Alpha2 -adrenoceptor function in arterial hypertension associated with obesity in dogs fed a high-fat diet

OBJECTIVE : To investigate the status of alpha2-adrenoceptors in a model of obesity-related arterial hypertension. DESIGN : A parallel study in dogs randomly assigned to a high-fat diet (HFD group, n = 6) or normal canine food (controls, n = 6) for 9 weeks. METHODS : Postsynaptic vascular alpha2-adrenoceptors were assessed through analysis of dose-pressor responses to clonidine [2.5, 5.0 and 15.0 microg/kg intravenously (i.v.)] after muscarinic, beta- and alpha1-adrenergic receptor blockade. Presynaptic and central alpha2-adrenoceptors were studied through measurement of changes in plasma concentrations of catecholamine induced by yohimbine (0.05 mg/kg i.v.). The number of platelet alpha2-adrenoceptors (expressed as fmol/mg protein) and the percentage in a state of high affinity were measured using [3H]RX821002. RESULTS : Clonidine, when administered to dogs that were under autonomic blockade, elicited a dose-dependent increase in blood pressure. The doses of clonidine required to induce a 50% maximum increase in systolic and diastolic blood pressures remained unchanged after 9 weeks of a high-fat diet (systolic: 6.0 +/- 0.3 microg/kg at baseline and 5.6 +/- 0.2 microg/kg after 9 weeks; diastolic: 4.2 +/- 0.2 microg/kg at baseline and 3.9 +/- 0.2 microg/kg after 9 weeks). After 9 weeks of the regimen, plasma concentrations of noradrenaline were significantly greater in the HFD group than in controls (337 +/- 22 pg/ml compared with 212 +/- 37 pg/ml). The increment in plasma concentrations of noradrenaline elicited by yohimbine after 9 weeks was smaller in the HFD group than in controls (93 +/- 44% compared with 181 +/- 46%; P = 0.024). In the HFD group, the number of platelet alpha2-adrenoceptors and the percentage that were in a state of high affinity were significantly lower after 9 weeks, compared with baseline (number: 239 +/- 21 fmol/mg protein at baseline and 95 +/- 7 fmol/mg protein after 9 weeks; high-affinity: 30 +/- 3% at baseline and 21 +/- 4% after 9 weeks; P < 0.05). CONCLUSIONS : These results suggest that presynaptic or central alpha2-adrenoceptor function, or both, is specifically impaired after 9 weeks of a high-fat diet. These modifications may account for the development of arterial hypertension in this model.     

Efficacy and safety of trimodulin,a novel polyclonal antibody preparation,in patients with severe community-acquired pneumonia: a randomized,placebo-controlled,double-blind,multicenter, phase II trial (CIGMA study)

Purpose

The CIGMA study investigated a novel human polyclonal antibody preparation (trimodulin) containing?~?23% immunoglobulin (Ig) M,?~?21% IgA, and?~?56% IgG as add-on therapy for patients with severe community-acquired pneumonia (sCAP).

Methods

In this double-blind, phase II study (NCT01420744), 160 patients with sCAP requiring invasive mechanical ventilation were randomized (1:1) to trimodulin (42 mg IgM/kg/day) or placebo for five consecutive days. Primary endpoint was ventilator-free days (VFDs). Secondary endpoints included 28-day all-cause and pneumonia-related mortality. Safety and tolerability were monitored. Exploratory post hoc analyses were performed in subsets stratified by baseline C-reactive protein (CRP;?≥?70 mg/L) and/or IgM (≤?0.8 g/L).

Results

Overall, there was no statistically significant difference in VFDs between trimodulin (mean 11.0, median 11 [n?=?81]) and placebo (mean 9.6; median 8 [n?=?79]; p?=?0.173). Twenty-eight-day all-cause mortality was 22.2% vs. 27.8%, respectively (p?=?0.465). Time to discharge from intensive care unit and mean duration of hospitalization were comparable between groups. Adverse-event incidences were comparable. Post hoc subset analyses, which included the majority of patients (58–78%), showed significant reductions in all-cause mortality (trimodulin vs. placebo) in patients with high CRP, low IgM, and high CRP/low IgM at baseline.

Conclusions

No significant differences were found in VFDs and mortality between trimodulin and placebo groups. Post hoc analyses supported improved outcome regarding mortality with trimodulin in subsets of patients with elevated CRP, reduced IgM, or both. These findings warrant further investigation.Trial registration: NCT01420744.

     

Allogeneic hematopoietic stem cell transplantation allows long-term complete remission and curability in high-risk Waldenstr?m’s macroglobulinemia. Results of a retrospective analysis of the Société Fran?aise de Greffe de Moelle et de Thérapie Cellulaire

Background

Patients with poor-risk Waldenström’s macroglobulinemia have suboptimal response and early post-treatment relapse with conventional therapies. Hence, new therapeutic approaches such as allogeneic stem cell transplantation should be evaluated in these patients.

