagious disease produced by Mycobacterium tuberculosis complex bacteria (MTBC), with a prevalence of 65:100,000 inhabitants in Romania (six times higher than the European average). The diagnosis usually relies on the detection of MTBC in culture. Although this is a sensitive method of detection and remains the "gold standard", the results are obtained after several weeks. Nucleic acid amplification tests (NAATs), being a quick and sensitive method, represent progress in the diagnosis of TB. The aim of this study is to assess the assumption that NAAT using Xpert MTB/RIF is an efficient method of TB diagnosis and has the capacity to reduce false-positive results. Pathological samples from 862 patients with TB suspicion were tested using microscopic examination, molecular testing and bacterial culture. The results show that the Xpert MTB/RIF Ultra test has a sensitivity of 95% and a specificity of 96.4% compared with 54.8% sensitivity and 99.5% specificity for Ziehl-Neelsen stain microscopy, and an average of 30 days gained in the diagnosis of TB compared with bacterial culture. The implementation of molecular testing in TB laboratories leads to an important increase in early diagnostics of the disease and the prompter isolation and treatment of infected patients.

Difficulties in the management of an Askin tumor in a pediatric patient with cystic fibrosis: case report and literature review.

Treating Ewing's Sarcoma of the thorax (Askin's tumor) with antineoplastic therapy in a malnourished cystic fibrosis patient colonized with Pseudomonas aeruginosa and Staphylococcus aureus may carry a significant potential for complications. We present the case of a known cystic fibrosis patient, diagnosed with Askin's tumor 5 years ago. Despite facing severe neutropenia, exacerbations of cystic fibrosis with Pseudomonas aeruginosa infections, and challenges in maintaining adequate caloric intake during the oncological treatment, the patient's outcome has been favorable. Chemotherapy doses had to be adjusted, and continuous antibiotic treatment was introduced throughout the course of therapy to reduce the frequency and intensity of exacerbations. Approximately 5 years after the cancer diagnosis, with no signs of relapse, the patient was started on CFTR (Cystic fibrosis transmembrane conductance regulator) modulator treatment. This intervention has successfully corrected the weight deficit. The coincidence of Ewing's sarcoma of the chest wall and cystic fibrosis in a single patient is 2.857 × 10-5% and to the best of our knowledge, this scenario has not been documented before.

PAH Pathogenic Variants and Clinical Correlations in a Group of Hyperphenylalaninemia Patients from North-Western Romania.

Phenylketonuria (PKU) is caused by mutations in the phenylalanine hydroxylase (PAH) gene and is characterized by altered amino acid metabolism. More than 1500 known PAH variants intricately determine a spectrum of metabolic phenotypes. We aim to report on clinical presentation and PAH variants identified in 23 hyperphenylalaninemia (HPA)/PKU Romanian patients. Our cohort exhibited classic PKU (73.9%, 17/23), mild PKU (17.4%, 4/23), and mild HPA (8.7%, 2/23). Severe central nervous system sequelae are frequent in our cohort in late-diagnosis symptomatic patients, which highlights yet again the significance of an early dietary treatment, neonatal screening and diagnosis, and facilitated access to treatment. Next-generation sequencing (NGS) identified a total of 11 PAH pathogenic variants, all previously reported, mostly missense changes (7/11) in important catalytic domains. c.1222C>T p.Arg408Trp was the most frequent variant, with an allele frequency of 56.5%. Twelve distinct genotypes were identified, the most frequent of which was p.Arg408Trp/p.Arg408Trp (34.8%, 8/23). Compound heterozygous genotypes were common (13/23), three of which had not been previously reported to the best of our knowledge; two correlated with cPKU and one showed an mPKU phenotype. Generally, there are genotype-phenotype correlation overlaps with the public data reported in BIOPKUdb; as our study shows, clinical correlates are subject to variation, in part due to uncontrolled or unknown epigenetic or environmental regulatory factors. We highlight the importance of establishing the genotype on top of using blood phenylalanine levels.

Research on demographic, clinical and paraclinical aspects in pregnant women infected with Toxoplasma gondii.

