Characteristics of feed efficiency within and across lactation in dairy cows and the effect of genetic selection.

The objective of the present study was to investigate the phenotypic inter- and intra-relationships within and among alternative feed efficiency metrics across different stages of lactation and parities; the expected effect of genetic selection for feed efficiency on the resulting phenotypic lactation profiles was also quantified. A total of 8,199 net energy intake (NEI) test-day records from 2,505 lactations on 1,290 cows were used. Derived efficiency traits were either ratio based or residual based; the latter were derived from least squares regression models. Residual energy intake (REI) was defined as NEI minus predicted energy requirements based on lactation performance; residual energy production (REP) was defined as net energy for lactation minus predicted energy requirements based on lactation performance. Energy conversion efficiency was defined as net energy for lactation divided by NEI. Pearson phenotypic correlations among traits were computed across lactation stages and parities, and the significance of the differences was determined using the Fisher r-to-z transformation. Sources of variation in the feed efficiency metrics were investigated using linear mixed models, which included the fixed effects of contemporary group, breed, parity, stage of lactation, and the 2-way interaction of parity by stage of lactation. With the exception of REI, parity was associated with all efficiency and production traits. Stage of lactation, as well as the 2-way interaction of parity by stage of lactation, were associated with all efficiency and production traits. Phenotypic correlations among the efficiency and production traits differed not only by stage of lactation but also by parity. For example, the strong phenotypic correlation between REI and energy balance (EB; 0.89) for cows in parity 3 or greater and early lactation was weaker for parity 1 cows at the same lactation stage (0.81), suggesting primiparous cows use the ingested energy for both milk production and growth. Nonetheless, these strong phenotypic correlations between REI and EB suggested negative REI animals (i.e., more efficient) are also in more negative EB. These correlations were further supported when assessing the effect on phenotypic performance of animals genetically divergent for feed intake and efficiency based on parental average. Animals genetically selected to have lower REI resulted in cows who consumed less NEI but were also in negative EB throughout the entire lactation. Nonetheless, such repercussions of negative EB do not imply that selection for negative REI (as defined here) should not be practiced, but instead should be undertaken within the framework of a balanced breeding objective, which includes traits such as reproduction and health.

Pharmacological Characterization of a Novel Beta 3 Adrenergic Agonist, Vibegron: Evaluation of Antimuscarinic Receptor Selectivity for Combination Therapy for Overactive Bladder.

Although the physiologic role of muscarinic receptors in bladder function and the therapeutic efficacy of muscarinic antagonists for the treatment of overactive bladder are well established, the role of ß3-adrenergic receptors (ß3ARs) and their potential as therapeutics is just emerging. In this manuscript, we characterized the pharmacology of a novel ß3AR agonist vibegron (MK-4618, KRP-114V) and explored mechanistic interactions of ß3AR agonism and muscarinic antagonism in urinary bladder function. Vibegron is a potent, selective full ß3AR agonist across species, and it dose dependently increased bladder capacity, decreased micturition pressure, and increased bladder compliance in rhesus monkeys. The relaxation effect of vibegron was enhanced when combined with muscarinic antagonists, but differentially influenced by muscarinic receptor subtype selectivity. The effect was greater when vibegron was co-administered with tolterodine, a nonselective antagonist, compared with coadministration with darifenacin, a selective M3 antagonist. Furthermore, a synergistic effect for bladder strip relaxation was observed with the combination of a ß3AR agonist and tolterodine in contrast to simple additivity with darifenacin. To determine expression in rhesus bladder, we employed a novel ß3AR agonist probe, [3H]MRL-037, that selectively labels ß3 receptors in both urothelium and detrusor smooth muscle. Vibegron administration caused a dose-dependent increase in circulating glycerol and fatty acid levels in rhesus and rat in vivo, suggesting these circulating lipids can be surrogate biomarkers. The translation of our observation to the clinic has yet to be determined, but the combination of ß3AR agonists with M2/M3 antimuscarinics has the potential to redefine the standard of care for the pharmacological treatment of overactive bladder.

