The PPARγ agonist pioglitazone produces a female-predominant inhibition of hyperalgesia associated with surgical incision, peripheral nerve injury, and painful diabetic neuropathy.

Pioglitazone, an agonist at peroxisome proliferator-activated receptor gamma, is FDA-approved for the treatment of insulin resistance in type 2 diabetes. Numerous studies in male rodents suggest that pioglitazone inhibits inflammatory and neuropathic pain, but few included female subjects. To address this gap, we compared the effects of pioglitazone in both sexes in the intraplantar methylglyoxal model (MG) model of chemical pain and painful diabetic neuropathy (PDN), the plantar incision model (PIM) of postoperative pain, the spared nerve injury (SNI) model of traumatic nerve injury, and the ZDF rat and db/db mouse models of PDN. We administered pioglitazone by one-time intrathecal or intraperitoneal injection or by adding it to chow for 6 weeks, followed by measurement of hypersensitivity to non-noxious mechanical, noxious mechanical, heat, and/or cold stimuli. In all mouse models, injection of pioglitazone decreased pain-like behaviors with greater potency and/or efficacy in females as compared to males: heat and mechanical hypersensitivity in the MG model (0.1-10 mg/kg); mechanical hypersensitivity in the PIM model (10 µg); mechanical and cold hypersensitivity in the SNI model (100 mg/kg); and heat hypersensitivity in the db/db model (100 mg/kg). Furthermore, co-administration of low doses of morphine (1 mg/kg) and pioglitazone (10 mg/kg) decreased SNI-induced mechanical and cold hypersensitivity in female but not male mice. In the ZDF rat, pioglitazone (100 mg/kg) decreased heat and mechanical hypersensitivity with no sex difference. In the db/db model, pioglitazone had no effect when given into chow for 6 weeks at 0.3, 3 or 30 mg/kg doses. We conclude that females exhibit greater anti-hyperalgesic responses to pioglitazone in mouse models of chemical-induced nociception, postsurgical pain, neuropathic pain, and PDN. These findings set the stage for clinical trials to determine whether pioglitazone has analgesic properties across a broad spectrum of chronic pain conditions, particularly in women.

GABA-A receptor activity in the noradrenergic locus coeruleus drives trigeminal neuropathic pain in the rat; contribution of NAα1 receptors in the medial prefrontal cortex.

Trigeminal neuropathic pain is described as constant excruciating facial pain. The study goal was to investigate the role of nucleus locus coeruleus (LC) in a model of chronic orofacial neuropathic pain (CCI-ION). The study examines LC's relationship to both the medullary dorsal horn receiving trigeminal nerve sensory innervation and the medial prefrontal cortex (mPFC). LC is a major source of CNS noradrenaline (NA) and a primary nucleus involved in pain modulation. Although descending inhibition of acute pain by LC is well established, contribution of the LC to facilitation of chronic neuropathic pain is also reported. In the present study, a rat orofacial pain model of trigeminal neuropathy was induced by chronic constrictive injury of the infraorbital nerve (CCI-ION). Orofacial neuropathic pain was indicated by development of whisker pad mechanical hypersensitivity. Hypersensitivity was alleviated by selective elimination of NA neurons, including LC (A6 cell group), with the neurotoxin anti-dopamine-ß-hydroxylase saporin (anti-DßH-saporin) microinjected either intracerebroventricularly (i.c.v.) or into trigeminal spinal nucleus caudalis (spVc). The GABAA receptor antagonist, bicuculline, administered directly into LC (week 8) inhibited hypersensitivity. This indicates a valence shift in which increased GABAA signaling ongoing in LC after trigeminal nerve injury paradoxically produces excitatory facilitation of the chronic pain state. Microinjection of NAα1 receptor antagonist, benoxathian, into mPFC attenuated whisker pad hypersensitivity, while NAα2 receptor antagonist, idazoxan, was ineffective. Thus, GABAA-mediated activation of NA neurons during CCI-ION can facilitate hypersensitivity through NAα1 receptors in the mPFC. These data indicate LC is a chronic pain generator.

