Seasonal variation of serotonin turnover in human cerebrospinal fluid,depressive symptoms and the role of the 5-HTTLPR

Studying monoaminergic seasonality is likely to improve our understanding of neurobiological mechanisms underlying season-associated physiological and pathophysiological behavior. Studies of monoaminergic seasonality and the influence of the serotonin-transporter-linked polymorphic region (5-HTTLPR) on serotonin seasonality have yielded conflicting results, possibly due to lack of power and absence of multi-year analyses. We aimed to assess the extent of seasonal monoamine turnover and examined the possible involvement of the 5-HTTLPR. To determine the influence of seasonality on monoamine turnover, 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured in the cerebrospinal fluid of 479 human subjects collected during a 3-year period. Cosine and non-parametric seasonal modeling were applied to both metabolites. We computed serotonin (5-HT) seasonality values and performed an association analysis with the s/l alleles of the 5-HTTLPR. Depressive symptomatology was assessed using the Beck Depression Inventory-II. Circannual variation in 5-HIAA fitted a spring-peak cosine model that was significantly associated with sampling month (P=0.0074). Season of sampling explained 5.4% (P=1.57 × 10⁻⁷) of the variance in 5-HIAA concentrations. The 5-HTTLPR s-allele was associated with increased 5-HIAA seasonality (standardized regression coefficient=0.12, P=0.020, N=393). 5-HIAA seasonality correlated with depressive symptoms (Spearman''s rho=0.13, P=0.018, N=345). In conclusion, we highlight a dose-dependent association of the 5-HTTLPR with 5-HIAA seasonality and a positive correlation between 5-HIAA seasonality and depressive symptomatology. The presented data set the stage for follow-up in clinical populations with a role for seasonality, such as affective disorders.     

Comparison of conventional and highly-sensitive troponin I measurement in ultra-marathon runners

Cardiac troponins are a mainstay in the diagnostic approach of patients with suspected acute coronary syndrome. Along with other causes of cardiac injury, strenuous aerobic exercise is an important source of troponin leakage from myocardium. Due to recent immunoassays development, there is no information on variation of highly-sensitive (HS) troponin I (TnI) in ultra-marathon runners. We studied 15 healthy trained Caucasian athletes before and immediately after completion of a 60 km, ultra-marathon. TnI was measured with both the conventional AccuTnI and the novel HS-AccuTnI immunoassays. At the end of the ultra-marathon the concentration of HS-AccuTnI significantly increased from the baseline value (19.2 ± 4.2 vs. 5.2 ± 0.8 ng/l; P = 0.001). The number of athletes displaying HS-AccuTnI values exceeding the 99th percentile of the reference limit was 2 (13%) pre-exercise, increasing significantly to 12 (80%; P < 0.001) post-exercise. Measurable value of AccuTnI were found in 1 (7%) and 12 (80%; P < 0.001) athletes pre- and post exercise, respectively. All AccuTnI values were below the 99th percentile reference limit pre-exercise, whereas this cut-off was overcome in 20% of athletes, post-exercise. These results suggest that the myocardium release of TnI during strenuous aerobic exercise mirrors that of troponin T. Moreover, the improved sensitivity of the HS-AccuTnI over the conventional assay makes it more suited for detecting even minor elevations of TnI in blood.     

Frequency and Intensity of Postoperative Surveillance After Curative Treatment of Pancreatic Cancer: A Cost-Effectiveness Analysis

Background

Few data exist to guide oncologic surveillance following curative treatment of pancreatic cancer. We sought to identify a rational, cost-effective postoperative surveillance strategy.

Methods

We constructed a Markov model to compare the cost-effectiveness of 5 postoperative surveillance strategies. No scheduled surveillance served as the baseline strategy. Clinical evaluation and carbohydrate antigen (CA) 19-9 testing without/with routine computed tomography and chest X-ray at either 6- or 3-month intervals served as the 4 comparison strategies of increasing intensity. We populated the model with symptom, recurrence, treatment, and survival data from patients who had received intensive surveillance after multimodality treatment at our institution between 1998 and 2008. Costs were based on Medicare payments (2011 US dollars).

Results

The baseline strategy of no scheduled surveillance was associated with a postoperative overall survival (OS) of 24.6 months and a cost of $3837/patient. Clinical evaluation and CA 19-9 assay every 6 months until recurrence was associated with a 32.8-month OS and a cost of $7496/patient, with an incremental cost-effectiveness ratio (ICER) of $5364/life-year (LY). Additional routine imaging every 6 months incrementally increased total cost by $3465 without increasing OS. ICERs associated with clinic visits every 3 months without/with routine imaging were $127,680 and $294,696/LY, respectively. Sensitivity analyses changed the strategies’ absolute costs but not the relative ranks of their ICERs.

