Disruption of sonic hedgehog signaling in Ellis-van Creveld dwarfism confers protection against bipolar affective disorder.

Ellis-van Creveld syndrome, an autosomal recessively inherited chondrodysplastic dwarfism, is frequent among Old Order Amish of Pennsylvania. Decades of longitudinal research on bipolar affective disorder (BPAD) revealed cosegregation of high numbers of EvC and Bipolar I (BPI) cases in several large Amish families descending from the same pioneer. Despite the high prevalence of both disorders in these families, no EvC individual has ever been reported with BPI. The proximity of the EVC gene to our previously reported chromosome 4p16 BPAD locus with protective alleles, coupled with detailed clinical observations that EvC and BPI do not occur in the same individuals, led us to hypothesize that the genetic defect causing EvC in the Amish confers protection from BPI. This hypothesis is supported by a significant negative association of these two disorders when contrasted with absence of disease (P=0.029, Fisher's exact test, two-sided, verified by permutation to estimate the null distribution of the test statistic). As homozygous Amish EVC mutations causing EvC dwarfism do so by disrupting sonic hedgehog (Shh) signaling, our data implicate Shh signaling in the underlying pathophysiology of BPAD. Understanding how disrupted Shh signaling protects against BPI could uncover variants in the Shh pathway that cause or increase risk for this and related mood disorders.

Correlation between bioelectrical spectroscopy and perometry in assessment of upper extremity swelling.

Lymphedema is a common side effect of breast cancer treatment and is associated with increased upper extremity volume, functional impairment, and pain. While there is no cure for lymphedema, physical therapy treatment can often alleviate symptoms. To measure the efficacy of treatment, accurate assessment of the limbs is important. Current methods of assessment are complex (water displacement), marginally accurate (circumferential measurements), or expensive (opto-electrical systems). A new method for estimating tissue fluid is bioelectrical spectroscopy (BIS). This method measures impedance to small currents applied to the body and is easily performed. Acceptance of BIS devices for assessment of limb fluid will be dependent on the establishment of sufficient reliability and validity, and the objective of this study was to evaluate reliability and validity of this device compared to perometry. Both upper limbs of ten subjects previously treated for breast cancer were measured using BIS and perometry. We found that inter-rater reliability (r = 0.987) and intrarater reliability (r = 0.993) were acceptably high for the BIS unit and concurrent validity was r = -0.904, when compared to perometry. These results confirm that BIS can produce valid and reliable data related to the assessment of upper limbs affected by lymphedema.

Biomarker qualification via public-private partnerships.

Biomarkers linked to patient outcomes (safety and efficacy) have an increasingly important role in drug development. Consequently, validation and qualification of such biomarkers are essential, often requiring large data sets from well-controlled randomized clinical trials. In the December 2009 issue of Clinical Pharmacology & Therapeutics, investigators utilizing data from four pharmaceutical companies and working under the auspices of the Biomarkers Consortium described the utility of adiponectin as an early predictor of glycemic control in diabetic patients taking peroxisome proliferator-activated receptor (PPAR) agonists. This work illustrates the advantages of large public-private partnerships for biomarker qualification.

Condom use in the year following a sexually transmitted disease clinic visit.

Consistent condom use can prevent sexually transmitted infections (STIs), but few studies have measured how the prevalence of consistent use changes over time. We measured the prevalence and correlates of consistent condom use over the course of a year. We did a secondary analysis of data from an HIV prevention trial in three sexually transmitted disease clinics. We assessed condom use during four three-month intervals for subjects and across their partnerships using unconditional logistic regression. Condom use was also assessed for subjects during all three-month intervals combined. The 2125 subjects reported on 5364 three-month intervals including 7249 partnership intervals. Condoms were always used by 24.1% of subjects and 33.2% of partnerships during a three-month interval. Over the year, 82% used condoms at least once but only 5.1% always used condoms. Always use of condom was more likely for subjects who had sex only once (66.5%) compared with >30 times (6.4%); one-time partnerships (64.1%) compared with main partnerships (22.2%); and in new partnerships (44.0%) compared with partnerships that were not new (24.5%). Although consistent condom use may prevent STIs, condoms were rarely used consistently during the year of follow-up.

A randomized trial of exercise and dietary counseling after liver transplantation.

We report results of a randomized clinical trial of a combined intervention of exercise and dietary counseling (ExD) after orthotopic liver transplantation (OLT). Of the 151 patients randomized into ExD or usual care (UC), 119 completed testing 2, 6 and 12 months post-OLT. Testing included assessment of exercise capacity (VO(2peak)), quadricep muscle strength, body composition (DXA), nutritional intake (Block 95) and health-related quality of life (SF-36). The intervention consisted of individualized counseling and follow-up to home-based exercise and dietary modification. Repeated measure ANOVA was performed to determine differences over time between ExD and UC with a secondary analysis to determine differences over time between adherers (Adh), nonadherers (Nadh) to the intervention and UC. The ExD group showed greater increases in VO(2peak) (p = 0.036), and self-reported general health (p = 0.038) compared to UC. Both groups demonstrated increases in muscle strength, body weight, body fat and other SF-36 scale scores. Adherence to the intervention was 37% with positive trends in VO(2peak) and body composition observed in Adh compared to Nadh and UC. These data suggest improvements in exercise capacity and body composition are achieved with nutrition and exercise behavior modifications initiated early after OLT and with regular follow-up.