Abnormal error processing in depressive states: a translational examination in humans and rats.

Depression has been associated with poor performance following errors, but the clinical implications, response to treatment and neurobiological mechanisms of this post-error behavioral adjustment abnormality remain unclear. To fill this gap in knowledge, we tested depressed patients in a partial hospital setting before and after treatment (cognitive behavior therapy combined with medication) using a flanker task. To evaluate the translational relevance of this metric in rodents, we performed a secondary analysis on existing data from rats tested in the 5-choice serial reaction time task after treatment with corticotropin-releasing factor (CRF), a stress peptide that produces depressive-like signs in rodent models relevant to depression. In addition, to examine the effect of treatment on post-error behavior in rodents, we examined a second cohort of rodents treated with JDTic, a kappa-opioid receptor antagonist that produces antidepressant-like effects in laboratory animals. In depressed patients, baseline post-error accuracy was lower than post-correct accuracy, and, as expected, post-error accuracy improved with treatment. Moreover, baseline post-error accuracy predicted attentional control and rumination (but not depressive symptoms) after treatment. In rats, CRF significantly degraded post-error accuracy, but not post-correct accuracy, and this effect was attenuated by JDTic. Our findings demonstrate deficits in post-error accuracy in depressed patients, as well as a rodent model relevant to depression. These deficits respond to intervention in both species. Although post-error behavior predicted treatment-related changes in attentional control and rumination, a relationship to depressive symptoms remains to be demonstrated.

Evaluation of engraftment and immunological tolerance after reduced intensity conditioning in a rhesus hematopoietic stem cell gene therapy model.

Reduced intensity conditioning (RIC) is desirable for hematopoietic stem cell (HSC) targeted gene therapy; however, RIC may be insufficient for efficient engraftment and inducing immunological tolerance to transgenes. We previously established long-term gene marking in our rhesus macaque autologous HSC transplantation model following 10 Gy total body irradiation (TBI). In this study, we evaluated RIC transplantation with 4 Gy TBI in two rhesus macaques that received equal parts of CD34(+) cells transduced with green fluorescent protein (GFP)-expressing lentiviral vector and empty vector not expressing transgenes. In both animals, equivalently low gene marking between GFP and empty vectors was observed 6 months post-transplantation, even with efficient transduction of CD34(+) cells in vitro. Autologous lymphocyte infusion with GFP marking resulted in an increase of gene marking in lymphocytes in a control animal with GFP tolerance, but not in the two RIC-transplanted animals. In vitro assays revealed strong cellular and humoral immune responses to GFP protein in the two RIC-transplanted animals, but this was not observed in controls. In summary, 4 Gy TBI is insufficient to permit engraftment of genetically modified HSCs and induce immunological tolerance to transgenes. Our findings should help in the design of conditioning regimens in gene therapy trials.

Risk factors for prehypertension in the community: a prospective analysis from the Western New York Health Study.

BACKGROUND AND AIM: Prehypertension is an increasingly highly prevalent condition in the general population, and is associated with an increased risk for coronary heart disease and stroke. However, evidence from population-based studies of the risk factors for prehypertension is scant. We sought to examine the predictors of progression from normotension to prehypertension in a community-based population from Western New York. METHODS AND RESULTS: A longitudinal analysis, over 6 years of follow-up, among 569 men and women (mean age 51.8 years) who were free of prehypertension, hypertension, cardiovascular disease and diabetes at the baseline examination, in the Western New York Health Study (WNYHS). Incident prehypertension at follow-up was defined as systolic blood pressure of 120-139 mm Hg and/or diastolic blood pressure of 80-89 mm Hg. The cumulative six year incidence of prehypertension was 33.5% (189/564). In bivariate analyses, there were several correlates of incident prehypertension, including age, BMI and waist circumference, impaired fasting glucose (IFG), uric acid, and baseline blood pressure levels. After multivariate adjustment, IFG at baseline [odds ratio (OR): 1.70, 95% CI: 1.07-2.69) and weight gain since age 25 (OR: 1.12, 1.04-1.21 per 10 lb increase)] were the strongest significant predictors of prehypertension at follow-up. Neither baseline waist circumference nor change in BMI were predictor variables in models when they were substituted for weight gain. CONCLUSIONS: Results from this study suggest early dysregulation of glucose metabolism and weight gain over the lifespan may represent important risk factors for prehypertension in the general population.