Genetics of alternative definitions of feed efficiency in grazing lactating dairy cows.

The objective of the present study was to estimate genetic parameters across lactation for measures of energy balance (EB) and a range of feed efficiency variables as well as to quantify the genetic inter-relationships between them. Net energy intake (NEI) from pasture and concentrate intake was estimated up to 8 times per lactation for 2,481 lactations from 1,274 Holstein-Friesian cows. A total of 8,134 individual feed intake measurements were used. Efficiency traits were either ratio based or residual based; the latter were derived from least squares regression models. Residual energy intake (REI) was defined as NEI minus predicted energy requirements [e.g., net energy of lactation (NEL), maintenance, and body tissue anabolism] or supplied from body tissue mobilization; residual energy production was defined as the difference between actual NEL and predicted NEL based on NEI, maintenance, and body tissue anabolism/catabolism. Energy conversion efficiency was defined as NEL divided by NEI. Random regression animal models were used to estimate residual, additive genetic, and permanent environmental (co)variances across lactation. Heritability across lactation stages varied from 0.03 to 0.36 for all efficiency traits. Within-trait genetic correlations tended to weaken as the interval between lactation stages compared lengthened for EB, REI, residual energy production, and NEI. Analysis of eigenvalues and associated eigenfunctions for EB and the efficiency traits indicate the ability to genetically alter the profile of these lactation curves to potentially improve dairy cow efficiency differently at different stages of lactation. Residual energy intake and EB were moderately to strongly genetically correlated with each other across lactation (genetic correlations ranged from 0.45 to 0.90), indicating that selection for lower REI alone (i.e., deemed efficient cows) would favor cows with a compromised energy status; nevertheless, selection for REI within a holistic breeding goal could be used to overcome such antagonisms. The smallest (8.90% of genetic variance) and middle (11.22% of genetic variance) eigenfunctions for REI changed sign during lactation, indicating the potential to alter the shape of the REI lactation profile. Results from the present study suggest exploitable genetic variation exists for a range of efficiency traits, and the magnitude of this variation is sufficiently large to justify consideration of the feed efficiency complex in future dairy breeding goals. Moreover, it is possible to alter the trajectories of the efficiency traits to suit a particular breeding objective, although this relies on very precise across-parity genetic parameter estimates, including genetic correlations with health and fertility traits (as well as other traits).

Inter-relationships among alternative definitions of feed efficiency in grazing lactating dairy cows.

International interest in feed efficiency, and in particular energy intake and residual energy intake (REI), is intensifying due to a greater global demand for animal-derived protein and energy sources. Feed efficiency is a trait of economic importance, and yet is overlooked in national dairy cow breeding goals. This is due primarily to a lack of accurate data on commercial animals, but also a lack of clarity on the most appropriate definition of the feed intake and utilization complex. The objective of the present study was to derive alternative definitions of energetic efficiency in grazing lactating dairy cows and to quantify the inter-relationships among these alternative definitions. Net energy intake (NEI) from pasture and concentrate intake was estimated up to 8 times per lactation for 2,693 lactations from 1,412 Holstein-Friesian cows. Energy values of feed were based on the French Net Energy system where 1 UFL is the net energy requirements for lactation equivalent of 1kg of air-dry barley. A total of 8,183 individual feed intake measurements were available. Energy balance was defined as the difference between NEI and energy expenditure. Efficiency traits were either ratio-based or residual-based; the latter were derived from least squares regression models. Residual energy intake was defined as NEI minus predicted energy to fulfill the requirements for the various energy sinks. The energy sinks (e.g., NEL, metabolic live weight) and additional contributors to energy kinetics (e.g., live weight loss) combined, explained 59% of the variation in NEI, implying that REI represented 41% of the variance in total NEI. The most efficient 10% of test-day records, as defined by REI (n=709), on average were associated with a 7.59 UFL/d less NEI (average NEI of the entire population was 16.23 UFL/d) than the least efficient 10% of test-day records based on REI (n=709). Additionally, the most efficient 10% of test-day records, as defined by REI, were associated with superior energy conversion efficiency (ECE, i.e., NEL divided by NEI; ECE=0.55) compared with the least efficient 10% of test-day records (ECE=0.33). Moreover, REI was positively correlated with energy balance, implying that more negative REI animals (i.e., deemed more efficient) are expected to be, on average, in greater negative energy balance. Many of the correlations among the 14 defined efficiency traits differed from unity, implying that each trait is measuring a different aspect of efficiency.

