Aging is a major risk factor for a large number of disorders and functional impairments. Therapeutic targeting of the aging process may therefore represent an innovative strategy in the quest for novel and broadly effective treatments against age-related diseases. The recent report of lifespan extension in mice treated with the FDA-approved mTOR inhibitor rapamycin represented the first demonstration of pharmacological extension of maximal lifespan in mammals. Longevity effects of rapamycin may, however, be due to rapamycin’s effects on specific life-limiting pathologies, such as cancers, and it remains unclear if this compound actually slows the rate of aging in mammals. Here, we present results from a comprehensive, large-scale assessment of a wide range of structural and functional aging phenotypes, which we performed to determine whether rapamycin slows the rate of aging in male C57BL/6J mice. While rapamycin did extend lifespan, it ameliorated few studied aging phenotypes. A subset of aging traits appeared to be rescued by rapamycin. Rapamycin, however, had similar effects on many of these traits in young animals, indicating that these effects were not due to a modulation of aging, but rather related to aging-independent drug effects. Therefore, our data largely dissociate rapamycin’s longevity effects from effects on aging itself.

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Rapamycin extends murine lifespan but has limited effects on aging

Chronic Granulomatous Disease

Protein and peptide therapeutics require parenteral administration, which can be a deterrent to medication adherence. For this reason, there have been extensive efforts to develop alternative delivery strategies, particularly for peptides such as insulin that are used to treat endocrine disorders. Oral delivery is especially desirable, but it faces substantial barriers related to the structural organization and physiological function of the gastrointestinal tract. This article highlights strategies designed to overcome these barriers, including permeation enhancers, inhibitors of gut enzymes, and mucus-penetrating and cell-penetrating peptides. It then focuses on the experience with oral peptides that have reached clinical trials, including insulin, calcitonin, parathyroid hormone and vasopressin, with an emphasis on the advances that have recently led to the landmark approval of an oral formulation of the glucagon-like peptide 1 receptor agonist semaglutide for the treatment of type 2 diabetes.

Advances in oral peptide therapeutics.

Glucose-6-phosphate dehydrogenase (G6PD) is expressed in all tissues, where it catalyses the first step in the pentose phosphate pathway. G6PD deficiency is prevalent throughout tropical and subtropical regions of the world because of the protection it affords during malaria infection. Although most affected individuals are asymptomatic, there is a risk of neonatal jaundice and acute haemolytic anaemia, triggered by infection and the ingestion of certain drugs and broad beans (favism). A rare but more severe form of G6PD deficiency is found throughout the world and is associated with chronic non-spherocytic haemolytic anaemia. Many deficient variants of G6PD have been described. DNA sequence analysis has shown that the vast majority of these are caused by single amino acid substitutions. The three-dimensional structure of G6PD shows a classical dinucleotide binding domain and a novel β + α domain involved in dimerization.

Glucose-6-phosphate dehydrogenase deficiency

Platelet size correlates with platelet activity and can be assessed by platelet volume indices (PVI). The PVI, mean platelet volume (MPV), is universally available with routine blood counts by automated hemograms and therefore is an attractive index to study in clinical scenarios. PVI are useful in assessing the etiology of thrombocytopenia. In addition, a normal platelet distribution width in the setting of thrombocytosis is highly suggestive of a reactive etiology. Higher MPV is also associated with the presence of cardiovascular risk factors, chest pain due to acute coronary syndrome, and adverse outcome after acute coronary syndrome. Results from studies evaluating MPV in patients with peripheral artery disease, unprovoked deep vein thrombosis, and pulmonary embolism further advocate a potential role for MPV in identifying patients at high risk of thrombosis.Nevertheless, most of these data come from retrospective studies some of which have small study populations and confounding factors influ...

Are platelet volume indices of clinical use? A multidisciplinary review.

Severe-glucose-6-phosphate dehydrogenase (G6PD) deficiency associated with chronic hemolytic anemia, granulocyte dysfunction, and increased susceptibility to infections: description of a new molecular variant (G6PD Barcelona)

Preanalytical treatment of EDTA-anticoagulated blood to ensure stabilization of the mean platelet volume and component measured with the ADVIA counters

BACKGROUND Platelet counts between 150 x 10(9)/l and 400 x 10(9)/l are considered as normal in the adult population. However in Spain it is not unusual to find lower counts in healthy people. SUBJECTS AND METHODS We have studied platelet counts in 1,430 prospective healthy platelet donors. In 93 we measured mean platelet volume (MPV) in a blood sample collected in citrate (1:4 v/v) in order to avoid the platelet swelling induced by EDTA. Complete blood counts were performed on a Bayer-Technicon H*1. A reference range of 95% was calculated for platelet count and MPV, and the relationship between platelet count and sex, age, hemoglobin and MPV was studied. RESULTS Mean (SD) platelet count (in x 10(9)/l) in men (195 [42]; n = 1,053) is lower (p < or = 0.0005) than in women (213 [47]; n = 377). The reference range in men is 123-295, in women 137-319 and in both 125 to 300. The mean (SD) for MPV (in fl) is 9.6 (0.7) (no significant differences between sexes) and the reference range is 7.8-11. There is an inverse linear relationship between the circulating platelets and their MPV measured in citrate at high concentration (r = -0.282, p = 0.006, n = 93) and in EDTA (r = -0.364, p < or = 0.0005, n = 1,430) and also between platelet count and Hb levels (r = -0.166, p < or = 0.0005). CONCLUSIONS The mean of platelet count in women is higher than in males in a sample of Spanish population. There is an inverse linear relationship between platelet count and their MPV measures measured in citrate at high concentration and in EDTA. The reference range for platelet count seems to be lower than in other populations of North European origin.