Constitutive µ-opioid receptor activity leads to long-term endogenous analgesia and dependence.

Opioid receptor antagonists increase hyperalgesia in humans and animals, which indicates that endogenous activation of opioid receptors provides relief from acute pain; however, the mechanisms of long-term opioid inhibition of pathological pain have remained elusive. We found that tissue injury produced µ-opioid receptor (MOR) constitutive activity (MOR(CA)) that repressed spinal nociceptive signaling for months. Pharmacological blockade during the posthyperalgesia state with MOR inverse agonists reinstated central pain sensitization and precipitated hallmarks of opioid withdrawal (including adenosine 3',5'-monophosphate overshoot and hyperalgesia) that required N-methyl-D-aspartate receptor activation of adenylyl cyclase type 1. Thus, MOR(CA) initiates both analgesic signaling and a compensatory opponent process that generates endogenous opioid dependence. Tonic MOR(CA) suppression of withdrawal hyperalgesia may prevent the transition from acute to chronic pain.

PPARγ activation blocks development and reduces established neuropathic pain in rats.

Peroxisome proliferator-activated receptor gamma (PPARγ) is emerging as a new pharmacotherapeutic target for chronic pain. When oral (3-30 mg/kg/day in chow for 7 wk) or twice-daily intraperitoneal (1-10 mg/kg/day for 2 wk) administration began before spared nerve injury (SNI), pioglitazone, a PPARγ agonist, dose-dependently prevented multiple behavioral signs of somatosensory hypersensitivity. The highest dose of intraperitoneal pioglitazone did not produce ataxia or reductions in transient mechanical and heat nociception, indicating that inhibitory effects on hypersensitivity were not secondary to adverse drug-induced behaviors or antinociception. Inhibitory effects on hypersensitivity persisted at least one week beyond cessation of pioglitazone administration, suggestive of long-lasting effects on gene expression. Blockade of PPARγ with GW9662, an irreversible and selective PPARγ antagonist, dose-dependently reduced the inhibitory effect of pioglitazone on hypersensitivity, indicating a PPARγ-dependent action. Remarkably, a single preemptive injection of pioglitazone 15 min before SNI attenuated hypersensitivity for at least 2 weeks; this was enhanced with a second injection delivered 12 h after SNI. Pioglitazone injections beginning after SNI also reduced hypersensitivity, albeit to a lesser degree than preemptive treatment. Intraperitoneal pioglitazone significantly reduced the nerve injury-induced up-regulation of cd11b, GFAP, and p-p38 in the dorsal horn, indicating a mechanism of action involving spinal microglia and/or astrocyte activation. Oral pioglitazone significantly reduced touch stimulus-evoked phospho-extracellular signal-related kinase (p-ERK) in lamina I-II, indicating a mechanism of action involving inhibition of central sensitization. We conclude that pioglitazone reduces spinal glial and stimulus-evoked p-ERK activation and that PPARγ activation blocks the development of and reduces established neuropathic pain.

Geochemical interactions between process-affected water from oil sands tailings ponds and North Alberta surficial sediments.

