HIV‑1 molecular epidemiology in the Balkans: a melting pot for high genetic diversity

The Balkans is a gateway between Europe, Asia, and the African continent, a fact with potential important consequences on the epidemiology of HIV?1 infection in the region. The duration of the HIV?1 epidemics in many countries of the Balkans is similar to the one in the Western European countries. However, striking differences exist in several countries of the region in both the epidemic situation and, even more so, in our knowledge about it. In particular, the molecular epidemiology of HIV in the Balkans is largely unknown. In order to gain some preliminary insight into HIV?1 diversity in the region, we reviewed the available molecular epidemiology data about HIV?1 diversity in 10 countries of the region: Albania, Bulgaria, Croatia, Greece, Montenegro, Romania, Slovenia, Serbia, Turkey, and Hungary, a neighboring country to four Balkan countries. The data were obtained either from published studies or in direct communication with the participating members. The existing molecular epidemiology data revealed a broad diversity in subtype distribution among Balkan countries. In several countries, subtype B is predominant (e.g. Serbia, Slovenia, and Hungary), while in others the proportion of non?B subtypes is much larger (Albania subtype A, Romania subtype F). In some areas, HIV?1 subtype distribution is marked by divergence between different risk groups or transmission routes (e.g. Croatia). Recently, HIV?1/AIDS epidemics in Eastern Europe have been among the fastest growing in the world. Many major contributing factors for the breakout and spread of these epidemics are present in many of the Balkan countries, as reflected through the process of social transition, wars, unemployment, extensive drug use, high sexual risk behavior, as well as other factors. Yet, in the Balkan countries the prevalence rate of HIV?1 infection is low, under 0.1 percent. Concomitantly, the molecular epidemiology of HIV?1 in the Balkans has not been thoroughly studied so far. The review and analysis of the available data indicate a broad diversity of circulating HIV?1 subtypes in the region, with the predominance of non?B clades in some countries, underscoring the need for an ongoing surveillance of HIV?1 diversity. The setup of a collaborative network might provide important information for the better management and control of the HIV?1 epidemic in the area.     

Immunolocalization of nestin, mesothelin and epithelial membrane antigen (EMA) in developing and adult serous membranes and mesotheliomas

The spatial and temporal distribution of epithelial membrane antigen (EMA), mesothelin and nestin was immunohistochemically analyzed in developing and adult human serous membranes and mesotheliomas in order to detect possible differences in the course of mesenchymal to epithelial transformation, which is associated with differentiation of mesothelial cells during normal development and tumorigenesis. Pleura and pericardium developing from the visceral mesoderm gradually transform into mesothelial cells and connective tissue. EMA appeared in mesothelium of both serous membranes during the early fetal period, whereas during further development, EMA expression was retained only in the pericardial mesothelium. It increased in both pleural mesothelium and connective tissue. Mesothelin appeared first in pericardial submesothelial cells and later in surface mesothelium, while in pleura it was immediately localized in mesothelium. In adult serous membranes, EMA and mesothelin were predominantly expressed in mesothelium. Nestin never appeared in mesothelium, but in connective tissues and myocardial cells and subsequently decreased during development, apart from in the walls of blood vessels. Mesothelial cells in the two serous membranes developed in two separate developmental pathways. We speculate that submesothelial pericardial and mesothelial pleural cells might belong to a population of stem cells. In epithelioid mesotheliomas, 13% of cells expressed nestin, 39% EMA and 7% mesothelin.     