Identification of proteomic biomarkers predicting prostate cancer aggressiveness and lethality despite biopsy-sampling error.

BACKGROUND: Key challenges of biopsy-based determination of prostate cancer aggressiveness include tumour heterogeneity, biopsy-sampling error, and variations in biopsy interpretation. The resulting uncertainty in risk assessment leads to significant overtreatment, with associated costs and morbidity. We developed a performance-based strategy to identify protein biomarkers predictive of prostate cancer aggressiveness and lethality regardless of biopsy-sampling variation. METHODS: Prostatectomy samples from a large patient cohort with long follow-up were blindly assessed by expert pathologists who identified the tissue regions with the highest and lowest Gleason grade from each patient. To simulate biopsy-sampling error, a core from a high- and a low-Gleason area from each patient sample was used to generate a 'high' and a 'low' tumour microarray, respectively. RESULTS: Using a quantitative proteomics approach, we identified from 160 candidates 12 biomarkers that predicted prostate cancer aggressiveness (surgical Gleason and TNM stage) and lethal outcome robustly in both high- and low-Gleason areas. Conversely, a previously reported lethal outcome-predictive marker signature for prostatectomy tissue was unable to perform under circumstances of maximal sampling error. CONCLUSIONS: Our results have important implications for cancer biomarker discovery in general and development of a sampling error-resistant clinical biopsy test for prediction of prostate cancer aggressiveness.

Seroprevalence of reproductive and infectious diseases in cattle: the case of Madre de Dios in the Peruvian southeastern tropics.

OBJECTIVE: The objective of this study was to determine the seroprevalence of reproductive and infectious diseases in tropical cattle in the Tambopata and Tahuamanu Provinces in the department of Madre de Dios, Peru. SAMPLE: 156 bovines from 7 cattle farms were sampled. These farms used exclusive grazing for food and natural mating for reproduction and did not have sanitary or vaccination programs. METHODS: The serum of blood samples was subjected to ELISA with commercial kits for the detection of antibodies against Neospora caninum, Mycobacterium avium subsp paratuberculosis (MAP), Leptospira interrogans, pestivirus bovine viral diarrhea virus-1, retrovirus bovine leukemia virus (BLV), orbivirus bluetongue virus (BTV), and herpesvirus bovine herpes virus-1 (BHV). The data were analyzed by means of association tests with χ2 (P < .05) and Spearman rank correlation (P < .05) in the SPSS v.15.0 software (IBM Corp). RESULTS: A low prevalence of antibodies to L interrogans, N caninum, M avium subsp paratuberculosis, bovine viral diarrhea virus-1 was found, but it was high to BTV, BLV, and BHV (100%, 53.85%, and 72.44%, respectively). The presence of BLV and BHV was higher in the Las Piedras District, bovines less than 5 years old, and cattle with breed characteristics of zebu and crossbred (P < .01). In addition, there was a significant correlation between both infections, showing 83.3% of BLV positivity that were also BHV positive (P < .01). CLINICAL RELEVANCE: The high prevalence of antibodies to BTV, BHV, and BLV could be due to livestock management practices, direct contact with infected animals, and variation of the presence of vectors and natural reservoirs in the context of climate change in the tropics.

The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged anti-retroviral therapy.