In Northern Alberta, the placement of out-of-pit oil sands tailings ponds atop natural buried sand channels is becoming increasingly common. Preliminary modeling of such a site suggests that process-affected (PA) pond water will infiltrate through the underlying clay till aquitard, reaching the sand channel. However, the impact of seepage upon native sediments and groundwater resources is not known. The goal of this study is to investigate the role of adsorption and ion exchange reactions in the clay till and their effect on the attenuation or release of inorganic species. This was evaluated using batch sorption experiments (traditional and a recent modification using less disturbed sediment samples) and geochemical modeling with PHREEQC. The results show that clay till sediments have the capacity to mitigate the high concentrations of ingressing sodium (600 mg L(-1)), with linear sorption partitioning coefficients (K(d)) of 0.45 L kg(-1). Ion exchange theory was required to account for all other cation behaviour, precluding the calculation of such coefficients for other species. Qualitative evidence suggests that chloride will behave conservatively, with high concentrations remaining in solution (375 mg L(-1)). As a whole, system behaviour was found to be controlled by a combination of competitive ion exchange, dissolution and precipitation reactions. Observations, supported by PHREEQC simulations, suggest that the influx of PA water will induce the dissolution of pre-existing sulphate salts. Sodium present in the process-affected water will exchange with sediment-bound calcium and magnesium, increasing the divalent ions' pore fluid concentrations, and leading to the precipitation of a calcium-magnesium carbonate mineral phase. Thus, in similar tailings pond settings, particularly if the glacial till coverage is thin or altogether absent, it is reasonable to expect that high concentrations of sodium and chloride will remain in solution, while sulphate concentrations will exceed those of the ingressing plume (150 mg L(-1)).

Polymorphisms in the platelet-specific collagen receptor GP6 are associated with risk of nonfatal myocardial infarction in Caucasians.

BACKGROUND AND AIMS: Glycoprotein 6 (GP6) is a platelet-specific collagen receptor implicated in the thrombotic pathway to acute myocardial infarction (AMI), but a possible genetic relationship between GP6 and AMI is poorly understood. We tested for the genetic association between AMI and single nucleotide polymorphisms (SNPs) in 24 loci, including GP6. METHODS AND RESULTS: We conducted a case-control study of AMI and GP6 in a community-based population (n = 652 cases, 625 controls). We also examined men and women separately and stratified the latter by use of hormone replacement therapy (HRT). Among both sexes, the strongest association was for a protective missense polymorphism (rs1163662) in the GP6 gene (OR = 0.70; Bonferroni-adjusted p < 0.05). SNPs in GP6 were also strongly associated with AMI among women who reported ever taking HRT, but not among women who never took HRT. Haplotype analyses were consistent with the single-SNP findings. CONCLUSIONS: In this sample of white non-Hispanic men and women, several SNPs in GP6 were significantly related to risk of AMI. Development of pharmacologic therapy directed towards platelet activity and thrombosis may reduce the incidence of AMI among at-risk groups.

Impaired fasting glucose and recurrent cardiovascular disease among survivors of a first acute myocardial infarction: evidence of a sex difference? The Western New York experience.

BACKGROUND AND AIMS: There is little epidemiological evidence regarding the association of impaired glucose metabolism with recurrent cardiovascular events. We therefore examined potential sex differences in the effect of impaired fasting glucose (IFG) on recurrent cardiovascular disease (CVD) in a community-based study of survivors of a first acute myocardial infarction (MI). METHODS AND RESULTS: This report focuses on 1226 incident MI cases (28.4% women) discharged alive from area hospitals in the Western New York Acute MI Study (1996-2004). Deaths and underlying cause of death were determined via query of the National Death Index (Plus) Retrieval Program with follow-up through December 31, 2004. Outcomes reported included fatal or non-fatal coronary heart disease (CHD) or coronary revascularization surgery and total stroke. Traditional CHD risk factors and other explanatory variables were determined by clinical examination after the first acute event. Impaired fasting glucose was defined as fasting blood glucose between 100 and 125mg/dl. During a mean follow-up of 4.5 years, there were 91 recurrent events (26.1%) in women and 173 recurrent events (19.7%) in men. After multivariable adjustment, the hazard ratios for recurrent cardiovascular events were 1.96 (95% CI: 1.15-3.16) and 2.59 (1.56-4.30) in women with IFG and with diabetes, respectively, compared to normoglycemic women. Among men, neither IFG nor diabetes was independently related to risk of recurrence. CONCLUSIONS: In this study, IFG was a strong risk factor for recurrent cardiovascular events only among women. These results suggest that increased cardiovascular risk in MI survivors begins at lower glucose levels in women than men.

