Clonal dysregulation of the antibody response to tetanus-toxoid after bone marrow transplantation

After bone marrow transplantation (BMT), a prolonged dysregulation of humoral immunity can be observed. In the present study, we investigated whether this is reflected in an abnormal production of specific antibodies (Ab) to the T-cell-dependent recall antigen tetanus-toxoid (TT). The study group consisted of children receiving transplants of an unmodified allogeneic graft and of adults receiving either a T-cell- depleted allogeneic or an unmodified autologous BM graft. Findings were compared with those in healthy controls. In pediatric graft recipients, who were routinely revaccinated early after BMT, the Ab response was quantitatively superior to that in adult graft recipients who did not receive early revaccination. In the majority of graft recipients, the time period after vaccination required to reach the peak level of antibodies was prolonged and the number of responding TT-specific B- cell clones was markedly decreased in comparison with controls. In controls, a low frequency of dominant B-cell clones may produce low quantities of homogeneous Ab components (H-Ab) against a heterogeneous background. However, in BM graft recipients, "overshooting" of Ab production by separate B-cell clones was observed, resulting in the development of H-Ab at a relatively high concentration. These abnormalities were present up to 10 years after BMT, irrespective of either the age of the recipient, the modulation of the graft, or the vaccination schedule used. It is hypothesized that the dysregulated Ab production is the consequence of activation of a restricted number of resting memory B cells, present in germinal centers, repopulating gradually after BMT. Our data show that routine revaccination early after BMT improves the humoral immune response. However, because of a clonally dysregulated Ab production, long-lasting qualitative defects may be present even after normalization of Ab titers.     

Recombinant human interleukin-11 stimulates multilineage hematopoietic recovery in mice after a myelosuppressive regimen of sublethal irradiation and carboplatin

Interleukin-11 (IL-11) is a novel multifunctional hematopoietic cytokine capable of stimulating cells of the myeloid, lymphoid, erythroid, and megakaryocytic lineages in vitro. We have tested the pleiotropic properties of this cytokine on the hematopoietic recovery of mice after a combined regimen of sublethal irradiation and carboplatin administration. This regimen results in severe myelosuppression, characterized by a prolonged period of thrombocytopenia and severe anemia. Administration of recombinant human IL-11 (rhIL-11; 250 micrograms/kg/d) had multilineage effects on bone marrow and spleen hematopoietic activity, increasing the number of megakaryocyte, erythroid, granulocyte, and macrophage progenitors compared with the vehicle-treated controls. This was reflected in the peripheral circulation by a reduction of both the platelet and hematocrit nadirs and a significantly reduced period of thrombocytopenia and anemia in the rhIL-11-treated mice. The results from this study support the broad spectrum of biologic activities that have been attributed to rhIL-11 in vitro and suggest that this cytokine may be an effective agent in the treatment of myelosuppression associated with cancer chemotherapy and bone marrow transplantation.     

Abnormal function of the bone marrow microenvironment in chronic myelogenous leukemia: role of malignant stromal macrophages