Replication-competent HIV-1 can be isolated from infected patients despite prolonged plasma virus suppression by anti-retroviral treatment. Recent studies have identified resting, memory CD4+ T lymphocytes as a long-lived latent reservoir of HIV-1 (refs. 4,5). Cross-sectional analyses indicate that the reservoir is rather small, between 103 and 107 cells per patient. In individuals whose plasma viremia levels are well suppressed by anti-retroviral therapy, peripheral blood mononuclear cells containing replication-competent HIV-1 were found to decay with a mean half-life of approximately 6 months, close to the decay characteristics of memory lymphocytes in humans and monkeys. In contrast, little decay was found in a less-selective patient population. We undertook this study to address this apparent discrepancy. Using a quantitative micro-culture assay, we demonstrate here that the latent reservoir decays with a mean half-life of 6.3 months in patients who consistently maintain plasma HIV-1 RNA levels of fewer than 50 copies/ml. Slower decay rates occur in individuals who experience intermittent episodes of plasma viremia. Our findings indicate that the persistence of the latent reservoir of HIV-1 despite prolonged treatment is due not only to its slow intrinsic decay characteristics but also to the inability of current drug regimens to completely block HIV-1 replication.

Effect of Photoperiod with Sunlight at Thermal Stress and Sperm Parameters in Guinea Pigs.

<b>Background and Objective:</b> Photoperiod can regulate reproductive physiological processes in mammals, in which improvements in testosterone concentration, testicular volume and seminal quality have been reported. The aim was to evaluate the influence of photoperiod treatments on guinea pigs' spermatic parameters. <b>Materials and Methods:</b> Thirty guinea pigs, between males and females, were distributed in two rooms with the photoperiodic treatment of 10 hrs light and 14 hrs dark (PT₁ with artificial photoperiod and PT₂ photoperiod with sunlight by opening windows from 08:00-18:00) and one without any direct light stimulus (PT₀) for 78 days. The temperature and humidity were recorded and the TH index was calculated for each room. The sperms were recovered in Tris base medium from the epididymis of 16 males to determine sperm concentration, motility, kinetic parameters, vitality, HOST, acrosomal integrity and DNA fragmentation. <b>Results:</b> Sperm values in PT₁ and PT₀ were similar but PT₂ obtained values lower in sperm concentration, non-progressive motility, total motility, VCL, ALH, vitality, HOST+, acrosomal integrity, sperm with non-fragmented DNA and no pregnancies were reported (0/5). A 100% pregnancy was observed in PT₀ (4/4) and 50% in PT₁ (2/4). However, precocity was evidenced in PT₁ compared to PT₀. PT₂ recorded higher peaks in temperature (33.8°C, THI 81, considered as thermal stress) compared to PT₀ (32.65°C, THI 81.8) and PT₁ (32.75°C, THI 81.6). <b>Conclusion:</b> An artificial photoperiod can improve sperm characteristics and reproductive precociousness of guinea pigs, unlike the photoperiod with sunlight, which generated low spermiogram values and absence of pregnancy due to thermal stress.

HIV-1 antigen-specific and -nonspecific B cell responses are sensitive to combination antiretroviral therapy.

We studied how combination antiviral therapy affects B cell abnormalities associated with HIV-1 infection, namely elevated circulating immunoglobulin (Ig)G antibody-secreting cell (ASC) frequencies and hypergammaglobulinemia. Within a few weeks of starting antiviral therapy, there is a marked decline in IgG-ASC frequency in both acutely and chronically infected people, whereas the hypergammaglobulinemia often present during chronic infection is more gradually resolved. These reductions are sustained while HIV-1 replication is suppressed. HIV-1 antigen-specific B cell responses are also affected by therapy, manifested by a rapid decline in circulating gp120-specific ASCs. Anti-gp120 titers slowly decrease in chronically infected individuals and usually fail to mature in acutely infected individuals who were promptly treated with antiretroviral therapy. Long-term nonprogressors have high titer antibody responses to HIV-1 antigens, but no detectable gp120-specific IgG-ASC, and normal (or subnormal) levels of total circulating IgG-ASC. Overall, we conclude that HIV-1 infection drives B cell hyperactivity, and that this polyclonal activation is rapidly responsive to decreases in viral replication caused by combination antiviral therapy.

