Serum adiponectin levels in hypogonadal males: influence of testosterone replacement therapy

OBJECTIVE: Adiponectin is an adipocyte-specific secretory protein which exhibits antiatherogenic, anti-inflammatory and antidiabetic properties. We hypothesized that testosterone plays an important role in the regulation of its secretion in humans, as adiponectin concentrations are higher in women than in men and as testosterone administration is accompanied by a reduction in serum adiponectin in animals and by reduced protein secretion in cultured adipocytes. This study aimed to evaluate adiponectin levels in hypogonadal men prior to and during testosterone replacement therapy. SUBJECTS AND METHODS: In a retrospective study, adiponectin, total and free testosterone, oestradiol, SHBG, total cholesterol and triglyceride levels were evaluated in 31 hypogonadal men [HM; age, mean +/- SEM: 36.5 +/- 2.4 years; body mass index (BMI) 24.6 +/- 0.8 kg/m2] and 29 weight-matched eugonadal men (EM; age 30.8 +/- 1.5 years; BMI 23.4 +/- 0.6 kg/m2). In 13 HM (age 33.9 +/- 3.2 years; BMI 24.2 +/- 0.9 kg/m2) the same parameters were also evaluated after 6 months of testosterone replacement therapy. Correlation analysis between adiponectin and hormonal, biochemical and anthropometric parameters was performed in all subjects. RESULTS: Testosterone, free testosterone and oestradiol concentrations were significantly lower in HM than in EM (4.4 +/- 0.4 nmol/l, 78.4 +/- 10.9 pmol/l and 36.1 +/- 3.0 pmol/l, respectively, in HM vs. 21.9 +/- 0.7 nmol/l, 507.9 +/- 13.8 pmol/l and 65.2 +/- 1.8 pmol/l, respectively, in EM, P < 0.0001), while SHBG levels in HM were higher than in EM (54.4 +/- 7.5 vs. 30.9 +/- 2.2 nmol/l, P < 0.005). Serum adiponectin levels in HM were significantly higher than in EM (9.53 +/- 0.73 vs. 6.80 +/- 0.55 microg/ml, P < 0.01). Calculation of the Pearson coefficient showed that adiponectin levels in HM were not correlated with any of the anthropometric and hormonal parameters examined, but showed a significant negative correlation with serum triglycerides (r = -0.38, P < 0.05). Serum adiponectin levels were negatively correlated with body weight (r = -0.41, P < 0.05) in EM but not with other anthropometric, hormonal or biochemical parameters. Six months after initiation of testosterone replacement therapy, which increased testosterone and free testosterone levels to the normal range, adiponectin levels were significantly reduced in HM (6.37 +/- 0.93 vs. 9.26 +/- 1.01 microg/ml, P < 0.01) and similar to those recorded in EM. CONCLUSIONS: Compared to eugonadal subjects, hypogonadal men show higher adiponectin levels which are reduced by testosterone replacement therapy. This study indicates that testosterone exerts a regulatory role on adiponectin secretion in humans.     

Factors associated with bronchiolitis obliterans syndrome and chronic graft‐versus‐host disease after allogeneic hematopoietic cell transplantation

Bronchiolitis obliterans syndrome (BOS) is a form of chronic graft vs. host disease (cGVHD) and a highly morbid pulmonary complication after allogeneic hematopoietic stem cell transplantation (HSCT). We assessed the prevalence and risk factors for BOS and cGVHD in a cohort of HSCT recipients, including those who received reduced intensity conditioning (RIC) HSCT. Between January 1, 2000 and June 30, 2010, all patients who underwent allogeneic HSCT at our institution (n = 1854) were retrospectively screened for the development of BOS by PFT criteria. We matched the BOS cases with two groups of control patients: (1) patients who had concurrent cGVHD without BOS and (2) those who developed neither cGVHD nor BOS. Comparisons between BOS patients and controls were conducted using t‐test or Fisher's exact tests. Multivariate regression analysis was performed to examine factors associated with BOS diagnosis. All statistical analyses were performed using SAS 9.2. We identified 89 patients (4.8%) meeting diagnostic criteria for BOS at a median time of 491 days (range: 48–2067) after HSCT. Eighty‐six (97%) of our BOS cohort had extra‐pulmonary cGVHD. In multivariate analysis compared to patients without cGVHD, patients who received busulfan‐based conditioning, had unrelated donors, and had female donors were significantly more likely to develop BOS, while ATG administration was associated with a lower risk of BOS. Our novel results suggest that busulfan conditioning, even in RIC transplantation, could be an important risk factor for BOS and cGVHD. Am. J. Hematol. 89:404–409, 2014. © 2013 Wiley Periodicals, Inc.     