Ovarian follicular concentration of IL-12, IL-15, IL-18 and p40 subunit of IL-12 and IL-23

BACKGROUND: The aim of the study was to determine the presence of interleukin (IL)-12, IL-15, IL-18 and p40 subunit of IL-12/IL-23 in follicular fluid from spontaneous cycles and the relation between the concentration of selected cytokines and IVF-embryo transfer outcome. METHODS: IVF-embryo transfer and enzyme immunoassay (EIA) (R&D Systems, Minneapolis, MN, USA and MBL, Nagoya, Japan) were used. RESULTS: Follicular fluid of women included in the IVF-embryo transfer procedure contained common p40 subunit of IL-12/IL-23 (median 70.1 pg/ml), IL-15 (median 1.3 pg/ml) and IL-18 (median 38.2 pg/ml). There was a significant negative correlation between follicular fluid concentrations of IL-15 and IL-18 (R=-0.392, P=0.003). Significantly higher concentrations of common p40 subunit of IL-12/IL-23 (median 79.8 pg/ml) were found in the follicular fluid taken from follicles containing oocytes, when compared with those without an oocyte (median 44.5 pg/ml, P=0.006). Patients who achieved clinical pregnancy had significantly decreased concentration of IL-15 (median 0.8 pg/ml) compared with patients without successful IVF-embryo transfer outcome (median 1.4 pg/ml, P=0.047). CONCLUSION: Follicular fluid collected from spontaneous cycles contains detectable levels of p40 subunit of IL-12/IL-23, IL-15 and IL-18. Increased concentrations of p40 subunit of IL-12/IL-23 in follicles containing oocytes suggest an important role of this cytokine in reproduction. Possible negative value of IL-15 as a predictor of IVF-embryo transfer success remains to be determined.     

Molecular aspects of apoptosis

Corresponding to its importance in cell count homeostasis in the body, apoptosis is a tightly regulated phenomenon. Both extracellular and intracellular molecules provide multiple regulatory and counter-regulatory pathways. Cell death is usually a response to the cell microenvironment, where the absence of certain factors (survival factors) or the presence of lethal factors promotes apoptosis. Surrounding cells, soluble mediators and the extracellular matrix regulate cell death and survival. Surrounding cells can synthesize survival or lethal factors. The intracellular regulation of apoptosis is also one of the forefront fields in biomedicine research. During the past five years, tremendous progress has been made in understanding apoptosis as a result of molecular identification of the key components of this intracellular suicide program. Biochemical activation of these key components of the cell death program is responsible for the morphological changes observed in apoptosis, including mitochondrial damage, nuclear membrane breakdown, DNA fragmentation, chromatin condensation and the formation of apoptotic bodies. Caspase activation plays a central role in the execution of apoptosis. Most caspases are constitutively expressed as inactive proenzymes (procaspases) in the cytosol and according to some reports in the mitohondria. Caspases are sequentially activated by proteolysis during apoptosis. In this review, we focus on the biochemical pathways that control caspase activation, particularly the activation pathways that are initiated by cell surface death receptors and mitochondria.     

The superficial ulnar artery originating from the left brachial artery

An anomalous superficial ulnar artery was found in the left arm of a 60-year-old man during anatomical dissection. It originated from the brachial artery approximately 6 cm distally to profound brachial artery. It crossed over the median nerve and coursed ventral to the nerve, but inferior to the bicipital aponeurosis and superficial to the flexor muscles. At the palm, it formed the superficial and deep palmar arches together with the branches of the radial artery. The clinical importance of the anomalous ulnar artery is discussed.     

The Emergence of SARS-CoV-2 within the Dog Population in Croatia: Host Factors and Clinical Outcome

Over a year into the COVID-19 pandemic, there is growing evidence that SARS-CoV-2 infections among dogs are more common than previously thought. In this study, the prevalence of SARS-CoV-2 antibodies was investigated in two dog populations. The first group was comprised of 1069 dogs admitted to the Veterinary Teaching Hospital for any given reason. The second group included dogs that shared households with confirmed COVID-19 cases in humans. This study group numbered 78 dogs. In COVID-19 infected households, 43.9% tested ELISA positive, and neutralising antibodies were detected in 25.64% of dogs. Those data are comparable with the secondary attack rate in the human population. With 14.69% of dogs in the general population testing ELISA positive, there was a surge of SARS-CoV-2 infections within the dog population amid the second wave of the pandemic. Noticeably seroprevalence of SARS-CoV-2 in the dog and the human population did not differ at the end of the study period. Male sex, breed and age were identified as significant risk factors. This study gives strong evidence that while acute dog infections are mostly asymptomatic, they can pose a significant risk to dog health. Due to the retrospective nature of this study, samples for viral isolation and PCR were unavailable. Still, seropositive dogs had a 1.97 times greater risk for developing central nervous symptoms.     