Peptide functionalized poly(L-lysine)-g-poly(ethylene glycol) on titanium: resistance to protein adsorption in full heparinized human blood plasma.

The graft copolymer poly(L-lysine)-graft-poly(ethylene glycol) (PLL-g-PEG) and its RGD- and RDG-functionalized derivatives (PLL-g-PEG/PEG-peptide) were assembled from aqueous solutions on titanium (oxide) surfaces. The polymers were characterized by NMR in order to determine quantitatively the grafting ratio, g (Lys monomer units/PEG side chains), and the fraction of the PEG side chains carrying the terminal peptide group. The titanium surfaces modified with the polymeric monomolecular adlayers were exposed to full heparinized blood plasma. The adsorbed masses were measured by in situ ellipsometry. The different PLL-g-PEG-coated surfaces showed, within the detection limit of the ellipsometric technique, no statistically significant protein adsorption during exposure to plasma for 30 min at 22 degrees C or 37 degrees C, whereas clean, uncoated titanium surfaces adsorbed approximately 350 ng/cm2 of plasma proteins. The high degree of resistance of the PEGylated surface to non-specific adsorption makes peptide-modified PLL-g-PEG a useful candidate for the surface modification of biomedical devices such as implants that are capable of eliciting specific interactions with integrin-type cell receptors even in the presence of full blood plasma. The results refer to short-term blood plasma exposure that cannot be extrapolated a priori to long-term clinical performance.

Altered temporal pattern of evoked afferent activity in a rat model of vincristine-induced painful peripheral neuropathy.

It is known that the level of activity in nociceptive primary afferent nerve fibers increases in neuropathic conditions that produce pain, but changes in the temporal patterning of action potentials have not been analyzed in any detail. Because the patterning of action potentials in sensory nerve fibers might play a role in the development of pathological pain states, we studied patterning of mechanical stimulus-evoked action potential trains in nociceptive primary afferents in a rat model of vincristine-induced painful peripheral neuropathy. Systemic administration of vincristine (100 microg/kg) caused approximately half the C-fiber nociceptors to become markedly hyperresponsive to mechanical stimulation. Instantaneous frequency plots showed that vincristine induced an irregular pattern of action-potential firing in hyperresponsive C-fibers, characterized by interspersed occurrences of high- and low-frequency firing. This pattern was associated with an increase in the percentage of interspike intervals 100-199 ms in duration compared with that in C-fibers from control rats and vincristine-treated C-fibers that did not become hyperresponsive. Variability in the temporal pattern of action potential firing was quantified by determining the coefficient of variability (CV2) for adjacent interspike intervals. This analysis revealed that vincristine altered the pattern of action-potential timing, so that combinations of higher firing frequency and higher variability occurred that were not observed in control fibers. The abnormal temporal structure of nociceptor responses induced by vincristine in some C-fiber nociceptors could contribute to the pathogenesis of chemotherapy-induced neuropathic pain, perhaps by inducing activity-dependent post-synaptic effects in sensory pathways.

Optical grating coupler biosensors.

By incorporating a grating in a planar optical waveguide one creates a device with which the spectrum of guided lightmodes can he measured. When the surface of the waveguide is exposed to different solutions, the peaks in the spectrum shift due to molecular interactions with the surface. Optical waveguide lightmode spectroscopy (OWLS) is a highly sensitive technique that is capable of real-time monitoring of these interactions. Since this integrated optical method is based on the measurement of the polarizability density (i.e., refractive index) in the vicinity of the waveguide surface, radioactive, fluorescent or other kinds of labeling are not required. In addition, measurement of at least two guided modes enables the absolute mass of adsorbed molecules to be determined. In this article, the technique will be described in some detail, and applications from different areas will be discussed. Selected examples will be presented to demonstrate how monitoring the modification of different metal oxides with polymers and the response of the coated oxides to biofluids help in the design of novel biomaterials; how OWLS is useful for accurate bioaffinity sensing, which is a key issue in the development of new drugs; and how the quantitative study of protein-DNA/RNA and cell surface interactions can enhance the understanding of processes in molecular and cellular biology.

Apolipoprotein E, amyloid, and Alzheimer disease.

Despite important inroads into the molecular pathology of Alzheimer disease, effective long-term treatment for the condition remains elusive. Among the many gene products that are recognized as factors in the disease is apolipoprotein ( (apoE). The risk that specific isoforms of apoE pose with regard to Alzheimer Disease clearly varies, and so the roles that apoE plays in the brain will be crucial to a full understanding of the disease and to efforts to develop effective therapies.

Does my mouse have Alzheimer's disease?