Evaluation of a rapamycin-regulated serotype 2 adeno-associated viral vector in macaque parotid glands.

OBJECTIVES: Salivary glands are useful target organs for local and systemic gene therapeutics. For such applications, the regulation of transgene expression is important. Previous studies by us in murine submandibular glands showed that a rapamycin transcriptional regulation system in a single serotype 2, adeno-associated viral (AAV2) vector was effective for this purpose. This study evaluated if such a vector was similarly useful in rhesus macaque parotid glands. METHODS: A recombinant AAV2 vector (AAV-TF-RhEpo-2.3w), encoding rhesus erythropoietin (RhEpo) and a rapamycin-inducible promoter, was constructed. The vector was administered to macaques at either of two doses [1.5 x 10(11) (low dose) or 1.5 x 10(12) (high dose) vector genomes] via cannulation of Stensen's duct. Animals were followed up for 12-14 weeks and treated at intervals with rapamycin (0.1 or 0.5 mg kg(-1)) to induce gene expression. Serum chemistry, hematology, and RhEpo levels were measured at interval. RESULTS: AAV-TF-RhEpo-2.3w administration led to low levels of rapamycin-inducible RhEpo expression in the serum of most macaques. In five animals, no significant changes were seen in serum chemistry and hematology values over the study. One macaque, however, developed pneumonia, became anemic and subsequently required euthanasia. After the onset of anemia, a single administration of rapamycin led to significant RhEpo production in this animal. CONCLUSION: Administration of AAV-TF-RhEpo-2.3w to macaque parotid glands was generally safe, but led only to low levels of serum RhEpo in healthy animals following rapamycin treatment.

AAV5-mediated gene transfer to the parotid glands of non-human primates.

Salivary glands are potentially useful target sites for multiple clinical applications of gene transfer. Previously, we have shown that serotype 2 adeno-associated viral (AAV2) vectors lead to stable gene transfer in the parotid glands of rhesus macaques. As AAV5 vectors result in considerably greater transgene expression in murine salivary glands than do AAV2 vectors, herein we have examined the use of AAV5 vectors in macaques at two different doses (n = 3 per group; 10(10) or 3 x 10(11) particles per gland). AAV5 vector delivery, as with AAV2 vectors, led to no untoward clinical, hematological or serum chemistry responses in macaques. The extent of AAV5-mediated expression of rhesus erythropoietin (RhEpo) was dose-dependent and similar to that seen with an AAV2 vector. However, unlike results with the AAV2 vector, AAV5 vector-mediated RhEpo expression was transient. Maximal expression peaked at day 56, was reduced by approximately 80% on day 84 and thereafter remained near background levels until day 182 (end of experiment). Quantitative PCR studies of high-dose vector biodistribution at this last time point showed much lower AAV5 copy numbers in the targeted parotid gland (approximately 1.7%) than found with the same AAV2 vector dose. Molecular analysis of the conformation of vector DNA indicated a markedly lower level of concatamerization for the AAV5 vector compared with that of a similar AAV2 vector. In addition, cellular immunological studies suggest that host response differences may occur with AAV2 and AAV5 vector delivery at this mucosal site. The aggregate data indicate that results with AAV5 vectors in murine salivary glands apparently do not extend to macaque glands.

Activation of peroxisome proliferator-activated receptor gamma in brain inhibits inflammatory pain, dorsal horn expression of Fos, and local edema.

