Cholesterol metabolism differs after statin therapy according to the type of hyperlipemia

AimNon-cholesterol sterols reflect cholesterol metabolism. Statins reduce cholesterol synthesis usually with a rise in cholesterol absorption. Common hyperlipemias have shown different patterns of cholesterol metabolism. We evaluated whether cholesterol absorption and synthesis may differ after statin therapy in primary hyperlipemias.Main methodsWe determined lipid profile, apoprotein B and serum sterols (lathosterol, sitosterol, campesterol by gas chromatography/mass spectrometry) before and after statins in 80 untreated hyperlipemic patients, 40 with polygenic hypercholesterolemia (PH) and 40 with familial combined hyperlipemia (FCH).Key findingsAt baseline in FCH lathosterol was significantly higher while campesterol and sitosterol were significantly lower than in PH. After statins, the reduction in LDL-C did not significantly differ between the two groups; in PH there was a significant decrease of lathosterol from 96.1 to 52.6 102 μmol/mmol cholesterol (p = 0.0001) with no significant modifications in campesterol and sitosterol; on the opposite, in FCH lathosterol decreased from 117 to 43 102 μmol/mmol cholesterol (p = 0.0001) and campesterol and sitosterol significantly increased from 38 to 48 102 μmol/mmol cholesterol (p = 0.0001), and from 75 to 86 102 μmol/mmol cholesterol, (p = 0.022), respectively. After statin therapy only in FCH Δ-LDL-C showed a significant inverse correlation with Δ-sitosterol and with Δ-campesterol.SignificancePrimary hyperlipemias show different patterns of response to statins: in PH LDL reduction appears completely “synthesis inhibition” dependent, while in FCH LDL decrease appears to be synthesis dependent, partially limited by absorption increase. Studying cholesterol metabolism before and after hypolipemic therapy might be useful in identifying the best tailored treatment.     

In situ and laboratory assessment of heart rate in a Mediterranean limpet using a noninvasive technique

Heart rate of the Mediterranean limpet Patella caerulea L. was investigated on the natural shore and in the laboratory by using a technique based on infrared phototransducers. Field recording occurred in the Gulf of Trieste (northern Adriatic) during March and June 1997. A consistent dependence of heart rate on temperature was observed in limpets both when submerged and when exposed to air in the two periods, but thermal acclimation was evident. During spontaneous activity at high tide, heart rate increased 1.5-1.7 times the values observed during resting in water at corresponding temperatures. The dependence of heart rate on temperature (10 degrees, 16 degrees, and 22 degrees C) and size (wet weight <1.25 and >1.30 g) in submerged limpets from different populations (northern Adriatic and Tyrrhenian) was tested in the laboratory by adopting a factorial design. The results showed a marked effect of temperature, body weight, and their interaction, independent from the site of origin. Smaller limpets showed a linear increase of heart rate in the whole range of temperature tests, while in the larger ones the increase between 10 degrees and 16 degrees C was greater than between 16 degrees and 22 degrees C. Heart rate decreased with increasing body size at control (16 degrees C) and high (22 degrees C) temperature, while at lower temperature (10 degrees C) no effect of body size was evident. When removed from their home scar, limpets increased heart rate to about 1.5 times the reference value. Finally, correlation of oxygen consumption with heart rate of submerged limpets maintained at a different temperature (10 degrees -22 degrees C) was statistically significant.     

Cardiac responses to salinity variations in two differently zoned Mediterranean limpets

Cardiac activity of two Mediterranean limpets was tested at different salinities. Patella caerulea inhabits the lower midlittoral where it is exposed to variations in salinity, while P. aspera experiences more stable salinity conditions in the infralittoral fringe. When exposed to moderate hypo- and hypersalinity (23 g l⁻¹ and 43 g l⁻¹) for 24 min, P. caerulea showed no significant variation in heart rate with respect to the control salinity (33 g l⁻¹), while P. aspera exhibited a significant increase in heart rate in both conditions. This suggests a rise in metabolic rate due to activation of behavioural responses or physiological regulation. When exposed to extremely low salinity (3 g l⁻¹) for 24 min, heart contractions ceased in most specimens of P. caerulea. A smaller number of specimens also displayed cessation of heart beat when exposed to extremely high salinity (63 g l⁻¹). The heart beat resumed quickly in all specimens when they were returned to control salinity conditions. In contrast, cardiac activity was not interrupted in any of the P. aspera specimens at the 3 g l⁻¹ and 63 g l⁻¹ salinity levels, but strong bradycardia was evident. Contractile activity of the heart ceased in all specimens of P. caerulea and P. aspera when they were exposed to prolonged hypo-osmotic stress (3 g l⁻¹ for 24 h). This acardia was largely reversible in P. caerulea, but most specimens of P. aspera did not recover from the treatment. Accepted: 3 July 1999     