Platelet count and mean platelet volume in the Spanish population

Background Anaemia and microcytosis are common post kidney transplantation. The aim of this study was to evaluate the potential role of mammalian target of rapamycin (mTOR) inhibition in the development of anaemia and microcytosis in healthy animals and in human erythroid cultures in vitro. Methods Rats with normal kidney function were treated with sirolimus (n = 7) or vehicle (n = 8) for 15 weeks. Hemograms were determined thereafter. In the sirolimus withdrawal part of the study, rats received sirolimus (SRL) for 67 days (n = 4) 1 mg/kg three times per week or for 30 days (n = 4) and were observed until Day 120. Hemograms were performed regularly. Peripheral blood mononuclear cells from healthy controls (HC; n = 8), kidney transplant patients with sirolimus treatment with (SRL + MC; n = 8) or without microcytosis (SRL - MC; n = 8) were isolated and cultured in the absence or presence of SRL (5 ng/mL). Results SRL-treated animals had a reduced mean corpuscular volume (MCV) and elevated erythrocyte count compared with control animals after 15 weeks of treatment. This effect was evident as early as 4 weeks (MCV: 61.5 ± 1.8 versus 57 ± 1.7 fL; P = 0.0156; Red blood count 7.4 ± 0.3 × 10(9)/L versus 8.6 ± 0.5 × 10(9)/L; P = 0.0156) and was reversible 90 days after SRL withdrawal. SRL in the culture medium of erythroid cultures led to fewer colonies in cultures from HC as well as from kidney transplant patients (without SRL: 34.2 ± 11.4 versus with SRL: 27.5 ± 9.9 BFU-E-derived colonies P = 0.03), regardless if the cultures were derived from recipients with normocytic or with microcytic erythrocytes. The presence of tacrolimus in the culture medium had no influence on the number and size of colonies. Conclusion mTOR inhibition induces microcytosis and polyglobulia, but not anaemia in healthy rats. This might be caused by growth inhibition of erythroid precursor cells.

/pdf/mtor-inhibition-and-erythropoiesis-microcytosis-or-anaemia-3oruva6zlb.pdf

mTOR inhibition and erythropoiesis: microcytosis or anaemia?

Summary. The activity of 18 red blood cell (RBC) enzymes and reduced glutathione (GSH) content were measured in 70 normal subjects, in 50 heterozygous β-thalassaemia carriers and in 50 non-thalassaemic patients with haemolytic anaemia and high reticulocyte counts. In addition, pyrimidine 5′nucleotidase (P5N) activity was also determined in 34 patients with hypochromic, microcytic, iron deficiency anaemia.



β-Thalassaemia trait was associated with an increase in almost all of the enzyme activities, except for 2,3-bisphosphoglycerate synthetase (BPGS) and glutathione reductase (GR) which were normal and for acetylcholinesterase (AChE) and P5N which were slightly and markedly decreased respectively. The increases in enzyme activities were similar to those observed in patients with non-thalassaemic reticulocytosis except for glyceraldehydephosphate dehydrogenase (GAPD), phos-phoglyceratekinase (PGK), pyruvate kinase (PK), glutathione peroxidase (GPX) and adenylate kinase (AK) which were higher than in non-thalassaemic group of patients with increased number of reticulocytes. No correlation was found between the severity of P5N deficiency and the intensity of basophilic stippling which was present in 46 of 50 thalassaemic carriers here studied. In addition, GSH content and UV absorption spectra of deproteinized thalassaemic RBC extracts were also found to be normal.



The present findings provide further information on the metabolic status of RBC in β-thalassaemia trait and suggest a possible molecular explanation for the frequently observed basophilic stippling in this disease.

Jou Jm

Papers

Severe-glucose-6-phosphate dehydrogenase (G6PD) deficiency associated with chronic hemolytic anemia, granulocyte dysfunction, and increased susceptibility to infections: description of a new molecular variant (G6PD Barcelona)

Preanalytical treatment of EDTA-anticoagulated blood to ensure stabilization of the mean platelet volume and component measured with the ADVIA counters

Platelet count and mean platelet volume in the Spanish population

mTOR inhibition and erythropoiesis: microcytosis or anaemia?

Pyrimidine 5′nucleotidase and several other red cell enzyme activities in β‐thalassaemia trait