Increased turnover of T lymphocytes in HIV-1 infection and its reduction by antiretroviral therapy.

The mechanism of CD4(+) T cell depletion in human immunodeficiency virus (HIV)-1 infection remains controversial. Using deuterated glucose to label the DNA of proliferating cells in vivo, we studied T cell dynamics in four normal subjects and seven HIV-1-infected patients naive to antiretroviral drugs. The results were analyzed using a newly developed mathematical model to determine fractional rates of lymphocyte proliferation and death. In CD4(+) T cells, mean proliferation and death rates were elevated by 6.3- and 2.9-fold, respectively, in infected patients compared with normal controls. In CD8(+) T cells, the mean proliferation rate was 7.7-fold higher in HIV-1 infection, but the mean death rate was not significantly increased. Five of the infected patients underwent subsequent deuterated glucose labeling studies after initiating antiretroviral therapy. The lymphocyte proliferation and death rates in both CD4(+) and CD8(+) cell populations were substantially reduced by 5-11 weeks and nearly normal by one year. Taken together, these new findings strongly indicate that CD4(+) lymphocyte depletion seen in AIDS is primarily a consequence of increased cellular destruction, not decreased cellular production.

Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA.

Although cytotoxic T lymphocytes (CTLs) are thought to be involved in the control of human immunodeficiency virus-type 1 (HIV-1) infection, it has not been possible to demonstrate a direct relation between CTL activity and plasma RNA viral load. Human leukocyte antigen-peptide tetrameric complexes offer a specific means to directly quantitate circulating CTLs ex vivo. With the use of the tetrameric complexes, a significant inverse correlation was observed between HIV-specific CTL frequency and plasma RNA viral load. In contrast, no significant association was detected between the clearance rate of productively infected cells and frequency of HIV-specific CTLs. These data are consistent with a significant role for HIV-specific CTLs in the control of HIV infection and suggest a considerable cytopathic effect of the virus in vivo.

Using bacteriophages to modulate Salmonella colonization of the chicken's gastrointestinal tract: lessons learned from in silico and in vivo modeling.

An increasing prevalence of antibiotic-resistant foodborne infections has resulted in considerable concern about how antimicrobials are used in meat and poultry production. Because many foodborne bacterial pathogens are commonly found among the intestinal bacterial community of poultry, new methods of prevention are being considered. Bacteriophage therapy is one such alternative method that has not been well developed in the United States; however, bacteriophages have been shown to be effective in modulating bacterial numbers in acute infection models. In this study we evaluated whether bacteriophages could theoretically reduce Salmonella colonization of the gastrointestinal tract of chickens. Using computer simulations, we studied bacteriophage and bacterial replication dynamics in a mathematical model based on parameters expected to occur in the intestinal environment. In addition, we performed in vivo experiments by administering SP6 bacteriophage and Salmonella orally to young chickens and compared the levels of phage and Salmonella shed in the feces to the models of replication dynamics. SP6 is an ideal candidate bacteriophage because its genome and target receptor are known. Although SP6 did not reduce the levels of Salmonella shed by treated birds, most of the isolates recovered from treated birds were not resistant to the bacteriophage. These results suggest that phage resistance may not be the primary limiting parameter of phage prophylaxis for modulating colonization of the intestine. Our findings that this phage could be replicated in vivo supports the attractiveness of phage use, because unlike antibiotics they may be amplified in vivo if given a suitable host on which to replicate. If successful, this approach to modulating bacterial colonization of the intestinal tract could have a tremendous effect on the meat and poultry industry by reducing the use of antimicrobial drugs and increasing the use of biological therapeutics.

Depression in adults with intellectual disability: symptoms and challenging behaviour.