Systemic administration of thiazolidinediones reduces peripheral inflammation in vivo, presumably by acting at peroxisome proliferator-activated receptor gamma (PPARgamma) in peripheral tissues. Based on a rapidly growing body of literature indicating the CNS as a functional target of PPARgamma actions, we postulated that brain PPARgamma modulates peripheral edema and the processing of inflammatory pain signals in the dorsal horn of the spinal cord. To test this in the plantar carrageenan model of inflammatory pain, we measured paw edema, heat hyperalgesia, and dorsal horn expression of the immediate-early gene c-fos after intracerebroventricular (ICV) administration of PPARgamma ligands or vehicle. We found that ICV rosiglitazone (0.5-50 microg) or 15d-PGJ(2) (50-200 microg), but not vehicle, dose-dependently reduced paw thickness, paw volume and behavioral withdrawal responses to noxious heat. These anti-inflammatory and anti-hyperalgesia effects result from direct actions in the brain and not diffusion to other sites, because intraperitoneal and intrathecal administration of rosiglitazone (50 microg) and 15d-PGJ(2) (200 microg) had no effect. PPARgamma agonists changed neither overt behavior nor motor coordination, indicating that non-specific behavioral effects do not contribute to PPAR ligand-induced anti-hyperalgesia. ICV administration of structurally dissimilar PPARgamma antagonists (either GW9662 or BADGE) reversed the anti-inflammatory and anti-hyperalgesic actions of both rosiglitazone and 15d-PGJ(2). To evaluate the effects of PPARgamma agonists on a classic marker of noxious stimulus-evoked gene expression, we quantified Fos protein expression in the dorsal horn. The number of carrageenan-induced Fos-like immunoreactive profiles was less in rosiglitazone-treated rats as compared to vehicle controls. We conclude that pharmacological activation of PPARgamma in the brain rapidly inhibits local edema and the spinal transmission of noxious inflammatory signals.

Analysis of origin and optimization of expansion and transduction of circulating peripheral blood endothelial progenitor cells in the rhesus macaque model.

Adult marrow-derived cells have been shown to contribute to various nonhematologic tissues and, conversely, primitive cells isolated from nonhematopoietic tissues have been shown to reconstitute hematopoiesis. Circulating endothelial progenitor cells (EPCs) have been reported to be at least partially donor derived after allogeneic bone marrow transplantation, and shown to contribute to neovascularization in murine ischemia models. However, it is unknown whether these EPCs are actually clonally derived from the same population of stem and progenitor cells that reconstitute hematopoiesis, or from another cell population found in the marrow or mobilized blood that is transferred during transplantation. To approach this question, we characterized circulating EPCs and also endothelial cells from large vessels harvested at autopsy from rhesus macaques previously transplanted with retrovirally transduced autologous CD34-enriched peripheral blood stem cells (PBSCs). Endothelial cells were grown in culture for 21-28 days and were characterized as CD31(+) CD14(-) via flow cytometry, as acLDL(+) UEA-1(+) via immunohistochemistry, and as Flk-1(+) by reverse transcriptase-polymerase chain reaction (RT-PCR). Animals had stable vector marking in hematopoietic lineages of 2-15%. Neither cultured circulating EPCs collected in steady state (n = 3), nor endothelial cells grown from large vessels (n = 2), had detectable retroviral marking. EPCs were CD34(+) and could be mobilized into the circulation with granulocyte colony-stimulating factor. Under ex vivo culture conditions, in which CD34(+) cells were optimized to transduce hematopoietic progenitor and stem cells, there was a marked depletion of EPCs. Transduction of EPCs was much more efficient under conditions supporting endothelial cell growth. Further elucidation of the origin and in vivo behavior of EPCs may be possible, using optimized transduction conditions and a vascular injury model.

Is type 2 diabetes a chronic inflammatory/autoimmune disease?