Reduced proportions of natural killer T cells are present in the relatives of lupus patients and are associated with autoimmunity

Introduction

Systemic lupus erythematosus is a genetically complex disease. Currently, the precise allelic polymorphisms associated with this condition remain largely unidentified. In part this reflects the fact that multiple genes, each having a relatively minor effect, act in concert to produce disease. Given this complexity, analysis of subclinical phenotypes may aid in the identification of susceptibility alleles. Here, we used flow cytometry to investigate whether some of the immune abnormalities that are seen in the peripheral blood lymphocyte population of lupus patients are seen in their first-degree relatives.

Methods

Peripheral blood mononuclear cells were isolated from the subjects, stained with fluorochrome-conjugated monoclonal antibodies to identify various cellular subsets, and analyzed by flow cytometry.

Results

We found reduced proportions of natural killer (NK)T cells among 367 first-degree relatives of lupus patients as compared with 102 control individuals. There were also slightly increased proportions of memory B and T cells, suggesting increased chronic low-grade activation of the immune system in first-degree relatives. However, only the deficiency of NKT cells was associated with a positive anti-nuclear antibody test and clinical autoimmune disease in family members. There was a significant association between mean parental, sibling, and proband values for the proportion of NKT cells, suggesting that this is a heritable trait.

Conclusions

The findings suggest that analysis of cellular phenotypes may enhance the ability to detect subclinical lupus and that genetically determined altered immunoregulation by NKT cells predisposes first-degree relatives of lupus patients to the development of autoimmunity.     

A European focus on proteomics

A report on the First International Symposium of the Austrian Proteomics Platform, Seefeld, Austria, 26-29 January 2004.     

Ribosomal RNA secondary structure: compensatory mutations and implications for phylogenetic analysis

Using sequence data from the 28S ribosomal RNA (rRNA) genes of selected vertebrates, we investigated the effects that constraints imposed by secondary structure have on the phylogenetic analysis of rRNA sequence data. Our analysis indicates that characters from both base-pairing regions (stems) and non-base-pairing regions (loops) contain phylogenetic information, as judged by the level of support of the phylogenetic results compared with a well-established tree based on both morphological and molecular data. The best results (the greatest level of support of well-accepted nodes) were obtained when the complete data set was used. However, some previously supported nodes were resolved using either the stem or loop bases alone. Stem bases sustain a greater number of compensatory mutations than would be expected at random, but the number is < 40% of that expected under a hypothesis of perfect compensation to maintain secondary structure. Therefore, we suggest that in phylogenetic analyses, the weighting of stem characters be reduced by no more than 20%, relative to that of loop characters. In contrast to previous suggestions, we do not recommend weighting of stem positions by one-half, compared with that of loop positions, because this overcompensates for the constraints that selection imposes on the secondary structure of rRNA.      

Exenatide promotes cognitive enhancement and positive brain metabolic changes in PS1-KI mice but has no effects in 3xTg-AD animals

Recent studies have shown that type 2 diabetes mellitus (T2DM) is a risk factor for cognitive dysfunction or dementia. Insulin resistance is often associated with T2DM and can induce defective insulin signaling in the central nervous system as well as increase the risk of cognitive impairment in the elderly. Glucagone like peptide-1 (GLP-1) is an incretin hormone and, like GLP-1 analogs, stimulates insulin secretion and has been employed in the treatment of T2DM. GLP-1 and GLP-1 analogs also enhance synaptic plasticity and counteract cognitive deficits in mouse models of neuronal dysfunction and/or degeneration. In this study, we investigated the potential neuroprotective effects of long-term treatment with exenatide, a GLP-1 analog, in two animal models of neuronal dysfunction: the PS1-KI and 3xTg-AD mice. We found that exenatide promoted beneficial effects on short- and long-term memory performances in PS1-KI but not in 3xTg-AD animals. In PS1-KI mice, the drug increased brain lactate dehydrogenase activity leading to a net increase in lactate levels, while no effects were observed on mitochondrial respiration. On the contrary, exenatide had no effects on brain metabolism of 3xTg-AD mice. In summary, our data indicate that exenatide improves cognition in PS1-KI mice, an effect likely driven by increasing the brain anaerobic glycolysis rate.