BACKGROUND: Psychiatric evaluation of adults with intellectual disability (ID) remains complex because of limitations in verbal abilities, atypical clinical presentation and challenging behaviour. This study examines the clinical presentation of adults with depression compared with bipolar disorder, anxiety disorders and non-psychiatric control patients. METHOD: This study is a retrospective record review of the initial psychiatric diagnostic evaluation for 300 adult patients with ID drawn from a clinic population. Patients with major depression (n = 85) were compared with those with bipolar disorder (n = 70), anxiety disorders (n = 30) and control patients without psychiatric disorder (n = 27). Key symptoms of depression assessed during the interview were examined as well as challenging behaviour. RESULTS: Three symptoms were useful in differentiating depressed patients from all other groups: sad mood, crying, and anhedonia. Withdrawal, suicidality, and awakening during the night were significant compared with anxiety patients and controls; however, few patients reported suicidality. Bipolar patients were significantly different from depressed patients for elevated mood, acute anger episodes, increase in verbalization, pressure of speech, talk of sexual themes, increase in appetite and poor concentration. Anxiety patients had more fearfulness without withdrawal, sad mood, crying, anhedonia and suicidality. Challenging behaviour was most pronounced in bipolar patients; for depressed patients, aggression and impulsivity were significant compared with anxiety patients and controls. Overall, the control patients presented with few symptoms in any category. CONCLUSIONS: Sad mood, crying and anhedonia are key significant features of depression. Most patients with ID cannot meet the required number of DSM criteria or suggested DM-ID adapted criteria for major depression. Many depressive symptoms were reported in modest numbers and this was probably related to deficiencies in self-report or observational skills of caregivers. Challenging behaviour is not diagnostically specific. It is, however, a key atypical feature of depression.

Genetic characterization of rebounding HIV-1 after cessation of highly active antiretroviral therapy.

Despite prolonged treatment with highly active antiretroviral therapy (HAART), infectious HIV-1 continues to replicate and to reside latently in resting memory CD4(+) T lymphocytes, creating a major obstacle to HIV-1 eradication. It is therefore not surprising to observe a prompt viral rebound after discontinuation of HAART. The nature of the rebounding virus, however, remains undefined. We now report on the genetic characterization of rebounding viruses in eight patients in whom plasma viremia was undetectable throughout about 3 years of HAART. Taking advantage of the extensive length polymorphism in HIV-1 env, we found that in five patients who did not show HIV-1 replication during treatment, the rebound virus was identical to those isolated from the latent reservoir. In three other patients, two of whom had been free of plasma viremia but had showed some residual viral replication, the rebound virus was genetically different from the latent reservoir virus, corresponding instead to minor viral variants detected during the course of treatment in lymphoid tissues. We conclude that in cases with apparent complete HIV-1 suppression by HAART, viral rebound after cessation of therapy could have originated from the activation of virus from the latent reservoir. In patients with incomplete suppression by chemotherapy, however, the viral rebound is likely triggered by ongoing, low-level replication of HIV-1, perhaps occurring in lymphoid tissues.

HIV-1-specific immune responses in subjects who temporarily contain virus replication after discontinuation of highly active antiretroviral therapy.

Therapeutic intervention with highly active antiretroviral therapy (HAART) can lead to suppression of HIV-1 plasma viremia to undetectable levels for 3 or more years. However, adherence to complex drug regimens can prove problematic, and subjects may temporarily discontinue HAART for variable periods. We studied 6 HIV-1-infected individuals who stopped therapy. Off HAART, levels of viremia were suppressed to fewer than 500 copies/mL in 2 subjects for more than 12 and more than 24 months, respectively, and in 1 subject for 4 months on 1 occasion. Three subjects failed to contain plasma viremia. Broad and strong HIV-1-specific immune responses were detected in subjects with prolonged suppression of viral replication. This longitudinal study suggests that containment of HIV-1 replication to low or undetectable levels after discontinuation of HAART is associated with strong virus-specific immune responses. Boosting of HIV-1-specific immune responses should be considered as an adjunctive treatment strategy for HIV-1-infected individuals on HAART.

Do the mentally retarded suffer from affective illness?

