Endogenous cytokine production protects T cells from spontaneous apoptosis during highly active antiretroviral therapy

Background

The availability of therapeutic regimens that effectively interfere with HIV‐1 replication provides novel opportunities to investigate mechanisms of T‐cell depletion as well as repopulation in infected individuals.

Methods

Nineteen HIV‐1‐infected individuals were investigated during one‐year follow‐up of highly active retroviral therapy (HAART). The frequencies of apoptotic T cells, as determined by propidium iodide, staining, TUNEL assay and analysis of annexin V, were assessed either in the absence or in the presence of anti‐interleukin (IL)2 and anti‐IL‐4 neutralizing Ab. Spontaneous and lectin‐induced cytokine production were assessed by ELISA.

Results

Increments of both naive and memory CD4 and CD8 T cells during HAART are accompanied by a decrease of T‐cell apoptosis that, after 12 months of HAART, reaches normal levels. This is associated with increments of both spontaneous and activation‐induced production of IL‐2 and IL‐4 by peripheral blood mononuclear cells (PBMCs), though only the latter was found defective at enrolment. During HAART, blocking of either IL‐2 or IL‐4 production by PBMCs using neutralizing Ab restores levels of T‐cell apoptosis consistent with those determined at enrolment. These data suggest that both IL‐2 and IL‐4 produced by PBMCs during HAART provide anti‐apoptotic signals that can contribute to an increased survival of T cells and may thus play a part in long‐term immune reconstitution.

Conclusions

An effective viral suppression and, possibly, effects of PI on molecular targets other than viral components, can support a progressive normalization of T‐cell survival that, at least in part, depends upon the restoration of proper soluble signals. These results provide evidence of a supporting role of endogenous cytokine production in peripheral T‐cell repopulation during an effective and prolonged viral suppression. This may be relevant for the definition of immune‐intervention targets aimed at immune reconstitution in HIV‐1‐infected patients.

     

Hematopoietic contribution to skeletal muscle regeneration by myelomonocytic precursors

Adult bone marrow-derived cells can participate in muscle regeneration after bone marrow transplantation. In recent studies a single hematopoietic stem cell (HSC) was shown to give rise to cells that not only reconstituted all of the lineages of the blood, but also contributed to mature muscle fibers. However, the relevant HSC derivative with this potential has not yet been definitively identified. Here we use fluorescence-activated cell sorter-based protocols to test distinct hematopoietic fractions and show that only fractions containing c-kit(+) immature myelomonocytic precursors are capable of contributing to muscle fibers after i.m. injection. Although these cells belong to the myeloid lineage, they do not include mature CD11b(+) myelomonocytic cells, such as macrophages. Of the four sources of mature macrophages tested that were derived either from monocytic culture, bone marrow, peripheral blood after granulocyte colony-stimulating factor mobilization, or injured muscle, none contributed to muscle. In addition, after transplantation of bone marrow isolated from CD11b-Cre-transgenic mice into the Cre-reporter strain (Z/EG), no GFP myofibers were detected, demonstrating that macrophages expressing CD11b do not fuse with myofibers. Irrespective of the underlying mechanisms, these data suggest that the HSC derivatives that integrate into regenerating muscle fibers exist in the pool of hematopoietic cells known as myelomonocytic progenitors.     

Do pleiotropic effects of statins beyond lipid alterations exist in vivo? What are they and how do they differ between statins?

The inhibition of cellular proliferation, the restoration of endothelial activity, the inhibition of platelet reactivity, and an antioxidant potential are only a few examples of pleiotropic effects of statins. This review analyzes the current knowledge on the pleiotropic properties of this class of drugs and examines the relevant data that support the presence of these effects in vivo. The favorable outcome of major trials of statins has indicated that pleiotropic factors indeed play a role in cardiovascular protection. In addition, recent data indicate that many pleiotropic effects influence mechanisms that belong to the extravascular compartment, as well. Perhaps, some of these properties may eventually justify additional indications for statins and improve the treatment of other diseases, including inflammation and cancer.     

