Plasma levels of adipokines in patients with Alzheimer's disease - where is the "breaking point" in Alzheimer's disease pathogenesis?

Peripheral insulin resistance is associated with decreasing adiponectin and increasing leptin plasma levels, and also with cognitive decline. The effects of adipokines on brain function have been published from both animal and human studies. In particular, the influence of leptin and adiponectin on the development of Alzheimer's disease (AD) has been extensively investigated. However, the association between adipsin and AD is as yet unknown. In 37 patients with AD and 65 controls that followed the same study protocol, we tested whether adiponectin, leptin, and adipsin could be used as biomarkers in the early stages of AD. In contrast with conclusions of cognition studies in insulin resistant states, our study found a correlation of impaired neuropsychological performance with increasing adiponectin and decreasing leptin in AD patients. Nevertheless, no significant differences between patients and controls were found. AD women had significantly increased adipsin compared to controls, and there was a positive correlation of adipsin with age and disease duration. Although adipokines do not appear to be suitable biomarkers for early AD diagnosis, they certainly play a role in the pathogenesis of AD. Further studies will be needed to explain the cause of the adipokine "breaking point" that leads to the pathogenesis of overt AD.

Associations of polymorphisms in the candidate genes for Alzheimer's disease BIN1, CLU, CR1 and PICALM with gestational diabetes and impaired glucose tolerance.

Alzheimer's disease (AD) is the most common type of dementia, with a prevalence that is rising every year. AD is associated with type 2 diabetes mellitus (T2DM) and insulin resistance, and is therefore sometimes called "type 3 diabetes mellitus". The aim of this study was to examine whether the variants of some candidate genes involved in the development of AD, namely BIN1 (rs744373), CLU (rs11136000), CR1 (rs3818361), and PICALM (rs3851179), are related to several disorders of glucose metabolism-gestational diabetes (GDM), T2DM and impaired glucose tolerance (IGT). Our study included 550 women with former GDM and 717 control women, 392 patients with T2DM and 180 non-diabetic controls, and 117 patients with IGT and 630 controls with normal glucose tolerance. Genotyping analysis was performed using specially-designed TaqMan assays. No significant associations of the genetic variants rs744373 in BIN1, rs11136000 in CLU, or rs3818361 in CR1 were found with GDM, T2DM or IGT, but rs3851179 in PICALM was associated with an increased risk of GDM. The frequency of the AD risk-associated C allele was significantly higher in the GDM group compared to controls: OR 1.21; 95% CI (1.03-1.44). This finding was not apparent in T2DM and IGT; conversely, the C allele of the PICALM SNP was protective for IGT: OR 0.67; 95% CI (0.51-0.89). This study demonstrates an association between PICALM rs3851179 and GDM as well as IGT. However, elucidation of the possible role of this gene in the pathogenesis of GDM requires further independent studies.

Reduced sulfotransferase SULT2A1 activity in patients with Alzheimer's disease.

Steroids are important components in the pathophysiology of Alzheimer's disease (AD). Although their role has been studied, the corresponding metabolomic data is limited. In the present study we evaluate the role of steroid sulfotransferase SULT2A1 in the pathophysiology of AD on the basis of circulating steroids (measured by GC-MS), in which the sulfation catalyzed by SULT2A1 dominates over glucuronidation (pregnenolone/sulfate, DHEA/sulfate, androstenediol/sulfate and 5alpha-reduced pregnane and androstane catabolites). To estimate a general trend of SUL2A1 activity in AD patients we compared the ratios of steroid conjugates to their unconjugated counterparts (C/U) in controls (11 men and 22 women) and AD patients (18 men and 16 women) for individual circulating steroids after adjustment for age and BMI using ANCOVA model including the factors AD status and gender. Decreased C/U ratio for the C19 steroids demonstrate an association between attenuated sulfation of C19 steroids in adrenal zona reticularis and the pathophysiology of AD.

Transforming growth factor beta and soluble endoglin in the healthy senior and in Alzheimer's disease patients.

OBJECTIVES: Senescence of the immune system and of endothelial cells can contribute to age-dependent vascular and neurodegenerative disorders including Alzheimer's disease. The aim of this study is an assessment of putative relationships of serum levels of transforming growth factor beta (TGFß) and soluble endoglin (sCD105) and neurodegeneration, and of changes of these molecules in the course of ageing. DESIGN: The subjects of the study consisted of three groups, the first one was 63 otherwise healthy middle - aged participants, 31 females, 32 males, of average age 35 years. The second group was formed by 58 healthy, self-dependent inhabitants of nursing homes, 44 females and 14 males, average age 83.5 years. The third group comprised of 129 Alzheimer's disease patients, 86 females, 43 males, of average age 80 years, with MMSE score that ranged from 16 to 20. MEASUREMENT: Serum levels of TGF beta and soluble endoglin were measured by the ELISA method in samples of peripheral blood using commercial kits. RESULTS: The serum level of TGFß was 34,339 ± 6,420 pg/ml in the healthy younger group, 37,555 ± 11,944 pg/ml in the healthy seniors, and 29,057 ± 11,455 pg/ml in Alzheimer's disease patients. Compared to healthy seniors, the serum level of TGFß was significantly decreased in Alzheimer's disease patients (p < 0.01). The serum level of endoglin were 4.88 ± 0.95 µg/ml in the healthy younger group; 6.11 ± 1.38 µg/ml in healthy seniors, and 7.20 ± 1.72 µg/ml in patients with Alzheimer's disease, respectively. The serum level of endoglin was significantly higher (p < 0.001) in senescent healthy persons compared to the younger control group. When compared with healthy seniors, patients with Alzheimer's disease had significantly elevated (p < 0.001) serum level of endoglin. CONCLUSIONS: Decreased levels of TGF ß in Alzheimer's disease may result in impairment of cerebral circulation reflected in the increased endoglin levels. These findings may indicate involvement of the immune system in Alzheimer's disease pathogenesis.

