Advanced molecular approaches in male infertility diagnosis†.

In the recent years a special attention has been given to a major health concern namely to male infertility, defined as the inability to conceive after 12 months of regular unprotected sexual intercourse, taken into account the statistics that highlight that sperm counts have dropped by 50-60% in recent decades. According to the WHO, infertility affects approximately 9% of couples globally, and the male factor is believed to be present in roughly 50% of cases, with exclusive responsibility in 30%. The aim of this article is to present an evidence-based approach for diagnosing male infertility that includes finding new solutions for diagnosis and critical outcomes, retrieving up-to-date studies and existing guidelines. The diverse factors that induce male infertility generated in a vast amount of data that needed to be analyzed by a clinician before a decision could be made for each individual. Modern medicine faces numerous obstacles as a result of the massive amount of data generated by the molecular biology discipline. To address complex clinical problems, vast data must be collected, analyzed, and used, which can be very challenging. The use of artificial intelligence (AI) methods to create a decision support system can help predict the diagnosis and guide treatment for infertile men, based on analysis of different data as environmental and lifestyle, clinical (sperm count, morphology, hormone testing, karyotype, etc.), and "omics" bigdata. Ultimately, the development of AI algorithms will assist clinicians in formulating diagnosis, making treatment decisions, and predicting outcomes for assisted reproduction techniques.

Plasma CXCL10 correlates with HAND in HIV-infected women.

HIV-associated neurocognitive disorder (HAND) is characterized by chronic immune activation. We aimed to identify biomarkers associated with HAND and to investigate their association with cognitive function and sex, in a homogenous cohort of HIV-infected (HIV+) young adults, parenterally infected during early childhood. One hundred forty-four HIV+ Romanian participants (51% women) without major confounders underwent standardized neurocognitive and medical evaluation in a cross-sectional study. IFN-γ, IL-1ß, IL-6, CCL2, CXCL8, CXCL10, and TNF-α were measured in plasma in all participants and in cerebrospinal fluid (CSF) in a subgroup of 56 study participants. Biomarkers were compared with neurocognitive outcomes, and the influence of sex and HIV disease biomarkers was assessed. In this cohort of young adults (median age of 24 years), the rate of neurocognitive impairment (NCI) was 36.1%. Median current CD4+ count was 479 cells/mm3 and 36.8% had detectable plasma viral load. Women had better HIV-associated overall status. In plasma, controlling for sex, higher levels of IL-6 and TNF-α were associated with NCI (p < 0.05). Plasma CXCL10 showed a significant interaction with sex (p = 0.02); higher values were associated with NCI in women only (p = 0.02). Individuals with undetectable viral load had significantly lower plasma CXCL10 (p < 0.001) and CCL2 (p = 0.02) levels, and CSF CXCL10 (p = 0.01), IL-6 (p = 0.04), and TNF-α (p = 0.04) levels. NCI in young men and women living with HIV was associated with higher IL-6 and TNF-α in plasma, but not in the CSF. CXCL10 was identified as a biomarker of NCI specifically in women with chronic HIV infection.

May inflammatory markers be used for monitoring the continuous positive airway pressure effect in patients with obstructive sleep apnea and arrhythmias?

INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) is defined by recurrent episodes of significant reduction or absence of the oro-nasal airflow during sleep, in the presence of thorax and abdominal movements and snoring. The pathophysiological consequences of intermittent hypoxia determined by OSAS are represented by systemic inflammation, the release of free oxygen radicals and activation of the sympathetic nervous system. Cardiac arrhythmias are a frequent comorbidity in patients with OSAS. HYPOTHESIS: We hypothesized that the continuous positive airway pressure (CPAP) therapy has an effect on inflammatory markers (erythrocyte sedimentation rate, fibrinogen, and red cell distribution width) in patients with OSAS and cardiac arrhythmias. EVALUATION OF THE HYPOTHESIS: We tested this hypothesis on 52 patients diagnosed with OSAS and cardiac arrhythmias, divided into two groups: group A (patients who received CPAP therapy and pharmacological therapy) and group B (only pharmacological therapy). The patients were evaluated at enrollment (T0), at 3 and 6 months. We did not find a statistically significant difference of erythrocyte sedimentation rate (ESR) and fibrinogen levels between the two groups. Regarding the red cell distribution width (RDW), the CPAP treatment seems to have improved the RDW values in patients who received this treatment. Also, in patients from group A, a significant decrease in the average heart rate was noticed after 3 months. CONSEQUENCES: Fibrinogen and ESR cannot be used for monitoring the CPAP therapy in patients with OSAS and arrhythmias. Instead, the beneficial effect of CPAP in patients with OSAS and cardiac arrhythmias can be monitored with the help of the RDW, which could also be used for evaluating the cardiovascular risk in patients with OSAS and arrhythmias.

