Impaired platelet activation in familial high density lipoprotein deficiency (Tangier disease)

ATP binding cassette transporter A1 (ABCA1) is involved in regulation of intracellular lipid trafficking and export of cholesterol from cells to high density lipoproteins. ABCA1 defects cause Tangier disease, a disorder characterized by absence of high density lipoprotein and thrombocytopenia. In the present study we have demonstrated that ABCA1 is expressed in human platelets and that fibrinogen binding and CD62 surface expression in response to collagen and low concentrations of thrombin, but not to ADP, are defective in platelets from Tangier patients and ABCA1-deficient animals. The expression of platelet membrane receptors such as GPVI, alpha2beta1 integrin, and GPIIb/IIIa, the collagen-induced changes in phosphatidylserine and cholesterol distribution, and the collagen-induced signal transduction examined by phosphorylation of LAT and p72syk and by intracellular Ca2+ mobilization were unaltered in Tangier platelets. The electron microscopy of Tangier platelets revealed reduced numbers of dense bodies and the presence of giant granules typically encountered in platelets from Chediak-Higashi syndrome. Further studies demonstrated impaired release of dense body content in platelets from Tangier patients and ABCA1-deficient animals. In addition, Tangier platelets were characterized by defective surface exposure of dense body and lysosomal markers (CD63, LAMP-1, LAMP-2, CD68) during collagen- and thrombin-induced stimulation and by abnormally high lysosomal pH. We conclude that intact ABCA1 function is necessary for proper maturation of dense bodies in platelets. The impaired release of the content of dense bodies may explain the defective activation of Tangier platelets by collagen and low concentrations of thrombin, but not by ADP.     

Urban and rural differences in mortality and causes of death in historical Poland

The purpose of this paper is to document and interpret urban-rural differences in mortality in the past. To this end, we used data on mortality in Wielkopolska, Poland, in the 19th century and at the beginning of the 20th century. The data on mortality in rural areas (N = 1,173,910 deceased), small towns (N = 573,903 deceased), and Poznań, the capital of the Wielkopolska region (N = 86,352 deceased), were gathered from original Prussian statistical yearbooks (Preussische Statistik). Causes of death were also analyzed (rural areas, N = 449,576 deceased; small towns, N = 238,365 deceased; Poznań, N = 61,512 deceased). Mortality measures such as crude death rate (CDR), infant death rate (IDR), and neonatal and postneonatal death rates were calculated. Life tables were constructed for both stationary and stable population models and measures of the opportunity for natural selection calculated (Crow's index I(m), potential gross reproduction rate R(pot), and biological state index I(bs)). Relative frequencies of leading causes of death were computed. Stratification depending on the place of residence was evident in all mortality measures as well as in the values of the life tables and the measures of the opportunity for natural selection, but it was reverse of what is observed today in developed countries. In Poznań (a large industrial city), the mortality situation was the least favorable. It was caused by large population density, lack of water supply and sewage systems (up to 1896), and bad working conditions. The values of CDR ranged between 26.89-31.46, and IDR between 190.6-280.5. Newborn life expectancy (for a stable population model) was 31.6 years, I(m) = 0.79, R(pot) = 0.85, and I(bs) = 0.47. The most common causes of death were tuberculosis, other diseases of the respiratory and circulatory systems, dysentery and diarrhea, and cancer. These diseases were less common in rural areas, so they had the most favorable values of mortality measures (CDR between 22.87-27.32, IDR between 181.8-219.4, life expectancy of newborn e(0) = 42.12, I(m) = 0.55, R(pot) = 0.93, I(bs) = 0.60). Infectious diseases (other than tuberculosis), frailty at birth, and frailty in old age were the most frequent causes of death in rural areas. Small towns (population <20,000) had a mortality intermediate between city and rural areas.     

Application of biochemical markers for identification of biological properties of animal semen

The use of biochemical markers for identification of biological properties of semen will help to develop new criteria that are accurate and objective in predicting and improving male fertility. Understanding and controlling the mechanisms involved in fertility is a key challenge, which is of fundamental importance in successful animal reproductive performance. Moreover, unraveling the unique molecular mechanism associated with sperm function might have considerable diagnostic value in the evaluation of male infertility. This review offered insights into some recent achievements and provided perspectives for possible applications of the biochemical markers of semen.     