Conclusions

Increasing the frequency and intensity of postoperative surveillance of patients after curative therapy for pancreatic cancer beyond clinical evaluation and CA 19-9 testing every 6 months increases cost but confers no clinically significant survival benefit.     

Resistance exercise in chronic heart failure: hemodynamic and metabolic adjustments

The aim of this study was to characterize hemodynamic and metabolic responses to dynamic resistance exercise in chronic heart failure patients (CHF) compared to healthy older men (CTR). We hypothesized that in controlled conditions; pharmacologically treated CHF should show the adaptations to the strength exercises similar to healthy subjects, demonstrating therefore the compatibility with the practical on field. We addressed the acute effects of dynamic resistance exercise in eight CHF patients and eleven age-matched CTRs, instrumented for expiratory gas and cardiovascular analysis. All subjects performed two series with up to twelve repetitions at 70 % of 1RM on a leg press machine. Arterial pressure and heart rate progressively increased throughout the movements and decreased on cessation, while stroke volume (Modelflow software) decreased by 30 % at the start and increased by 10 % at cessation. Cardiac output increased at cessation only. All values were lower in CHF, but the changes during the exercises were not significantly different from those of CTR. Oxygen consumption increased during the exercises and continued increasing thereafter up to 60–70 % V’O_2max (absolute changes were smaller in CHF). We concluded that the response to dynamic resistance exercise is characterized by a sharp hindrance to the output of blood from the heart, which reduces stroke volume and enhances arterial pressure in CHF as well as in CTR. The simultaneous increase in heart rate kept cardiac output unaltered. The most important differences concerned a reduced metabolic response during exercise in CHF, even more evident in rest. Chronic heart failure syndrome and its treatment do not interfere with the cardiovascular responses to these kinds of physical activities. This finding can be considered a step forward in demonstrating that patients with chronic heart failure can, in controlled conditions, safely practice these essential exercises to preserve their muscle integrity.     

Transient neonatal hemolytic anemia due to the novel gamma globin gene mutation HBG2:C.290T>C,p.Leu97Pro (hemoglobin Wareham)

Unstable gamma globin variants can cause transient neonatal hemolytic anemia. We have identified a novel variant in a newborn who presented with jaundice and anemia requiring phototherapy and red blood cell transfusion. The patient was found to be heterozygous for the mutation HGB2:c.290T>C, p.Leu97Pro, which we have termed hemoglobin (Hb) Wareham. This substitution is expected to generate an unstable hemoglobin with increased oxygen affinity based on the homologous mutation previously described in the beta globin gene, which is termed as Hb Debrousse. The patient fully recovered by 9 months of age as expected with the transition from fetal to adult hemoglobin.     

The severe combined immunodeficient-human peripheral blood stem cell (SCID-huPBSC) mouse: a xenotransplant model for huPBSC-initiated hematopoiesis

Mononuclear cells (MNCs) containing peripheral blood stem cells (PBSCs) were obtained from solid-tumor patients undergoing mobilizing chemotherapy followed by granulocyte colony-stimulating factor for PBSC transplantation-supported dose-intensified anticancer chemotherapy and were transplanted into unconditioned "nonleaky" young severe combined immunodeficient mice. Multilineage engraftment was shown by flow cytometry and immunocytochemistry using monoclonal antibodies to various human cell surface antigens as well as identification of human immunoglobulin in murine sera. Within a dose range of MNCs suitable for transplantation (10 to 36 x 10(6) cells/graft) the number of CD34+ cells injected (optimal at > 0.7 x 10(6)/graft) determined the yield of human cells produced in recipient animals. Engraftment of hu PBSC preparations resulted in prolonged generation of physiologic levels of human cytokines including interleukin-3 (IL-3), IL-6, and granulocyte- macrophage colony-stimulating factor, which were detectable in the murine blood over a period of at least 4 months. In vivo survival of immature human progenitor cells was preserved even 9 months after transplantation. Because human IL-3 is known to stimulate early hematopoiesis, a rat fibroblast cell line was stably transfected with a retroviral vector carrying the human IL-3 gene and cotransplanted subcutaneously as additional source of growth factor. Cotransplants of this cell line producing sustained in vivo levels of circulating human IL-3 for at least 12 weeks significantly accelerated the process of engraftment of huPBSC and spurred the spread of mature human cells to the murine spleen, liver, thymus, and peripheral blood. Cotransplants of allogeneic human bone marrow stromal cells derived from long-term cultures resulted in a comparable--though less prominent--support of engraftment.