Atrial septal defect in an elderly woman-a case report.

RATIONALE: The atrial septal defect is one of the most common congenital anomalies in adults, but it is rarely diagnosed. It is characterized by a defect in the interatrial septum that allows pulmonary venous return to pass from the left to the right atrium. OBJECTIVE: A case of a 75-year-old female who presented with dyspnea, orthopnea, lower extremities swelling and palpitations is reported here. She had a 3 years history of atrial fibrillation and one-year history of cardiac failure NYHA (New York Heart Association) class Ⅱ. METHODS AND RESULTS: Transthoracic echocardiography revealed a dilated right atrium of 74,2 mm, a dilated left atrium of 55,2 mm, a dilated left ventricle of 64/72,3 mm, a dilated right ventricle of 44,4 mm. Atrial septal defect ostium secundum type, with left-to-right shunt. Severe tricuspid insufficiency with a maximum gradient of 55,4 mm Hg. 4th degree mitral insufficiency. Severe pulmonary hypertension of 75 mm Hg. The ejection fraction of 29%. Atrial fibrillation. Interventricular sept with paradoxical motion. DISCUSSION: Ostium secundum defect is the most common type of atrial septal defect and accounts for 60-70% of all cases. The malformation often goes unnoticed for decades because symptoms may be absent and because physical signs are subtle. Symptoms usually take 30-40 years to develop. They are the consequences of pulmonary hypertension, atrial tachyarrhythmias and, sometimes, associated mitral valve disease. The echocardiography can establish the size and location of the atrial septal defect, the magnitude and hemodynamic impact of the left-to-right shunt, and the presence and degree of pulmonary hypertension. The particularity of this case is that the patient lived for over 70 years almost asymptomatic.

Left atrial thrombus: a case report.

RATIONALE: Echocardiography is essential in establishing the diagnosis in patients with cardiac masses. The differentiation between myxomas and thrombi is sometimes difficult, but is critical in making the right therapeutical decision. OBJECTIVE: A 70-year-old female presented to the Emergency Department with palpitations, dyspnea and anterior epistaxis. She had a 3 years history of atrial fibrillation and chronic heart failure NYHA class III. METHOD AND RESULT: Two-dimensional transthoracic echocardiography showed the thickening of the mitral valves with moderate mitral insufficiency and a mobile round mass in the left atrium, heterogeneous, inhomogeneous, 18 mm in size, attached with a narrow stalk to the interatrial septum, reaching mitral annular plane; tricuspid insufficiency with a maximum 30 mmHg gradient, intact interatrial septum, akinesia of two thirds of basal inferior wall, 42% ejection fraction. DISCUSSION: The two-dimensional transesophageal echocardiography confirmed the intraatrial mass. Epistaxis was considered to be due to heart failure and the increased venous pressure. The patient was referred to the cardiovascular surgery clinic, but refused surgery. Anticoagulation with fraxiparine 0,6 ml/day was started and continued for 3 weeks, after cessation of epistaxis by nasal tamponament. Then echocardiography was repeated, with no remnant mass in the left atrium. The conclusion was that the mass must have been a thrombus that has melted away. In this particular case, the left intraatrial thrombus may have been due to the presence of atrial fibrillation.

JAK2, the JAK2 V617F mutant and cytokine receptors.