Peaceful use of disastrous neurotoxicants

The increasing exposure to environmental neurotoxicants in the last decades caused serious health problems in the world population. Some of the neurotoxic agents are being used in agriculture and household such as insecticides and rodenticides and others are of natural origin like snake and scorpion venoms. Additional group of harmful substances is the chemical warfare agents including nerve and blistering agents that are known for their disastrous effects on neuronal tissues. The present paper presents a combination of epidemiological/clinical and molecular approaches for investigating the effect of certain groups of neurotoxicants on a variety of pathologies.The work of Finkelstein and coworkers describes epidemiological and clinical studies on acute and chronic organophosphate (OP)-induced neurotoxicity in certain populations in Israel. They mainly investigated the neurotoxic effects of low-level long-term exposure to OP in agricultural areas but also dealt with acute exposures as well. A molecular approach to OP mechanism of neuronal injury was described by Milatovic and coworkers. They demonstrated OP-induced oxidative injury in pyramidal neurons in the CA1 hippocampal area and its suppression by antioxidants. Lecht and coworkers described the novel snake venom angioneurins as important mediators of the physiological cross-talk between the cardiovascular and nervous systems. They also showed that under certain conditions these angioneurins may induce pathologies such as tumor development or disruption of the vascular barrier function during envenomation. Additional mechanistic/therapeutic approach was presented by Brodsky, Rosengarten, Proscura, Shapira and Wormser. They developed a novel anti-inflammatory peptide that reduced skin irritation induced by heat and sulfur mustard (SM) stimuli. Since SM causes neuropsychiatric symptoms and alterations in neurological functions this peptide may serve as a potential treatment of neuronal injuries caused by environmental neurotoxicants.These reviews highlight different aspects of neurotoxicity, addressing epidemiology and mechanisms of toxicity; and identifying novel potential therapies.     

Driver mutations determine survival in smokers and never‐smokers with stage IIIB/IV lung adenocarcinomas

BACKGROUND:

The authors previously demonstrated that never‐smokers with stage IIIB/IV nonsmall cell lung cancer (NSCLC) lived 50% longer than former/current smokers. This observation persisted after adjusting for age, performance status, and sex. In this study, the authors hypothesized that smoking‐dependent differences in the distribution of driver mutations may explain differences in prognosis between these subgroups.

METHODS:

In total, 293 never‐smokers and 382 former/current smokers with lung adenocarcinoma who underwent testing for epidermal growth factor receptor (EGFR) mutations and v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and rearrangements in anaplastic lymphoma kinase (ALK) between 2009 and 2010 were investigated. Clinical outcomes and patient characteristics were collected. Survival probabilities were estimated using the Kaplan‐Meier method. Group comparison was performed with log‐rank tests and Cox proportional hazards methods.

RESULTS:

Although the overall incidence of these mutations was nearly identical (55% never‐smokers vs 57% current/former smokers; P = .48), there were significant differences in the distribution of mutations between these groups for EGFR mutations (37% never‐smokers vs 14% former/current smokers; P < .0001), KRAS mutations (4% never‐smokers vs 43% former/current smokers; P < .0001), and ALK rearrangements (12% never‐smokers vs 2% former/current smokers; P < .0001). Among never‐smokers and former/current smokers, the prognosis differed significantly by genotype. Patients who had KRAS mutations had the poorest survival. Smoking status, however, had no influence on survival within each genotype.

CONCLUSIONS:

Never‐smokers and former/current smokers with lung adenocarcinomas were not homogeneous subgroups. Each was made up of individuals whose tumors had a unique distribution of driver mutations, which were associated with different prognoses, irrespective of smoking history. Cancer 2012. © 2012 American Cancer Society.