Tales of testosterone: Advancing our understanding of environmental endocrinology through studies of neotropical birds.

Studies of birds have greatly advanced our understanding of how testosterone modulates complex phenotypes, specifically its role in mediating male reproductive and associated behaviors. Yet most of the foundational studies have been limited to northern latitude breeding species despite the fact that they represent only a small fraction of worldwide avian diversity. In contrast, phylogenetic, life-history, and mating system diversity all reach their apex in neotropical avifauna and yet these birds, along with more southern latitude species, remain very poorly understood from an endocrine perspective. Despite the relatively limited previous work on taxa breeding in Central and South America, empirical findings have had a disproportionately large impact on our understanding of testosterone's role in everything from geographic variation to behavioral roles and neuroplasticity. Here, we synthesize how studies of neotropical breeding avifauna have advanced our understanding of how testosterone's actions can and are associated with the broad patterns of phenotypic diversity that we see in birds. In addition, we outline how these studies can be used individually or in a comparative context to address fundamental questions about the environmental endocrinology of testosterone and to understand the diversity of roles that testosterone plays in mediating behavioral variation, reproductive strategies, and associated life-history trade-offs.

Kinematic and kinetic gait deviations in males long after anterior cruciate ligament reconstruction.

BACKGROUND: Biomechanical deviations long (approx. 5years) after anterior cruciate ligament reconstruction have not been quantified in males, despite their distinct risk profile as compared to females. These deviations can indicate altered joint loading during chronic, repetitive motions. METHODS: Cross-sectional study, comparing kinematic and kinetic variables between 15 male anterior cruciate ligament reconstructed patients and 15 healthy controls. During walking and running gait, measurements were taken of impact dynamics, knee and hip sagittal plane angles and moments, and knee varus angles and adduction moments. FINDINGS: Comparing affected limbs to control limbs, significantly lower maximum (P=0.001) and initial (P=0.003) loading rates were found during running, but not in walking. Hip angles were lower for affected limbs of patients compared to the control group (P=0.039) in walking, but not during running. Between-limb comparisons showed important differences in symmetry of the affected patients. Maximum force during running was higher in the unaffected limb (P=0.015), which was linked with a higher loading rate (P=0.008). Knee flexion angle was reduced by 2° on average for the affected limb during running (P=0.010), and both walking and running knee and hip moments showed differences. Knee varus angle showed a 1° difference during walking (P<0.001), but not during running. Knee adduction moment was significantly lower (more valgus) during both walking and running. INTERPRETATION: Male anterior cruciate ligament reconstructed patients demonstrate persistent, clinically important gait asymmetries and differences from healthy controls long after surgery in kinematics, kinetics, and impact biomechanics.

Graft-versus-host disease after double-unit cord blood transplantation has unique features and an association with engrafting unit-to-recipient HLA match.

Manifestations of and risk factors for graft-versus-host disease (GVHD) after double-unit cord blood transplantation (DCBT) are not firmly established. We evaluated 115 DCBT recipients (median age, 37 years) who underwent transplantation for hematologic malignancies with myeloablative or nonmyeloablative conditioning and calcineurin inhibitor/mycophenolate mofetil immunosuppression. Incidence of day 180 grades II to IV and III to IV acute GVHD (aGVHD) were 53% (95% confidence interval, 44 to 62) and 23% (95% confidence interval, 15 to 31), respectively, with a median onset of 40 days (range, 14 to 169). Eighty percent of patients with grades II to IV aGVHD had gut involvement, and 79% and 85% had day 28 treatment responses to systemic corticosteroids or budesonide, respectively. Of 89 engrafted patients cancer-free at day 100, 54% subsequently had active GVHD, with 79% of those affected having persistent or recurrent aGVHD or overlap syndrome. Late GVHD in the form of classic chronic GVHD was uncommon. Notably, grades III to IV aGVHD incidence was lower if the engrafting unit human leukocyte antigen (HLA)-A, -B, -DRB1 allele match was >4/6 to the recipient (hazard ratio, 0.385; P = .031), whereas engrafting unit infused nucleated cell dose and unit-to-unit HLA match were not significant. GVHD after DCBT was common in our study, predominantly affected the gut, and had a high therapy response, and late GVHD frequently had acute features. Our findings support the consideration of HLA- A,-B,-DRB1 allele donor-recipient (but not unit-unit) HLA match in unit selection, a practice change in the field. Moreover, new prophylaxis strategies that target the gastrointestinal tract are needed.