The classification of diabetes mellitus into 2 main types, defined as Type 1 and 2 diabetes (T1DM, T2DM) relies mostly on the requirement of insulin therapy and on the presence of detectable immunologic abnormalities. However, this distinction is far from straightforward and there is considerable overlap between these 2 types of diabetes. Islet cell autoimmunity, which is characteristic of T1DM, appears in fact to be present in up to 10-15% of subjects diagnosed clinically with T2DM. In the UK Prospective Diabetes Study (UKPDS), it was reported that in patients diagnosed with in T2DM, the presence of autoantibodies to the enzyme glutamic acid decarboxylase (GAD) and cytoplasmic islet cell antibodies (ICA) were a predictor of insulin requirement as compared with patients not carrying these autoantibodies. These results are strikingly similar to a number of prospective studies carried out in childhood diabetes. If islet cell autoimmunity is truly present in 10-15% of subjects clinically diagnosed with T2DM, up to two million Americans might have an unidentified autoimmune form of T2DM, a prevalence similar to that of recent onset childhood diabetes. In addition, we found that in a subset of T2DM patients, a pronounced activation of the acute phase response that seems to be associated with islet cell autoimmunity. These results may in part explain the defect in insulin secretion as well as insulin resistance seen in T2DM. The identification of a subgroup of individuals at risk of developing T2DM using autoantibody as well as inflammatory markers is of public health interest, not only for the correct classification of diabetes, but also because immunomodulatory therapeutic strategies could potentially be instituted sufficiently early in a large number of patients diagnosed as having T2DM and most likely delay the onset of insulin requirement and the complications related with hyperglycemia.

A reappraisal of the reported dose equivalents at the boundary of the University of California Radiation Laboratory during the early days of Bevatron operation.

The Bevatron of the Lawrence Berkeley National Laboratory operated with no permanent shielding-roof from 1954 to 1962. Neutron fluences measured at the laboratory perimeter reached a maximum in 1959, and were reported as an annual dose equivalent of 8.1 mSv (54% of the then operative radiation limit). The addition of temporary local shielding and improved operational techniques subsequently led to a steady decline in dose equivalent at the laboratory perimeter. A permanent concrete shielding-roof was constructed in 1962. In those early years of operation the reported dose equivalent, H, was derived from a measured total neutron fluence, phi, and an estimated spectrum-weighted fluence to dose equivalent conversion coefficient, (g), where H= (g) phi. The uncertainty in H was almost entirely due to the uncertainty in (g). While the measurements of phi were accurate the estimates of (g) were quite crude and depended upon measurements of average neutron energy, on assumptions about the shape of the neutron energy spectrum, and primitive values of fluence to dose equivalent conversion coefficients for monoenergetic neutrons. These early reported dose equivalents were known to be overestimated. This paper has reappraised the dose equivalents in the light of better information now available. Environmental neutron spectra have been calculated which more accurately correspond to the operational conditions of the Bevatron in the 1950s and early 1960s. than did those spectra available at that time. A new fluence to dose equivalent conversion function based on the latest data and for isotropic irradiation geometry was developed. From these two parameters better estimates of the coefficient (g) were determined and compared with the earlier values. From this reappraisal it is shown that the early reported dose equivalents were conservative by a factor of at least five.

Quality of life in geriatric depression: a comparison of remitters, partial responders, and nonresponders.

The authors examined patterns of improvement in quality of life (QOL) in elderly patients with recurrent major depression (MDD) after acute treatment. One hundred elderly (age 60-88 years) patients with recurrent MDD were randomized to receive either bupropion sustained-release (100 mg-300 mg/day) or paroxetine (10 mg-40 mg/day) for 6 weeks. Treatment with both paroxetine and bupropion was associated with improvements in QOL. Lower perceived Physical- and Social-Functioning QOL ratings at baseline were associated with lower treatment response. Improvement in depression symptom ratings correlated significantly with improvement in QOL on many domains, but accounted for less than one-quarter of the total variance. Remitters showed significantly (P<0.001) greater improvement than both Partial Responders and Nonresponders on various measures. Findings support the importance of treating elderly depressed patients to full remission to maximize impact on both emotional and physical QOL domains.