Recently, a unique recurrent somatic mutation was identified as a major molecular event in polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis. Expression of this mutant in cytokine-dependent hematopoietic cell lines induces autonomous growth. This effect is enhanced by overexpression of cytokine receptors, and can be inhibited by co-expression at higher levels of the wild type JAK2, which may compete for a limited pool of receptors. In JAK2-deficient cells, we showed that JAK2 V617F can transmit signals from ligand-activated TpoR or EpoR. Furthermore, the mutant JAK2 can be demonstrated to stimulate traffic of the EpoR. Thus, JAK2 V617F mutant must be able to interact via its intact FERM-SH2 domains with the cytosolic domains of cytokine receptors. A synergy between JAK2 V617F and insulin-like growth factor 1 receptor (IGF1R) can be detected in cytokine-dependent cell proliferation. Once cells are rendered autonomous by expression of JAK2 V617F, IGF1 acquires the ability to activate the JAK-STAT pathway. Thus, expression of JAK2 V617F may explain the described hypersensitivity of PV erythroid progenitors to IGF1. The V617 is conserved in two other mammalian JAKs, JAK1 and Tyk2. The homologous mutants JAK1 V658F and Tyk2 V678F are also active in proliferation and transcriptional assays. Such mutants may be found in human cancers or autoimmune diseases. In contrast, the JAK3 M592F does not lead to activation of JAK3. Current hypotheses on how JAK2 V617F contributes to three myeloproliferative diseases, and which other events may favor one disease versus another, are discussed.

Phagocytic function of monocytes in children with human immunodeficiency virus type 1 infection.

We investigated the phagocytic function of monocytes in 7- to 10-year-old children horizontally infected with human immunodeficiency virus type 1 (HIV-1) in comparison to that in healthy sex- and age-matched controls. CR3-mediated phagocytosis was increased in patients with HIV-associated pulmonary tuberculosis, independently of CD4 counts and p24 antigenemia.

Apoptosis is induced in both drug-sensitive and multidrug-resistant hepatoma cells by somatostatin analogue TT-232.

Clinical resistance to chemotherapeutic drugs is an important problem in the treatment of cancer; the circumvention of resistance has become one of the basic goals of cancer therapy. The most frequent form of primary liver cancer is hepatocellular carcinoma, which is essentially refractory to chemotherapy. We earlier showed that TT-232, a new somatostatin analogue developed in our laboratory, exerted a strong antiproliferative effect both in vitro and in vivo, but no growth hormone release inhibitory or antisecretory activity. Here we report that TT-232 has a pronounced antiproliferative effect on differentiated and dedifferentiated, drug-sensitive and multidrug-resistant hepatocellular carcinoma cell lines. TT-232 induces apoptosis at comparable levels in all these hepatoma variants demonstrating that the multidrug resistance of hepatomas does not correlate with a reduced susceptibility to apoptosis induction. These results clearly reveal that the machinery involved in apoptosis is functional in both drug-sensitive and resistant hepatoma variants and can be activated by the somatostatin analogue TT-232.

Dynamics of the HIV-1 variability in adults from Bucharest, 1992-1998.

Variability is a hallmark of HIV viruses both at the genetic and the phenotypic level. Viral sequencing and phylogenetic analysis of many isolates revealed specific distribution of HIV-1 subtypes according to the geographic location and route of transmission. In Romania, the currently available data coming from the study of pediatric HIV infection suggest the predominance of subtype F. However, there are few data concerning the distribution of HIV-1 subtypes among adults. We investigated the changes in the distribution of different HIV-1 subtypes among HIV-1 infected adult patients from Bucharest over a 6 years period (1992-1998) by means of V3 binding assays. The analysis of the relative incidence of different HIV-1 serotypes revealed the steady predominance of serotype F (50-75%) among the adults from Bucharest and a small but constant increase of the number of samples with serotype B- from 5% in 1994 to 14% in 1998. In contrast, the serotype E is either absent or weakly represented (4%) during the period of the study. All over the years there was a relatively high proportion (6-30%) of non-reactive samples. This could be an indication for the possible emergence of new or recombinant HIV-1 subtypes.