Live (vaccines) from New York.

Over 40 000 hematopoietic cell transplantations (HCT) are performed worldwide each year, increasing the number of transplant survivors returning to school, the work place and overseas travel. Outbreaks of measles and mumps in immunocompetent individuals and the increased morbidity associated with primary varicella and shingles in older individuals highlight the need for effective vaccination of these vulnerable patients. In current post-HCT vaccination guidelines, only the measles, mumps and rubella vaccine (MMR) and the live-attenuated varicella vaccine (LAVV) designed to prevent primary varicella in varicella zoster seronegative individuals are permissible post HCT and only in select patient groups. All other vaccines, including the shingles vaccines, are contraindicated post HCT. Current data, primarily in pediatric HCT recipients, demonstrate a 60-70% response following a single MMR or LAVV. A two-dose schedule increases the seroconversion rate following these vaccines. This review will highlight published studies on the immunogenicity of MMR and the LAVV, areas in which data on these vaccines are lacking, the criteria for their use in patients transplanted at our center and potential studies to answer questions posed by the growing number of transplant survivors and their physicians on how to safely administer live-attenuated viral vaccines.

Alternative donor SCT for the treatment of MHC class II deficiency.

MHC Class II deficiency is a rare primary immunodeficiency disease characterized by absent HLA Class II expression resulting in CD4 lymphopenia, lack of Ag-specific responses and recurrent infection. Without successful allogeneic SCT, most children succumb to infection within the first decade of life. To date, alternative donor transplants for this disorder have been inferior to SCT for other forms of combined immunodeficiency disease due to an increased incidence of graft rejection, GVHD and death from infections generally acquired before haematopoietic cell transplantation. This study details the transplant outcome of 16 affected children consecutively transplanted at four centers since 1990, 8 of whom required mechanical ventilation pretransplant. Stem cells were derived from an HLA-mismatched family member (n=10), an HLA-matched unrelated adult donor (n=4), or an unrelated cord blood donor (n=2). Graft failure occurred in five children, all of whom underwent a second SCT. Six patients developed acute GVHD although no patient developed chronic GVHD after primary transplantation. CD4 T-cell reconstitution remained below the normal range for age, suggesting defective thymopoiesis after allo-SCT. Nonetheless, 69% of children survive without GVHD at a median follow-up of 5.7 years, indicating improved outcomes compared with previous studies.

Fatigue in bronchiectasis.

BACKGROUND: Fatigue is a complex, disabling symptom in non-CF bronchiectasis (nCF-Br). Fatigue can be formally measured using the validated fatigue impact scale (FIS). The relationship between fatigue and clinically important factors such as airflow obstruction, breathlessness or Pseudomonas aeruginosa infection in nCF-Br is unclear. AIM: To measure the correlation between FIS scores and markers of disease severity in nCF-Br. DESIGN: A prospective cohort study. METHODS: Patients attending a specialist service were studied. Lung function (FEV(1)% predicted), Medical Research Council dyspnoea score (MRCD), sputum culture results and FIS were recorded. Patients were categorized according to sputum culture into three subgroups: Pseudomonas 'colonization', 'isolation' and neither. RESULTS: One hundred and seventeen consecutive patients were included. Average FEV(1)% predicted was 64% (SD ±28%). Twelve (10%) patients had Pseudomonas aeruginosa isolation; 47 (40%) patients had P. aeruginosa colonization. Fatigue levels were similar in patients with and without colonization (median 38 versus 32, P = 0.155). Significant fatigue (FIS > 40) was similar in all three Pseudomonas subgroups (P = 0.31, chi-square). Fatigue correlated with MRCD score (r = 0.57, P < 0.001) and FEV(1)% predicted (r = -0.30, P = 0.001). FEV(1)% predicted was lower in patients who had ever isolated or been colonized with P. aeruginosa (P ≤ 0.001). CONCLUSION: There are significant correlations between FIS score and MRCD score and FEV(1)% predicted in bronchiectasis. Pseudomonas aeruginosa infection appears to be associated with poorer lung function, and higher MRCD scores, yet there is no significant association between P. aeruginosa status and fatigue.