Dignity and palliative care in dementia.

Care for patients with dementia poses multiple challenges to the caretaker, including issues concerning maintaining patient dignity. In this paper, we discuss dignity in the context of patient autonomy, self-respect and appreciation, and explore issues that relate to dignity of patients in dementia care. As patients become incapacitated by the disease, it becomes the caretaker's responsibility to assure that the patient continues to live with dignity. The uniform manifestation of dementia symptoms across individuals allows for implementation of patient-friendly activities to address their special needs and allow them to express the remaining autonomy. In advanced dementia, a beneficial long-term care outcome becomes secondary and should give way to strategies to maintain patient comfort and dignity. Although it may be challenging to stress dignity in a patient with advanced dementia, where multiple serious health problems are likely to co-exist, it remains important to realize that dignity can be, should be and must be supported, maintained and, in some situations, regained.

Angiopoietin-1, angiopoietin-2 and Tie-2 in tumour and non-tumour tissues during growth of experimental melanoma.

Tumour progression is dependent on the formation of new vessels in tumour tissue. Tumour cells produce a variety of factors that influence vessel growth and maintenance both in tumour and tumour-adjacent tissues. Angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2) and their tyrosine kinase receptor Tie-2 have been shown to play an important role in the processes of growth and remodelling of normal as well as tumour vessels. We studied gene expression of the angiogenic factors Ang-1 and Ang-2 and of their tyrosine kinase receptor Tie-2 in the tumour and non-tumour tissues of mice bearing the experimental melanoma B16. Using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR we measured Ang-1, Ang-2 and Tie-2 mRNA levels in the tumour, bone marrow, liver and spleen. Melanoma tissue overexpressed Ang-2 mRNA compared with spleen, liver and bone marrow of normal mice, suggesting its role during melanoma progression. On the other hand, there was a significant decrease in Ang-2 mRNA level in bone marrow cells collected on days 5 and 10 of tumour growth compared with the expression of Ang-2 mRNA in the bone marrow of normal mice and those collected on days 15 and 20 of tumour growth. These data demonstrate, for the first time, an ectopic effect of the tumour on the gene coding for an angiogenic factor, and also suggest that tumour growth may influence angiogenesis and/or vasculogenesis in distant organs.

Reversed-phase high-performance liquid chromatography of peptides of porcine pepsin prepared by the use of various forms of immobilized alpha-chymotrypsin.

Reversed-phase high-performance liquid chromatography (RP-HPLC) separation was used for the comparison of peptide maps of pepsin after its digestions by different forms of immobilized alpha-chymotrypsin. Porcine pepsin was hydrolysed with soluble alpha-chymotrypsin, with alpha-chymotrypsins glycosylated with lactose or galactose coupled to hydrazide derivative of cellulose, with alpha-chymotrypsin attached to poly(acrylamide-allyl glycoside) copolymer or to glycosylated hydroxyalkyl methacrylate copolymer Separon or to agarose gel Sepharose 4B. Efficiency of enzymatic protein cleavage with regard to peptide mapping of porcine pepsin has been examined by the use of alpha-chymotrypsins immobilized by different methods. Best results were achieved after hydrolysis with alpha-chymotrypsin immobilized on poly(acrylamide-allyl glycoside) copolymers. Alpha-chymotrypsin immobilized by this way has further three times higher relative specific activity in comparison with the soluble one. Modified alpha-chymotrypsin was not suitable for efficient pepsin cleavage.

Severe coagulopathy after a bite of a green bush viper (Atheris squamiger): case report and biochemical analysis of the venom.

A 34 year old male bitten by an adult Atheris squamiger snake developed symptoms of nausea, vomiting, diarrhea which were followed by drowsiness and impaired breathing. Local hemorrhage, edema and pain at the bite-site occurred, but no systemic bleeding or hemorrhagic diathesis developed. All clinical and laboratory parameters were in the normal range except for afibrinogenemia, thrombocytopenia and slight proteinuria. Replacement therapy (fibrinogen and platelet concentrates) and treatment of shock stabilized the patient within 2d and coagulation returned to normal. Atheris squamiger venom was subjected to biochemical and biological analysis. The LD50 of the venom was 5 mg/kg (mice, s.c.). It produced local hemorrhage corresponding to about 25% of the activity of puff adder venom (Bitis arietans). In vitro the venom had a fibrinogen-converting activity, it did not activate purified prothrombin but very likely contained a F V and Ca2+-dependent prothrombin activator. The venom exhibited strong platelet-aggregating activity, which was not inhibited by protease inhibitors and by EDTA or EGTA. The venom also aggregated acetylsalicylic acid treated platelets indicating, that the arachidonic acid pathway was not essential for activation. Rat serum rapidly inhibited the platelet-aggregating activity of the venom; human serum, however, had only a partial inhibitory effect. Preliminary experiments showed that platelet-aggregating activity may be separated from fibrinogen-converting activity by anion-exchange chromatography.