Toxoplasmosis is a zoonotic disease caused by the Toxoplasma gondii protozoan parasite. The aim of this study was to determine the frequency of acute toxoplasmosis or its presence in the medical history of 240 pregnant women, depending on age and geographical background. The second purpose was to analyze several medical aspects (clinical and paraclinical) in pregnant women with acute toxoplasmosis. The study identified several serological changes including positive toxoplasma IgM, IgG, and IgA antibodies. The chemiluminescence immunoassay (CLIA) method was used to detect T. gondii-specific IgM and IgG antibodies and the enzyme immunoassay (EIA) method to detect T. gondii-specific IgA antibodies. Of the 96 pregnant women (40%) infected with T. gondii, approximately 1/3 had acquired acute infection and 2/3 had a history of prior acute infection (P<0.0001). No statistically significant differences according to age groups (P=0.9384) were found in terms of serological profile. The number of patients with negative serology was significantly higher in urban areas than in rural areas (P<0.0001). The highest incidence among the pregnant women with acute toxoplasmosis with a single chain of ganglia affected was represented by those with the involvement of cervical lymph nodes (75%), the difference compared to the involvement of other chains of ganglia being statistically significant (P=0.0087). All 35 pregnant women with acute toxoplasmosis tested positive for T. gondii-specific IgM antibodies. Most pregnant women with acute T. gondii infection (57.1%) tested negative for T. gondii-specific IgM antibody serum titres within 3-6 months of presentation. The difference compared to other intervals from the moment pregnant women sought care was statistically significant (P=00002). Only 80% of all pregnant women with acute toxoplasmosis tested positive for T. gondii-specific IgA antibodies. Pregnant women with acute toxoplasmosis have a 3.3 times higher risk of pregnancy loss.

Influence of diet and sport on the risk of sleep apnea in patients with metabolic syndrome associated with hypothyroidism - a 4-year survey.

Apnea is a common problem observed among obese individuals, affecting the quality of sleep and increasing cardiovascular risk and mortality. The current study monitored the risk of obstructive sleep apnea (OSA) following diet therapy and sports-associated diet therapy in patients with metabolic syndrome (MS) and hypothyroidism. The subjects included in the study were divided into 3 groups: control group (CG) (n=36), diet therapy group (DG) (including patients following a personalized diet therapy program) (n=76), and diet therapy and sports group (DSG) (which considered patients doing sports in addition to following a personalized diet therapy program) (n=80). The evaluation methods included body analysis (body mass index, fat mass, and visceral fat), paraclinical analysis (homeostasis model assessment of insulin resistance), assessment of difficulty in breathing, stress monitoring, hypothyroidism, and risk of OSA. The OSA index was assessed using the Berlin Questionnaire of Sleep Apnea and Epworth Sleepiness Scale. The correlation between OSA with body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR) index, fat mass, and visceral fat showed a statistically significant positive ratio (p<0.05; F=3.871). The obtained results indicated that diet therapy and physical activity reduced the OSA risk by 78.72%.

Biomarker Changes in Pediatric Patients With COVID-19: A Retrospective Study from a Single Center Database.

BACKGROUND/AIM: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for generating a global pandemic with deadly consequences and life changes worldwide. With the appearance of the new variants of the virus, clinical manifestations have been reported in the pediatric population, some with severe evolution. The aim of this study was to identify the laboratory parameters necessary to establish an effective therapy. PATIENTS AND METHODS: In the period from August 2020 to September 2021, 234 pediatric patients met the inclusion criteria and were selected for the study. After confirming the COVID-19 diagnosis, laboratory parameters were analyzed and compared to the severity of the illness. RESULTS: Thrombocytopenia (p<0.001), leukocytosis (p<0.001), and lymphopenia (p<0.001) correlated with the severity of the disease. Also, D-dimer values were closely monitored due to the high association of this parameter with an unsatisfactory prognosis and a severe form of the disease. CONCLUSION: The D-dimer values and complete blood count are useful parameters in COVID-19 evaluation in children.

Physical, Psychological and Sexual Abuse of the Minor in the Families from the Northwestern Region of Romania- Social and Medical Forensics.