Curcumin affects components of the chromosomal passenger complex and induces mitotic catastrophe in apoptosis-resistant Bcr-Abl-expressing cells

The Bcr-Abl oncoprotein plays a major role in the development and progression of chronic myeloid leukemia and is a determinant of chemotherapy resistance occurring during the blast crisis phase of the disease. The aim of this article was to investigate the possibility of combating the resistance to apoptosis caused by Bcr-Abl by inducing an alternative cell death process. As a model of chronic myeloid leukemia, we employed Bcr-Abl-transfected mouse progenitor 32D cells with low and high Bcr-Abl expression levels corresponding to drug-sensitive and drug-resistant cells, respectively. The drug curcumin (diferuloylmethane), a known potent inducer of cell death in many cancer cells, was investigated for efficacy with Bcr-Abl-expressing cells. Curcumin strongly inhibited cell proliferation and affected cell viability by inducing apoptotic symptoms in all tested cells; however, apoptosis was a relatively late event. G(2)-M cell cycle arrest, together with increased mitotic index and cellular and nuclear morphology resembling those described for mitotic catastrophe, was observed and preceded caspase-3 activation and DNA fragmentation. Mitosis-arrested cells displayed abnormal chromatin organization, multipolar chromosome segregation, aberrant cytokinesis, and multinucleated cells-morphologic changes typical of mitotic catastrophe. We found that the mitotic cell death symptoms correlated with attenuated expression of survivin, a member of the chromosomal passenger complex, and mislocalization of Aurora B, the partner of survivin in the chromosomal passenger complex. Inhibition of survivin expression with small interfering RNA exhibited similar mitotic disturbances, thus implicating survivin as a major, albeit not the only, target for curcumin action. This study shows that curcumin can overcome the broad resistance to cell death caused by expression of Bcr-Abl and suggests that curcumin may be a promising agent for new combination regimens for drug-resistant chronic myeloid leukemia.     

Evaluation of genetic biodiversity in farm-bred and wild raccoon dogs in Poland

The aim of the study was to analyze the intra- and inter-group diversity in farm-raised and wild raccoon dogs with the use of molecular markers. Genetic differences between the particular raccoon dog groups were observed, accompanied by a relatively high intra-group genetic variation. It was noted that the wild raccoon dogs were characterized by the highest genetic diversity, compared to the three study groups of farm-bred raccoon dogs. Wild raccoon dogs and farm-bred raccoon dogs constitute separate phylogenetic groups. The results obtained suggest that farm breeding may lead to differentiation into a different phylogenetic lineage than that of the wild raccoon dogs. In each case, the genetic distance between the animals bred on the individual farms was lower than the distances between the farm-raised and wild animals. Since the Polish farm breeding is based entirely on phenotype ranking, the genotype of "native" animals is still closely related to that of wild animals.     

Brain-derived heat shock protein 70-peptide complexes induce NK cell-dependent tolerance to experimental autoimmune encephalomyelitis

Heat shock proteins (Hsp) are markedly up-regulated at sites of inflammation during autoimmune diseases like experimental autoimmune encephalomyelitis (EAE). In this study, we show that Hsp70-peptide complexes (pc) isolated from brains of mice with EAE prevented the development of EAE clinically and pathologically when administered before proteolipid protein 139-151 (PLP139-151) immunization. In contrast, pure Hsp70 or Hsp70-pc derived from brains of healthy mice or other inflamed tissue did not modulate the expression of EAE. In animals in which EAE had been suppressed by Hsp70-pc, lymphocytes showed increased cell death in response to PLP139-151 that correlated with elevated IFN-gamma and NO production. Coculture of spleen cells from Hsp70-pc immunized mice with spleen cells from untreated EAE mice, in addition to depletion experiments, showed that NK cells reduced reactivity to PLP139-151. Transfer of NK cells from Hsp70-pc-immunized mice to recipients sensitized for EAE abolished disease development. Thus, we propose that Hsp70 demonstrate the ability to bind to peptides generated during brain inflammation and to induce a regulatory NK cell population that is capable of preventing subsequent autoimmunization for EAE.     

Effects of acute hyperosmolality on blood-brain barrier function in ovine fetuses and lambs

We examined the effects of hyperosmolality on blood-brain barrier (BBB) permeability during development to test the vulnerability of the immature barrier to stress. The BBB response to hyperosmolality was quantified using the blood-to-brain transfer constant (Ki) with alpha-aminoisobutyric acid in fetuses at 60% and 90% gestation, premature, newborn, and older lambs. Ki plotted against osmolality increased as a function of increases in osmolality in all groups and brain regions. The relationship was described (P < 0.05) by a segmented regression model. At lower osmolalities, changes in Ki were minimal, but after a break point (threshold) was reached, the increase (P < 0.05) was linear. We examined the responses of Ki to hyperosmolality within each brain region by comparing the thresholds and slopes of the second regression segment. Lower thresholds and higher slopes imply greater vulnerability to hyperosmolality in the younger groups. Thresholds increased (P < 0.05) with development in the thalamus, superior colliculus, pons, and spinal cord, and slopes of the second regression segment decreased (P < 0.05) in the cerebellum, hippocampus, inferior colliculus, medulla, and spinal cord. BBB resistance to hyperosmolality increased (P < 0.05) with development in most brain regions. The pattern of the Ki plotted against osmolality was (P < 0.05) heterogenous among brain regions in fetuses and premature and newborn lambs, but not in older lambs. We conclude that 1) BBB permeability increased as a function of changes in osmolality, 2) the barrier becomes more resistant to hyperosmolality during development, and 3) the permeability response to hyperosmolality is heterogenous among brain regions in fetuses and premature and newborn lambs.