Twenty-five published reports were reviewed regarding the occurrence of affective illness, ie, depression and mania, in mentally retarded individuals, using the DSM-III criteria to assess the validity of both diagnoses. Individuals with mental retardation (MR) were found to manifest the full range of affective disorders. Developmentally impaired social functioning and intelligence influence the clinical presentation, but not the development, of affective symptomatology. Affective disorder diagnoses can be made for patients with all levels of MR severity. In individuals with MR of mild and moderate severity, the diagnosis can be made using standard DSM-III criteria. For those with severe and profound MR, a clinically useful diagnosis can be based on changes in behavior and vegetative functioning, as well as family history of affective illness. The psychiatrically symptomatic person with MR should always be evaluated for affective symptomatology and be considered as a candidate for the full range of treatments, including psychotherapy and pharmacotherapy with antidepressants as well as lithium carbonate.

Efficacy and safety of CDX-301, recombinant human Flt3L, at expanding dendritic cells and hematopoietic stem cells in healthy human volunteers.

Fms-like tyrosine kinase-3 ligand (Flt3L) uniquely binds the Flt3 (CD135) receptor expressed on hematopoietic stem cells (HSCs), early progenitor cells, immature thymocytes and steady-state dendritic cells (DCs) and induces their proliferation, differentiation, development and mobilization in the bone marrow, peripheral blood and lymphoid organs. CDX-301 has an identical amino-acid sequence and comparable biological activity to the previously tested rhuFlt3L, which ceased clinical development over a decade ago. This Phase 1 trial assessed the safety, pharmacokinetic, pharmacodynamic and immunologic profile of CDX-301, explored alternate dosing regimens and examined the impact of rhuFlt3L on key immune cell subsets. Thirty healthy volunteers received CDX-301 (1-75 µg/kg/day) over 5-10 days. One event of Grade 3 community-acquired pneumonia occurred. There were no other infections, dose-limiting toxicities or serious adverse events. CDX-301 resulted in effective peripheral expansion of monocytes, hematopoietic stem and progenitor cells and key subsets of myeloid DCs and plasmacytoid DCs, with no clear effect on regulatory T cells. These data from healthy volunteers support the potential for CDX-301, as monotherapy or in combination with other agents, in various indications including allogeneic HSC transplantation and immunotherapy, but the effects of CDX-301 will need to be investigated in each of these patient populations.

Serotonergic modulation of dopamine measured with [11C]raclopride and PET in normal human subjects.

OBJECTIVE: This study was undertaken to measure serotonergic modulation of dopamine in vivo by using positron emission tomography (PET), a radiotracer for the striatal dopamine D2 receptor ([11C]raclopride), and a pharmacologic challenge of the serotonin system (d,l-fenfluramine). METHOD: Two PET studies using [11C]raclopride were performed in 11 normal male subjects before administration of the serotonin-releasing agent and reuptake inhibitor fenfluramine (60 mg p.o.) and 3 hours afterward. A graphical analysis method was used with the [11C]raclopride data to derive the distribution volume of D2 receptors. Plasma levels of fenfluramine, norfenfluramine, homovanillic acid (HVA), cortisol, and prolactin were determined. RESULTS: Levels of fenfluramine and prolactin were elevated 2 hours after fenfluramine administration and remained significantly elevated during the second scan, while levels of HVA and cortisol were not altered significantly during the time of scanning. A significant decrease in the specific binding (striatum) and the nonspecific binding subtracted from the specific binding (striatum minus cerebellum) of [11C]raclopride was observed. The rate of metabolism of [11C]raclopride and the nonspecific binding (cerebellum) were not significantly altered by the fenfluramine intervention. CONCLUSIONS: The observed decrease in [11C]raclopride binding is consistent with an increase in dopamine concentrations and with the ability of serotonin to stimulate dopamine activity. The ability to measure serotonergic modulation of dopamine in vivo may have implications for the study of etiologic and therapeutic mechanisms in schizophrenia, major depressive disorder, obsessive-compulsive disorder, and substance abuse.