BACKGROUND: In Romania, the abuse within the family of the minor child is a widespread phenomenon, its extent is insufficiently known because of ignorance/not reporting all the existing cases. METHODS: The participants of the research are represented by two independent groups from the NW Romania 2007-2011, one for sociological study (1544 parents and 1283 children) and another for forensic statistical study (2761 cases of abused children). The sociological study was carried out by analyzing questionnaires applied in schools located in Bihor County, both to children and parents. The statistical analysis was carried out by studying the cases of the physically, sexually, and psychologically abused minors, recorded at Bihor County Forensic Service. RESULTS: Physical neglect and physical abuse are the most common forms of child abuse. The forensic analysis highlight that most of the victims are male from urban areas. Physical abuse is more common in the 16-18 age group, psychological abuse in children aged between 6-10 yr, and sexual abuse in children under the age of 14 years. Girls were subject to sexual abuse, neglect, and emotional abuse, more frequently in rural areas; boys were most often victims of exploitation, physical, and emotional abuse in both urban and rural areas. CONCLUSION: The results of the study led to the formulation of general guidelines on this phenomenon and highlight the need for proposals to improve the current situation of child abuse within the family.

Greig Cephalopolysyndactyly Contiguous Gene Syndrome: Case Report and Literature Review.

Greig cephalopolysyndactyly syndrome (GCPS) is a rare genetic disorder (about 200 cases reported), characterized by macrocephaly, hypertelorism, and polysyndactyly. Most of the reported GCPS cases are the results of heterozygous loss of function mutations affecting the GLI3 gene (OMIM# 175700), while a small proportion of cases arise from large deletions on chromosome 7p14 encompassing the GLI3 gene. To our knowledge, only 6 patients have been reported to have a deletion with an exact size (given by genomic coordinates) and a gene content larger than 1 Mb involving the GLI3 gene. This report presents a patient with Greig cephalopolysyndactyly contiguous gene syndrome (GCP-CGS) diagnosed with a large, 18 Mb deletion on chromosome 7p14.2-p11.2. Similar cases are reviewed in the literature for a more accurate comparison between genotype and phenotype.

Framing Cause-Effect Relationship of Acute Coronary Syndrome in Patients with Chronic Kidney Disease.

The main causes of death in patients with chronic kidney disease (CKD) are of cardiovascular nature. The interaction between traditional cardiovascular risk factors (CVRF) and non-traditional risk factors (RF) triggers various complex pathophysiological mechanisms that will lead to accelerated atherosclerosis in the context of decreased renal function. In terms of mortality, CKD should be considered equivalent to ischemic coronary artery disease (CAD) and properly monitored. Vascular calcification, endothelial dysfunction, oxidative stress, anemia, and inflammatory syndrome represents the main uremic RF triggered by accumulation of the uremic toxins in CKD subjects. Proteinuria that appears due to kidney function decline may initiate an inflammatory status and alteration of the coagulation-fibrinolysis systems, favorizing acute coronary syndromes (ACS) occurrence. All these factors represent potential targets for future therapy that may improve CKD patient's survival and prevention of CV events. Once installed, the CAD in CKD population is associated with negative outcome and increased mortality rate, that is the reason why discovering the complex pathophysiological connections between the two conditions and a proper control of the uremic RF are crucial and may represent the solutions for influencing the prognostic. Exclusion of CKD subjects from the important trials dealing with ACS and improper use of the therapeutical options because of the declined kidney functioned are issues that need to be surpassed. New ongoing trials with CKD subjects and platelets reactivity studies offers new perspectives for a better clinical approach and the expected results will clarify many aspects.

Unusual extramedullary relapses in a case of common B-cell acute lymphoblastic leukemia. Case report and review of literature.

BACKGROUND: Acute lymphoblastic leukemia (ALL) represents the most common malignancy in children with an overall cure rate of 85%. Relapses occur in 20% of the cases. Commonly, extramedullary relapses (EMRs) involve central nervous system (CNS) or testes. Unusual EMRs in ALL are relatively rare reported. CASE PRESENTATION: The authors present a 24-year-old woman with ALL, who experienced three unusual EMRs. In 2007, she was diagnosed with B-cell precursor (BCP)-ALL - high-risk (HR) group, and she was treated according to ALL Intercontinental Berlin-Frankfurt-Münster (IC-BFM) 2002∕HR Protocol. She entered complete remission (CR). In 2012, a vaginal wall solid mass infiltrate occurs. Biopsy concluded for EMR of ALL. Chemotherapy was restarted; the patient responded again with CR. Magnetic resonance imaging (MRI) and positron emission tomography∕computed tomography (PET∕CT) examinations during follow-up revealed supraclavicular, mesenteric, and retroperitoneal lymphadenopathies (2014). Pathological examination of the supraclavicular lymph node showed a benign pattern: schwannoma. The patient's evolution worsened, imposing a biopsy from the retroperitoneal tumor which revealed a second EMR of ALL. Again, ALL-REZ BFM 2002 Protocol was started, followed by haploidentical mother-to-child peripheral blood hematopoietic stem cell transplantation (HSCT). After suffering a few managed complications related to the transplant, our patient achieved CR again. In 2017, 10 years after the initial diagnosis, the patient presented for the third time an EMR (gastric wall) and eventually died due to progression of the disease. CONCLUSIONS: The patient presented an extremely aggressive type of ALL with three unusual EMRs: vaginal, retroperitoneal and gastric.