The bone marrow microenvironment supports and regulates the proliferation and differentiation of hematopoietic cells. Dysregulated hematopoiesis in chronic myelogenous leukemia (CML) is caused, at least in part, by abnormalities in CML hematopoietic progenitors leading to altered interactions with the marrow microenvironment. The role of the microenvironment itself in CML has not been well characterized. We examined the capacity of CML stroma to support the growth of long-term culture-initiating cells (LTC-IC) obtained from normal and CML marrow. The growth of normal LTC-IC on CML stroma was significantly reduced compared with normal stroma. This did not appear to be related to abnormal production of soluble factors by CML stroma because normal LTC- IC grew equally well in Transwells above CML stroma as in Transwells above normal stroma. In addition, CML and normal stromal supernatants contained similar quantities of both growth-stimulatory (granulocyte colony-stimulating factor (CSF), interleukin-6, stem cell factor, granulocyte-macrophage CSF, and interleukin-1 beta) and growth- inhibitory cytokines (transforming growth factor-beta, macrophage inflammatory protein-1 alpha, and tumor necrosis factor-alpha). The relative proportion of different cell types in CML and normal stroma was similar. However, polymerase chain reaction and fluorescence in situ hybridization studies showed the presence of bcr-abl-positivo cells in CML stroma, which were CD14+ stromal macrophages. To assess the effect of these malignant macrophages on stromal function, CML and normal stromal cells were separated by fluorescence-activated cell sorting into stromal mesenchymal cell (CD14-) and macrophage (CD14+) populations. CML and normal CD14- cells supported the growth of normal LTC-IC equally well. However, the addition of CML macrophages to normal or CML CD14- mesenchymal cells resulted in impaired progenitor support. This finding indicates that the abnormal function of CML bone marrow stroma is related to the presence of malignant macrophages. In contrast to normal LTC-IC, the growth of CML LTC-IC on allogeneic CML stromal layers was not impaired and was significantly better than that of normal LTC-IC cocultured with the same CML stromal layers. These studies demonstrate that, in addition to abnormalities in CML progenitors themselves, abnormalities in the CML marrow microenvironment related to the presence of malignant stromal macrophages may contribute to the selective expansion of leukemic progenitors and suppression of normal hematopoiesis in CML.     

Beyond recidivism: changes in health and social service involvement following exposure to drug treatment court

Background

The majority of Drug Treatment Court (DTC) research has examined the impact of DTCs on criminal recidivism. Comparatively little research has addressed the association between DTC participation and engagement with community-based health and social services. The present study investigated changes in participant involvement with outpatient healthcare and income assistance within a DTC cohort. We hypothesized that involvement with community-based (outpatient) health and social services would increase post-DTC participation, and that service levels would be higher among program graduates and offenders with histories of co-occurring mental and substance use disorders.

Methods

Participants were 631 offenders at the DTC in Vancouver, Canada (DTCV). Administrative data representing hospital, outpatient medical care, and income assistance were examined one-year pre/post program to assess differences over time. Generalized estimating equations were used to investigate the association between changes in service use and program involvement. We also examined the relationship between level of service use and offender characteristics.

Results

Members of the cohort were disproportionately Aboriginal (33 %), had been sentenced 2.7 times in the 2 years preceding their index offence, and 50 % had been diagnosed with a non substance-related mental disorder in the five years preceding the index offence. The mean number of outpatient services post DTCV was 51, and the mean amount of social assistance paid was $5,897. Outpatient service use increased following exposure to DTCV (Adjusted Rate Ratio (ARR)?=?1.45) and was significantly higher among women (ARR?=?1.47), program graduation (ARR?=?1.23), and those previously diagnosed with concurrent substance use and mental disorders (ARR?=?4.92). Overall, hospital admissions did not increase post-program, although rates were significantly higher among women (ARR?=?1.76) and those with concurrent disorders (ARR?=?2.71). Income assistance increased significantly post program (ARR?=?1.16), and was significantly higher among women (ARR?=?1.03), and those diagnosed with substance use disorders (ARR?=?1.42) and concurrent disorders (ARR?=?1.72).

Conclusions

These findings suggest that the DTCV was a catalyst for increased participant engagement with community health and social supports, and that rates of service use were consistently higher among women and individuals with concurrent disorders. Research is needed to investigate the potential link between health and social support and reductions in recidivism associated with DTCs.