Assessment of rapid remobilization intervals with G-CSF and SCF in murine and rhesus macaque models.

BACKGROUND: Defining the optimum regimen and time for repeat peripheral blood progenitor cell mobilization would have important clinical applications. STUDY DESIGN AND METHODS: Remobilization with SCF and G-CSF at 2 weeks after an initial mobilization in mice and at 2 or 4 weeks after an initial mobilization in nonhuman primates was examined. In mice, competitive repopulation assays were used to measure long-term progenitor cell-repopulating activity. In monkeys, mobilization of hematopoietic progenitor CFUs was used as a surrogate marker for progenitor cell-repopulating ability. RESULTS: Efficacy of progenitor cell remobilization differed in the two animal species. In mice, peripheral blood progenitor cell-repopulating ability with repeat mobilization at 2 weeks was 70 percent of that with the initial mobilization. In monkeys, there was no significant difference in peripheral blood progenitor cell mobilization between the initial and the repeat mobilizations at 2 weeks. In mobilizations separated by 4 weeks, however, peripheral blood progenitor cell mobilization was higher than that with initial mobilizations. CONCLUSION: In animal models, mobilization of peripheral blood progenitor cells with remobilization after a 2-week interval is similar to or moderately decreased from that with the initial mobilization. Progenitor cell collection at this time point may be useful in certain clinical circumstances. A 4-week interval between remobilizations may be preferable. Clinical trials in humans would be useful to clarify these issues.

Modeling preclinical cardiovascular risk for use in epidemiologic studies: Miami community health study.

To develop a method for assessing preclinical cardiovascular disease risk, models of resting cardiovascular regulation and of insulin metabolic syndrome were derived from information collected from 1991 to 1996 in a culturally heterogeneous sample of 319 healthy men and women (aged 25-44 years) from Miami-Dade County, Florida. The model of resting cardiovascular regulation used 8 noninvasive measures of autonomic and cardiovascular function. Three factors were derived: 1) parasympathetic, 2) inotropy, and 3) systemic vascular resistance. The model of insulin metabolic syndrome used 12 measures assessing body mass, insulin, glucose, and lipid metabolism. Four factors were derived: 1) body mass and fat distribution, 2) glucose level and regulation, 3) insulin level and regulation, and 4) plasma lipid levels. Analyses of the association of the two models revealed that subjects with lower cardiac contractility had greater body mass, higher fasting and postload insulin and glucose levels, and lower insulin sensitivity. Subjects with greater vascular resistance had greater body mass, higher total cholesterol and triglyceride levels, and lower high density lipoprotein cholesterol levels. These findings indicate that preclinical cardiovascular disease risk may involve pathophysiologic processes in which cardiac inotropic and vasodilatory functions are linked to specific aspects of insulin metabolic syndrome.

Avoidance of stimulation improves engraftment of cultured and retrovirally transduced hematopoietic cells in primates.

Recent reports suggest that cells in active cell cycle have an engraftment defect compared with quiescent cells. We used nonhuman primates to investigate this finding, which has direct implications for clinical transplantation and gene therapy applications. Transfer of rhesus CD34(+) cells to culture in stem cell factor (SCF) on the CH-296 fibronectin fragment (FN) after 4 days of culture in stimulatory cytokines maintained cell viability but decreased cycling. Using retroviral marking with two different gene transfer vectors, we compared the engraftment potential of cytokine-stimulated cells versus those transferred to nonstimulatory conditions (SCF on FN alone) before reinfusion. In vivo competitive repopulation studies showed that the level of marking originating from the cells continued in culture for 2 days with SCF on FN following a 4-day stimulatory transduction was significantly higher than the level of marking coming from cells transduced for 4 days and reinfused without the 2-day culture under nonstimulatory conditions. We observed stable in vivo overall gene marking levels of up to 29%. This approach may allow more efficient engraftment of transduced or ex vivo expanded cells by avoiding active cell cycling at the time of reinfusion.