Effects of combining modern recovery techniques with neurotrophic medication and standard treatment in stroke patients.

Stroke is the main cause of disability after age 65, leaving survivors with sequels that require care and recovery treatment lasting years. It is estimated that by the year 2030 this pathology will be leading cause of mortality. To determine the efficacy of Lokomat training combined with neurotrophic medication and balneo-physiotherapeutic treatment in rehabilitation of post-stroke patients, a prospective study of 3 parallel groups was conducted: Group I (n = 22) - Lokomat, balneo-physiotherapy, and Cerebrolysin; Group II (n = 18) - Lokomat associated with balneo-physiotherapy; and Group III (n = 30) - balneo-physiotherapy alone (Control group). Patients were evaluated physically, neurologically, and functionally, according to the evolution of their motor deficiency, spasticity, functional independence and health-related quality of life. Patient improvement is significantly better (p < 0.05) in the group with associated therapies, especially during the first 6 months. Evolution was significantly better in all groups at 12 months than initially (p < 0.05), for all studied parameters and with the best effects in Group I (the three therapies combined). Association of Lokomat training with neurotrophic factors and classic recovery techniques improves the rehabilitation process in stroke patients.

Effects of the Hormone Replacement Therapy and of Soy Isoflavones on Bone Resorption in Postmenopause.

Postmenopausal osteoporosis is the most common form of osteoporosis and one of the major public health problems in developed countries. The prevalence of this condition, associated with the physiological stage of menopause, is continuously increasing. This study evaluated the effectiveness of soy isoflavones as compared to hormone replacement therapy (HRT) in low doses, on the prevention of postmenopausal osteoporosis, by determining bone mineral density (BMD) and urinary deoxypyridinoline (D-pyr) in physiological postmenopausal women. The study was conducted over a period of 12 months, on three parallel groups, which included a total of 325 postmenopausal women (HRT group: n = 95; phytoestrogens group: n = 124; control group: n = 106). At the one-year evaluation, we observed T-score normalization in a small number of cases (5.26%, 2.42% and 0.00%, respectively). The average values of D-Pyr decreased by 11.38% in the group treated with phytoestrogens (p < 0.05) and by 15.32% in the group that followed HRT (p < 0.05); it increased by 4.38% in the control group (p > 0.05). Both therapies have beneficial effects on bone metabolism, leading to a significant decrease in the evolution of bone resorption and there are no major differences between the efficacy of HRT and phytoestrogens in terms of the effects on BMD and bone resorption.

Double autosomal trisomy with mosaicism 47,XY(+8)∕47,XY(+21). Morphological and genetic changes of a rare case.

The co-occurrence in the same individual of two numerical chromosomal abnormalities (double aneuploidy) is a very rare condition, especially for autosomes. Clinical presentations are variable depending on the predominating aneuploidy. The authors present a rare case of a male infant with multiple congenital anomalies: craniofacial dysmorphism, short neck, agenesis of the corpus callosum, ventricular septal defect, bilateral broad hallux, large first interdigital space of the toes, plantar furrows, prominent calcaneus and right kidney agenesis. The karyotype identified 82% of mitosis with trisomy 8 (47,XY,+8) and 18% with trisomy 21 (47,XY,+21). The evolution was fatal because of eating difficulties, severe growth retardation and recurrent respiratory infections. He died at the age of five months. We report this case as a very rare double autosomal mosaicism, with a complete clinical and morphological description, as the first documented case in Romania.