Role of quorum sensing in bacterial infections

Quorum sensing(QS) is cell communication that is widely used by bacterial pathogens to coordinate the expression of several collective traits, including the production of multiple virulence factors, biofilm formation, and swarming motility once a population threshold is reached. Several lines of evidence indicate that QS enhances virulence of bacterial pathogens in animal models as well as in human infections; however, its relative importance for bacterial pathogenesis is still incomplete. In this review, we discuss the present evidence from in vitro and in vivo experiments in animal models, as well as from clinical studies, that link QS systems with human infections. We focus on two major QS bacterial models, the opportunistic Gram negative bacteria Pseudomonas aeruginosa and the Gram positive Staphylococcus aureus, which are also two of the main agents responsible of nosocomial and wound infections. In addition, QS communication systems in other bacterial, eukaryotic pathogens, and even immune and cancer cells are also reviewed, and finally, the new approaches proposed to combat bacterial infections by the attenuation of their QS communication systems and virulence are also discussed.     

EVIDENCE FOR ISOKINETIC KNEE TORQUE ASYMMETRIES IN MALE LONG DISTANCE‐TRAINED RUNNERS

Purpose/Background

Strength asymmetries are related to knee injuries and such injuries are frequently observed among runners. The purpose of this study was to examine whether long‐distance runners have symmetric performance during knee isokinetic testing at two angular velocities.

Methods

Twenty‐three healthy and well‐trained male long‐distance runners performed open‐chain isokinetic trials for assessment of concentric quadriceps and hamstrings contractions at velocities of 60 °·s^‐1 and 240 °·s^‐1. Data were compared between the lower limbs at different velocities.

Results

Peak torque and total work were similar between the limbs. Asymmetry was observed for knee flexor power at 240 °·s^‐1 (237 ± 45 W and 205 ± 53 W, in the preferred and non‐preferred limb, respectively). Asymmetry indexes for flexor power were different between the velocities tested (13.1% and 2.21% for 240 °·s^‐1 and 60 °·s^‐1, respectively).

Conclusion

A limb asymmetry was observed among runners for knee flexor power, mainly at higher angular velocities (240 °·s^‐1). In addition, H/Q ratios were observed to be contraction velocity dependent.

Level of Evidence

3     

Abdominal obesity is associated with potassium depletion and changes in glucose homeostasis during diuretic therapy

The activation of the renin-angiotensin system (RAS) is an important mechanism that contributes to hypertension in obese individuals. Thiazide diuretics also activate the RAS in response to volume contraction and can lead to a decrease in serum potassium values and glucose metabolism abnormalities. To evaluate the impact of abdominal obesity on potassium depletion and glucose homeostasis in hypertensive patients receiving thiazide therapy, the authors studied 329 hypertensive patients without known diabetes or impaired renal function. Patients were stratified into 2 major groups according to whether they used thiazide diuretic therapy, and each group was further divided in 2 subgroups according to the presence of abdominal obesity. The authors demonstrated that obese patients receiving diuretic therapy had lower plasma potassium levels and higher glucose values compared with nonobese patients receiving diuretic therapy. In conclusion, abdominal obesity predisposes to potassium depletion during diuretic therapy in association with effects on glucose homeostasis.     