Design and Methods

We examined the long-term outcome of allogeneic stem cell transplantation in Waldenström’s macroglobulinemia by studying the records of 24 patients reported in the SFGM-TC database and one transplanted in the bone marrow unit in Hamburg.

Results

Median age at the time of transplant was 48 years (range, 24–64). The patients had previously received a median of 3 lines of therapy (range, 1–6) and 44% of them had refractory disease at time of transplant. Allogeneic stem cell transplantation after myeloablative (n=12) or reduced-intensity (n=13) conditioning yielded an overall response rate of 92% and immunofixation-negative complete remission in 50% of evaluable patients. With a median follow-up of 64 months among survivors (range, 11–149 months), 5-year overall survival and progression-free survival rates were respectively, 67% (95% CI: 46–81) and 58% (95% CI: 38–75). The 5-year estimated risk of progression was 25% (95% CI: 10–36%), with only one relapse among the 12 patients who entered complete remission, versus 5 in the 12 patients who did not. Only one of the 6 relapses occurred more than three years post-transplant.

Conclusions

Allogeneic stem cell transplantation yields a high rate of complete remissions and is potentially curative in poor-risk Waldenström’s macroglobulinemia.     

Microcirculatory abnormalities in patients with severe influenza A (H1N1) infection

Purpose

This study was designed to evaluate the degree of microcirculatory abnormalities in patients with severe influenza A (H1N1) infection.

Methods

We assessed the sublingual microcirculation in seven consecutive patients with acute lung injury related to influenza A (H1N1) infection. The evaluation was carried out using sidestream dark field (SDF) imaging within the first 96 hr after the patients were admitted to the intensive care unit. Thenar oxygen saturation (StO₂) was also measured with near-infrared spectroscopy (NIRS) during a vascular occlusion test. In addition, the Lung Injury Score (LIS) and the APACHE II and SOFA scores were recorded.

Results

All patients received invasive mechanical ventilation and at least one of the following adjuvant therapies: inhaled nitric oxide (n = 4), extracorporeal membrane oxygenation (n = 1), prone position (n = 4), recruitment maneuver (n = 3), and hydrocortisone 50 mg·hr^?6 (n = 6). The median time from admission to microcirculatory assessment was 21 hr. Three patients had bacterial superinfection. The median LIS and PaO₂/F _i O₂ were 2.5 (2.25-3.25) and 178 (158-212), respectively. Three subjects were treated with norepinephrine. During a vascular occlusion test, the microcirculation was moderately to severely compromised with a NIRS ascending slope of 2.39%·sec^?1 (1.75-2.67%·sec^?1), 66% (60-86%) of perfused small vessels in the sublingual microcirculation, and a microvascular flow index of 1.9 (1.3-2.6). The degree of microcirculatory abnormalities detected by the NIRS and SDF imaging techniques was correlated with the severity of the disease, as reflected by the SOFA and APACHE II scores.

Conclusions

The microcirculation as assessed by SDF imaging and NIRS techniques was compromised in patients with acute respiratory distress syndrome (ARDS) and influenza A (H1N1) infection.     

Hb Lepore-Leiden: A New δ/β Rearrangement Associated with a β-Thalassemia Minor Phenotype

The Lepore hemoglobins (Hbs) are a group of structural defects resulting from different recombination events between the δ- and β-globin genes. They may come with different β-thalassemia (β-thal) minor-like phenotypes in the carrier and with variably severe phenotypes in the rare homozygote, and in the common compound heterozygote with β-thal. The most seriously affected patients are those of Yugoslavian origin presenting with severe transfusion-dependent hemolytic anemia, dyserythropoiesis, hepatosplenomegaly and skeletal malformations. Because of genetic risk, couples where both partners are carriers of these combinations may require prognosis and prenatal diagnosis. In these cases, recognition of the defect must be done with particular care. We report a case of Hb Lepore induced by a yet unknown crossover event found in a 24-year-old Turkish male and compare the novel mutation with those previously reported.     

High-intensity focused ultrasound in prostate cancer; a systematic literature review of the French Association of Urology

We discuss the efficacy and safety of high-intensity focused ultrasound (HIFU) in patients with prostate cancer, to define the best indications for HIFU in daily clinical practice as primary therapy. We searched Medline and Embase for clinical studies evaluating the efficacy and safety of HIFU in prostate cancer (July 2007), and abstracts presented at the 2005-2007 annual meetings of the European Association of Urology and American Urological Association were screened. In all, 37 articles/abstracts were selected. As the data on HIFU as salvage therapy were limited, we focused on HIFU as primary therapy. Studies consisted of case series only. Included patients were approximately 70 years old with T1-T2 N0M0 disease, Gleason Score or=70 years) with T1-T2 N0M0 disease, a Gleason score of <7, a PSA level of <15 ng/mL and a prostate volume of <40 mL. In these patients HIFU achieves short-term cancer control, as shown by a high percentage of negative biopsies and significantly reduced PSA levels. The median-term survival data also seem promising, but long-term follow-up studies are needed to further evaluate cancer-specific and overall survival rates before the indications for primary therapy can be expanded.