Allogeneic cellular and autologous stem cell therapy for sickle cell disease: 'whom, when and how'.

Sickle cell disease (SCD) is an autosomal recessive inherited hematological disorder characterized by chronic hemolysis and vaso-occlusion, resulting in multiorgan dysfunction and premature death. The only known curative therapy for patients with severe SCD is myeloablative conditioning and allo-SCT from HLA-matched sibling donors. In this state of the art review, we discuss current and future considerations including patient selection/eligibility, intensity of conditioning regimens, allogeneic graft sources, graft manipulation, mixed donor chimerism, organ function and stability and autologous gene correction stem cell strategies. Recent novel approaches to promote mixed donor chimerism have included the use of matched unrelated adult donors, umbilical cord blood donors, haploidentical familial donors and the utilization of nonmyeloablative, such as reduced intensity and reduced toxicity conditioning regimens. Future strategies will include gene therapy and autologous gene correction stem cell designs. Prospects are bright for novel stem and cellular approaches for patients with severe SCD, and we are currently at the end of the beginning for utilizing cellular therapeutics for the curative treatment of this chronic and debilitating condition.

Anti-reflux surgery in lung transplant recipients: outcomes and effects on quality of life.

Fundoplication may improve survival after lung transplantation. Little is known about the effects of fundoplication on quality of life in these patients. The aim of this study was to assess the safety of fundoplication in lung transplant recipients and its effects on quality of life. Between June 1, 2008 and December 31, 2010, a prospective study of lung transplant recipients undergoing fundoplication was undertaken. Quality of life was assessed before and after surgery. Body mass index (BMI) and pulmonary function were followed up. 16 patients, mean ± sd age 38 ± 11.9 yrs, underwent laparoscopic Nissen fundoplication. There was no peri-operative mortality or major complications. Mean ± SD hospital stay was 2.6 ± 0.9 days. 15 out of 16 patients were satisfied with the results of surgery post fundoplication. There was a significant improvement in reflux symptom index and DeMeester questionnaires and gastrointestinal quality of life index scores at 6 months. Mean BMI decreased significantly after fundoplication (p = 0.01). Patients operated on for deteriorating lung function had a statistically significant decrease in the rate of lung function decline after fundoplication (p = 0.008). Laparoscopic fundoplication is safe in selected lung transplant recipients. Patient benefit is suggested by improved symptoms and satisfaction. This procedure is acceptable, improves quality of life and may reduce deterioration of lung function.

Legionella jordanis in hematopoietic SCT patients radiographically mimicking invasive mold infection.

Opportunistic pulmonary infections are a major cause of post-transplant morbidity and mortality. Among these infections, Aspergillus is a common cause of fatal pneumonia. Owing to the precarious clinical condition of many patients who acquire invasive mold infections, clinicians often treat them on the basis of radiographic findings, such as the halo sign. However, in patients who do not respond to treatment or who have uncommon presentations, bronchoscopy or lung biopsy looking for other pathogens should be considered. This study describes two cases in which the radiographic halo signs characteristic of Aspergillus were in fact due to Legionella jordanis, a pathogen that has been culture proven only in two patients previously (both of whom had underlying lung pathology) and diagnosed by serologic evidence in several other patients. In immunocompromised patients, Legionella can present as a cavitary lesion. Thus, presumptive treatment for this organism should be considered in post-transplant patients who do not have a classic presentation for invasive fungal infection and/or who fail to respond to conventional treatment. These cases illustrate the importance of obtaining tissue cultures to differentiate among the wide variety of pathogens present in this patient population.

Second-line age-adjusted International Prognostic Index in patients with advanced non-Hodgkin lymphoma after T-cell depleted allogeneic hematopoietic SCT.