Sequential infusion of donor‐derived dendritic cells with donor lymphocyte infusion for relapsed hematologic cancers after allogeneic hematopoietic stem cell transplantation

Donor lymphocyte infusion (DLI) is often given to induce a graft‐versus‐leukemia (GVL) effect after allogeneic hematopoietic stem cell transplantation (HSCT). However, efficacy of DLI is limited in most hematologic cancers. As antigen presenting cells, dendritic cells (DC) bolster immune responses. We conducted a Phase I trial testing the coinfusion of DC followed by DLI. DC were generated by culturing peripheral blood mononuclear cells from HLA matched‐related donors in GM‐CSF and IL‐4 for 7 days, followed by TNF‐α for 3 days. DC were administered intravenously on 3 dose levels (5 × 10⁶; 1 × 10⁷; 5 × 10⁷ cells). DLI (3 × 10⁷ CD3+ cells/kg) was administered intravenously 1 day after the DC. Sixteen patients with hematologic cancers relapsed after HSCT were treated. A maximum tolerated dose for DC was not reached. Two of 16 patients met criteria for DLT within 10 weeks of the infusion: 1 idiopathic respiratory failure, 1 ventricular cardiac arrest. None developed grade III/IV GVHD. One patient developed grade II acute intestinal graft‐vs.‐host disease (GVHD) and 1 chronic GVHD within 6 months of the infusion. Both resolved with corticosteroids. Four of 14 patients evaluable for disease response achieved durable remissions and are alive and cancer free 6.7, 8.4, 8.8, and 10.1 years from infusion. Sequential infusion of donor‐derived DC with DLI is feasible in patients with relapsed hematologic cancers after allogeneic HSCT. Future studies may consider donor DC preloaded with tumor antigens to investigate whether DC infusion could augment the GVL effect. Am. J. Hematol. 89:1092–1096, 2014. © 2014 Wiley Periodicals, Inc.     

Influence of plaque calcium on neointimal hyperplasia following bare metal and drug-eluting stent implantation.

OBJECTIVES: To examine the influence of vessel wall calcium on neointimal hyperplasia (NIH) following bare metal stent (BMS) and drug-eluting stent (DES) implantation. BACKGROUND: While procedural complications with coronary stenting in calcified lesions are well reported, little is known about subsequent NIH on plaque calcium following either BMS or DES implantation. METHODS: In the Study to COmpare REstenosis Rate between QueST and QuaDDS-QP2 (SCORE) trial, 6 months follow-up volumetric intravascular ultrasound data were available for 41 lesions (BMS, 19; DES, 22). NIH thicknesses on superficial, deep, and noncalcified plaque were calculated at every 0.5 mm intervals over the stented segment. Calcified and less-calcified cross-sections were defined as those containing arcs of plaque calcium > or = 90 degrees and < 90 degrees , respectively. RESULTS: In BMS, mean NIH thickness on both superficial (0.24 +/- 0.23 mm) and deep calcium (0.25 +/- 0.21 mm) was significantly smaller than that of noncalcified plaque (0.31 +/- 0.22 mm) (P < 0.0005). NIH area was significantly smaller in calcified cross-sections compared to less-calcified cross-sections (2.1 +/- 1.2 mm2 vs. 3.1 +/- 1.9 mm2, P < 0.0001). While in contrast, in DES, mean NIH thickness was similar, irrespective of the presence or location of calcium (0.03 +/- 0.05 mm vs. 0.03 +/- 0.06 mm vs. 0.03 +/- 0.05 mm, superficial vs. deep vs. noncalcified plaque, P = NS). NIH area was also similar between calcified and less-calcified cross-sections (0.3 +/- 0.6 mm2 vs. 0.3 +/- 0.6 mm2, P = NS). CONCLUSIONS: These results suggest that while plaque calcium may influence NIH following BMS implantation, NIH suppression using DES does not appear to be affected by the presence or location of calcium.     