Quality of diabetes care predicts the development of cardiovascular events: results of the QuED study

Background and aimIn the context of the QuED Study we assessed whether a quality of care summary score was able to predict the development of cardiovascular (CV) events in patients with type 2 diabetes.Methods and resultsThe score was calculated using process and intermediate outcome indicators (HbA_1c, blood pressure, low-density lipoprotein cholesterol, microalbuminuria) and ranged from 0 to 40. Overall, 3235 patients were enrolled, of whom 492 developed a CV event after a median follow-up of 5 years. The incidence rate (per 1000 person-years) of CV events was 62.4 in patients with a score ≤10, 54.8 in those with a score between 15 and 20, and 39.8 in those with a score >20. In adjusted multilevel regression models, the risk to develop a CV event was 89% greater in patients with a score of ≤10 (rate ratio [RR] = 1.89; 95% confidence interval [CI] 1.43–2.50) and 43% higher in those with a score between 10 and 20 (RR = 1.43; 95% CI 1.14–1.79), as compared to those with a score >20. A difference between centers of 5 points in the mean quality score was associated with a difference of 16% in CV event risk (RR = 0.84; 95% CI 0.72–0.98).ConclusionOur study documented for the first time a close relationship between a score of quality of diabetes care and long-term outcomes.     

Impact of physicians' beliefs and practices on cholesterol levels in patients with type 2 diabetes: a longitudinal assessment

Background

Clinical trials demonstrate significant benefit from cholesterol management for patients with type 2 diabetes. The aim of this work was to explore the correlates of lipid management in patients with type 2 diabetes, including the subjective beliefs of physicians, setting of care, and patient-related factors.

Methods

This longitudinal outcomes research study involved 2359 patients with type 2 diabetes recruited by 111 general practitioners and 214 physicians practicing in diabetes clinics. Physicians' beliefs were assessed through a questionnaire administered when the study started in 1998. Main outcome measures were total cholesterol (TC) and LDL cholesterol (LDL-C) levels over 3 years and the proportion of patients treated with lipid-lowering drugs (LLDs).

Results

Less than one-third of the physicians (27%) stated that they routinely started pharmacologic therapy for TC values ≥200 mg/dL (more aggressive), whereas 46% considered a TC level ≥240 mg/dL as the threshold for the initiation of treatment (less aggressive). During 3 years of observation, mean TC and LDL-C levels decreased from 215 ± 40 mg/dL to 203 ± 37 mg/dL and from 135 ± 36 mg/dL to 126 ± 35 mg/dL respectively, while the proportion of patients treated with LLDs increased from 13.2% to 24.6%; in particular, among individuals cared for by the more aggressive physicians, 30.0% were taking LLDs after 3 years, while only 17.7% of those followed by the less aggressive physicians and 18.1% of those followed by >1 physician were being treated with LLDs. Multilevel analysis showed that physicians' beliefs were an independent predictor of TC levels over the 3-year period. In patients treated with LLDs, TC levels decreased on average by 14%, and LDL-C levels decreased by 20%.

Conclusion

Our data show that physicians' beliefs in more aggressive management strategies will result in better mean TC values over a 3-year period.     

Role of Rab27 in synaptic transmission at the squid giant synapse

Small GTPase Rab is a member of a large family of Ras-related proteins, highly conserved in eukaryotic cells, and thought to regulate specific type(s) and/or specific step(s) in intracellular membrane trafficking. Given our interest in synaptic transmission, we addressed the possibility that Rab27 (a close isoform of Rab3) could be involved in cytosolic synaptic vesicle mobilization. Indeed, preterminal injection of a specific antibody against squid Rab27 (anti-sqRab27 antibody) combined with confocal microscopy demonstrated that Rab27 is present on squid synaptic vesicles. Electrophysiological study of injected synapses showed that the anti-sqRab27 antibody inhibited synaptic release in a stimulation-dependent manner without affecting presynaptic action potentials or inward Ca²⁺ current. This result was confirmed in in vitro synaptosomes by using total internal reflection fluorescence microscopy. Thus, synaptosomal Ca²⁺-stimulated release of FM1-43 dye was greatly impaired by intraterminal anti-sqRab27 antibody. Ultrastructural analysis of the injected giant preterminal further showed a reduced number of docked synaptic vesicles and an increase in nondocked vesicular profiles distant from the active zone. These results, taken together, indicate that Rab27 is primarily involved in the maturation of recycled vesicles and/or their transport to the presynaptic active zone in the squid giant synapse.