T-cell depleted allogeneic hematopoietic SCT (TCD-HSCT) have shown durable disease-free survival with a low risk of GVHD in patients with AML. We investigated this approach in 61 patients with primary refractory or relapsed non-Hodgkin lymphoma (NHL), who underwent TCD-HSCT from January 1992 through September 2004. Patients received myeloablative cytoreduction consisting of hyperfractionated total body irradiation, followed by either thiotepa and cyclophosphamide (45 patients) or thiotepa and fludarabine (16 patients). We determined the second-line age-adjusted International Prognostic Index score (sAAIPI) before transplant transplant. Median follow-up of surviving patients is 6 years. The 10-year OS and EFS were 50% and 43%, respectively. The relapse rate at 10 years was 21% in patients with chemosensitive disease and 52% in those with resistant disease at time of HSCT. Nine of the 18 patients who relapsed entered a subsequent CR. OS (P=0.01) correlated with the sAAIPI. The incidence of grades II-IV acute GVHD was 18%. We conclude that allogeneic TCD-HSCT can induce high rates of OS and EFS in advanced NHL with a low incidence of GVHD. Furthermore, the sAAIPI can predict outcomes and may be used to select the most appropriate patients for this type of transplant.

Comparison of the effectiveness of painting onto the hand and immersing the hand in a bag, in pre-operative skin preparation of the hand.

The main goal of pre-operative skin preparation is to reduce the risk of postoperative wound infections by removing transient and commensal organisms from the skin. The aim of this study was to compare two methods of application of antiseptic solution in their effectiveness in removing these organisms from the skin. Fifty volunteers participated in the study. In 25 patients, the left hand was prepared using a standard paint technique and the right hand using the bag technique; in the other 25 the right was painted and the left was prepared using the bag technique. Three areas of the hand were examined: the paronychium of the thumb, the second web space and the hyponychium of the middle finger. Bacterial cultures were assessed after 5 days for growth. The bag technique proved better at removing organisms from the skin when comparing each site, and when comparing the total number of colony forming units (P = 0.002 for the thumb, P = 0.013 for the second web space and P = 0.003 for the middle finger). We concluded that pre-operative application of povidoneiodine to a hand using a non-sterile bag technique is more effective in removing skin organisms than the standard paint technique.

Long-term follow-up of patients treated with daclizumab for steroid-refractory acute graft-vs-host disease.

Daclizumab has been shown to have activity in acute GVHD, but appears to be associated with an increased risk of infection. To investigate further the long-term effects of daclizumab, we performed a retrospective review of 57 patients who underwent an allogeneic hematopoietic stem cell transplant from January 1993 through June 2000 and were treated with daclizumab for steroid-refractory acute GVHD. The median number of daclizumab doses given was 5 (range 1-22). GVHD was assessed at baseline, days 15, 29 and 43. By day 43, 54% patients had an improvement in their overall GVHD score, including 76% patients aged < or =18. Opportunistic infections developed in 95% patients. Forty-three patients (75%) died following treatment with daclizumab. The causes of death included active GVHD and infection (79%), active GVHD (5%), chronic GVHD (2%) and relapse (14%). Patients with grade 3-4 GVHD had a significantly shorter median survival than patients with grade 1-2 GVHD (2.0 vs 5.1 months, P=0.001). Daclizumab has no infusion-related toxicity, is active in steroid-refractory GVHD, especially among pediatric patients, but is associated with significant morbidity and mortality due to infectious complications. Careful patient selection and aggressive prophylaxis against viral and fungal infections are recommended.

Final height in pediatric patients after hyperfractionated total body irradiation and stem cell transplantation.

Impaired linear growth has been shown to occur in individuals treated during childhood with single-dose and fractionated total body irradiation (TBI) before stem cell transplantation. Our objective was to describe the final heights attained and patient/treatment factors correlating with final height in a cohort of childhood cancer survivors treated with hyperfractionated TBI (total dose 1375 or 1500 cGy). Thirty individuals (18 men) were included in the study. The mean final height standard deviation score (s.d.s.) was -1.9 +/- 0.2, significantly lower than height s.d.s. at TBI (-0.2 +/- 0.2, P < 0.001). Final height s.d.s. was significantly correlated with age at diagnosis, age at TBI and target height (P = 0.04, P < 0.001, P < 0.001, respectively). Treatment with growth hormone (GH) (n = 7) maintained mean height s.d.s. at -2.0 from the onset of GH therapy until attainment of final height. The mean final sitting height s.d.s. was -2.2 +/- 0.2 (n = 16), significantly shorter than mean final standing height s.d.s. (P < 0.01). In conclusion, treatment with hyperfractionated TBI is associated with a reduction in standing height and an even greater reduction in sitting height. Final height after hyperfractionated TBI was similar to that reported after fractionated TBI.