Evaluation of miniature manometric techniques for the measurement of esophageal body pressure waves

BACKGROUND AND AIMS: Perfused miniature manometric assemblies with lumina of 0.4-0.5 mm i.d. have been developed. Reduced luminal size offers the advantages of reduced assembly bulk and increased assembly complexity with greater numbers of lumina and lower manometric infusion volumes because of a slower perfusion rate. This study investigated the recording fidelity of miniature manometric assemblies in the measurement of esophageal peristalsis. METHODS: Four miniature manometric assemblies, each containing manometric lumina of either 0.4 or 0.5 mm i.d., were evaluated at 100 and 180 cm lengths. The fidelity of miniature manometric luminal recordings were evaluated in vivo during esophageal peristalsis by using a simultaneous comparison with the standard lumina and an intraluminal strain gauge. RESULTS: During esophageal peristalsis, miniature manometric lumina recorded the peak amplitude of pressure waves, with an accuracy at perfusion rates of 0.04 mL/min (0.4 mm, i.d.) and 0.15 mL/min (0.5 mm, i.d.). CONCLUSION: Miniature manometric assemblies of lengths that are practical for use in humans are suitable for recording esophageal peristalsis.     

Low concentrations of STI571 in the cerebrospinal fluid: a case report

We report a 53-year-old man with lymphoid blast crisis of Ph+ chronic myeloid leukaemia who was treated with STI571, a selective inhibitor of the enzymatic activity of BCR-ABL. He responded excellently to STI571 (600 mg/d), obtaining a complete cytogenetic remission after 3 months of therapy. Although remission in the bone marrow was sustained, the patient developed an isolated central nervous system relapse. Subsequent analyses of STI571 concentrations in the cerebrospinal fluid (CSF) revealed 2-log lower CSF levels of STI571 than corresponding plasma levels. These are the first data demonstrating a low penetration of orally administered STI571 into the CSF in humans.     

Combination immunotherapy with rituximab and interleukin 2 in patients with relapsed or refractory follicular non-Hodgkin's lymphoma

Rituximab has significant activity as a single agent in the treatment of follicular non-Hodgkin's lymphoma (NHL). Interleukin 2 (IL-2) is a lymphokine that increases effector cell number. In an effort to augment antibody-dependent cell-mediated cytotoxicity (ADCC) associated with rituximab therapy, low-dose IL-2 was added to a standard rituximab regimen and patients were evaluated for safety and efficacy. Twenty patients with relapsed or refractory follicular NHL were treated with IL-2 (1.2 MIU/m(2)/d for 56 d subcutaneously) as outpatients. Rituximab (375 mg/m(2)) was given on d 15, 22, 29 and 36. The regimen was well tolerated and only three patients required dose adjustments in IL-2. Infusional toxicity associated with rituximab was not exacerbated by IL-2. Peripheral blood immunophenotyping demonstrated significant increases in circulating CD8+ and CD56+ lymphocytes in all evaluable patients (P = 0.0002). Increases in total eosinophil number were observed in all patients. Eleven patients responded to therapy, for an overall response rate of 55%. Four additional patients had stable disease. For these 15 patients, the median time to progression exceeded 13 months. We conclude concomitant cytokine therapy to enhance ADCC with monoclonal antibody therapy was well tolerated and did not exacerbate antibody-related infusional toxicity. Further studies of this rational combination are warranted and ongoing.     

Dracunculus medinensis and Schistosoma mansoni contain opiate alkaloids

The results of analysis, by high-performance liquid chromatography coupled with electrochemical detection and by nano-electrospray-ionization, double quadrupole/orthogonal-acceleration, time-of-flight mass spectrometry, indicate that adult Dracunculus medinensis and Schistosoma mansoni both contain the opiate alkaloid morphine and that D. medinesis also contains the active metabolite of morphine, morphine 6-glucuronide. From these and previous observations, it would appear that many helminths are probably using opiate alkaloids as potent immunosuppressive and antinociceptive signal molecules, to down-regulate immunosurveillance responsiveness and pain signalling in their hosts.