     

Prevalence of metabolic syndrome in retired National Football League players

The National Institute of Occupational Safety and Health mortality study of National Football League (NFL) players concluded that retired NFL linemen have an increased risk of cardiovascular death compared with both nonlinemen and the general population. Though elevated body mass index contributed to the increased cardiac risk of linemen, it could not fully account for the mortality observed, suggesting that other unmeasured cardiovascular risk factors were involved. We performed a cross-sectional prevalence study of metabolic syndrome (MS), and its individual component criteria, in 510 retired NFL players who were recruited to multicity health screenings from February 2004 through June 2006. The International Diabetes Federation criteria were used to define MS. The MS component criteria of body mass index>30 kg/m2, reduced high-density lipoprotein, and raised fasting glucose were more prevalent in linemen compared with nonlinemen (85.4% vs 50.3%, p<0.001; 42.1% vs 32.7%, p=0.04; 60.4% vs 37.6%, p<0.001, respectively). Metabolic syndrome was more prevalent in linemen compared with nonlinemen (59.8% vs 30.1%, p<0.001). In conclusion, linemen exhibited a high prevalence of MS, almost double the prevalence of their nonlinemen counterparts. These findings may partially explain the increased risk for cardiovascular death observed in retired linemen and could have significant public health implications for preprofessional training regimens and postprofessional health maintenance.     

Cardiovascular risk after bariatric surgery for obesity

Obese patients have an increased prevalence of cardiovascular (CV) risk factors, which improve with bariatric surgery, but whether bariatric surgery reduces long-term CV events remains ill defined. A systematic review of published research was conducted, and CV risk models were applied in a validation cohort previously published. A standardized MEDLINE search using terms associated with obesity, bariatric surgery, and CV risk factors identified 6 test studies. The validation cohort consisted of a population-based, historical cohort of 197 patients who underwent Roux-en-Y gastric bypass and 163 control patients, identified through the Rochester Epidemiology Project. Framingham and Prospective Cardiovascular Munster Heart Study (PROCAM) risk scores were applied to calculate 10-year CV risk. In the validation cohort, absolute 10-year Framingham risk score for CV events was lower at follow-up in the bariatric surgery group (7.0% to 3.5%, p <0.001) compared with controls (7.1% to 6.5%, p = 0.13), with an intergroup absolute difference in risk reduction of 3% (p <0.001). PROCAM risk in the bariatric surgery group decreased from 4.1% to 2.0% (p <0.001), whereas the control group exhibited only a modest decrease (4.4% to 3.8%, p = 0.08). Using mean data from the validation study, the trend and directionality in risk was similar in the Roux-en-Y group. The test studies confirmed the directionality of CV risk, with estimated relative risk reductions for bariatric surgery patients ranging from 18% to 79% using the Framingham risk score compared with 8% to 62% using the PROCAM risk score. In conclusion, bariatric surgery predicts long-term decreases in CV risk in obese patients.     

Effects of beta-blocker therapy on ventilatory responses to exercise in patients with heart failure

BACKGROUND: Ventilatory efficiency is the increase in ventilation relative to carbon dioxide production during exercise. Congestive heart failure (CHF) is associated with decreased ventilatory efficiency. beta-blockers improve hemodynamics, prolong survival, and improve functional class in patients with CHF, though peak exercise performance may not improve. We hypothesized beta-blockers increase ventilatory efficiency in patients with CHF. METHODS AND RESULTS: The study group comprised 614 subjects with left ventricular ejection fraction < or = 40% referred for cardiopulmonary exercise testing. Clinical and exercise data were reviewed and recorded. For comparison, subjects were divided into those treated with beta-blockers (n = 195) and those not treated (n = 419). Subjects on beta-blockers had lower minute ventilation (12 +/- 4 versus 14 +/- 4 L/min, P < .001) at rest, which remained lower during submaximal and maximal exercise, by 4 and 6 L/min, respectively (P = .001). Ventilatory efficiency was increased in subjects treated with beta-blockers at submaximal (32 +/- 6 versus 34 +/- 7, P = .002) and maximal (34 +/- 7 versus 37 +/- 10, P = .005) exercise. Differences between treatment subgroups remained significant by covariate analysis; beta-blockers were also independently associated with decreased minute ventilation by multiple regression. CONCLUSION: Beta-blockers may be associated with increased ventilatory efficiency in CHF patients, which may contribute to improved functional class and quality of life.