Small animal models that manifest many of the characteristic neuropathological and behavioral features of Alzheimer's disease (AD) have been developed and have proven of great value for studying the pathogenesis of this disorder at the molecular, cellular and behavioral levels. The great progress made in our understanding of the genetic factors that either cause or contribute to the risk of developing AD has prompted many laboratories to create transgenic (tg) mice that overexpress specific genes which cause familial forms of the disease. Several of these tg mice display neuropathological and behavioral features of AD including amyloid beta-peptide (A beta) and amyloid deposits, neuritic plaques, gliosis, synaptic alterations and signs of neurodegeneration as well as memory impairment. Despite these similarities, important differences in neuropathology and behavior between these tg mouse models and AD have also been observed, and to date no perfect animal model has emerged. Moreover, ascertaining which elements of the neuropathological and behavioral phenotype of these various strains of tg mice are relevant to that observed in AD continues to be a challenge. Here we provide a critical review of the AD-like neuropathology and behavioral phenotypes of several well-known and utilized tg mice that express human APP transgenes.

Lack of adherence with the analgesic regimen: a significant barrier to effective cancer pain management.

PURPOSE: To evaluate oncology outpatients' level of adherence to their analgesic regimen during a 5-week period. PATIENTS AND METHODS: A random sample of 65 adult oncology outpatients with a Karnofsky performance status score of >or= 50, an average pain intensity score of >or= 2.5, and radiographic evidence of bone metastasis were recruited for this longitudinal study from seven outpatient settings. On a daily basis, patients rated their level of pain intensity and recorded pain medication intake. Adherence rates for opioid analgesics prescribed on an around-the-clock (ATC) and on an as-needed (PRN) basis were calculated on a weekly basis. RESULTS: Overall adherence rates for ATC opioid analgesics ranged from 84.5% to 90.8% and, for PRN analgesics, from 22.2% to 26.6%. No significant differences over time were found in either of these adherence rates. CONCLUSION: One factor that seems to contribute to ineffective cancer pain management is poor adherence to the analgesic regimen.

Acquired immune deficiency syndrome and the increase in non-Hodgkin lymphoma incidence in New Jersey from 1979 to 1996.

BACKGROUND: In New Jersey, the age-adjusted incidence rate of non-Hodgkin lymphoma (NHL) increased more than a third from 1979 to 1996, the largest increase among the major cancers. METHODS: Data from a linkage of New Jersey's population-based cancer and acquired immune deficiency syndrome (AIDS) registries were used to obtain two sets of annual age specific incidence rates and estimated average annual percentage changes in the incidence rates, for each of five adult age groups within each gender, from Poisson regression models that 1) included all the NHL cases and 2) excluded the cases of AIDS-NHL. RESULTS: During 1979-1996, of the NHL cases aged 15 years and older reported to the cancer registry, 687 (6%) of the 11,725 male cases and 139 (1%) of the 10,785 female cases were AIDS-NHL. The highest percentages of AIDS-NHL were in the younger age groups--15-29, 30-39, and 40-49 years. Among both men and women, average annual percentage increases in NHL occurred overall (3.1 and 3.0, respectively), and in each age group, ranging from 1.6 and 1.9, respectively, in the 50-59 years age group to 6.6 and 4.2, respectively, in the 30-39 years age group (P <<0.01). Excluding AIDS-NHL, the estimated average annual percentage increases in NHL were greatest in the 30-39 and the 60 years and older age groups among men, and these two age groups plus the 15-29 years age group among women, ranging between 2.4 and 2.9 (P < 0.05). CONCLUSIONS: As elsewhere, factors in addition to AIDS are involved in the increasing incidence of NHL in New Jersey. Because diagnostic and classification changes probably do not explain the entire increase unrelated to AIDS, other risk factors are likely responsible. Public health interventions to reduce the incidence of NHL not related to AIDS are problematic until more is known about the causes of NHL.

Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease.

Parkinson's disease is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra, decreased striatal dopamine levels, and consequent extrapyramidal motor dysfunction. We now report that minocycline, a semisynthetic tetracycline, recently shown to have neuroprotective effects in animal models of stroke/ischemic injury and Huntington's disease, prevents nigrostriatal dopaminergic neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Minocycline treatment also blocked dopamine depletion in the striatum as well as in the nucleus accumbens after MPTP administration. The neuroprotective effect of minocycline is associated with marked reductions in inducible NO synthase (iNOS) and caspase 1 expression. In vitro studies using primary cultures of mesencephalic and cerebellar granule neurons (CGN) and/or glia demonstrate that minocycline inhibits both 1-methyl-4-phenylpyridinium (MPP(+))-mediated iNOS expression and NO-induced neurotoxicity, but MPP(+)-induced neurotoxicity is inhibited only in the presence of glia. Further, minocycline also inhibits NO-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) in CGN and the p38 MAPK inhibitor, SB203580, blocks NO toxicity of CGN. Our results suggest that minocycline blocks MPTP neurotoxicity in vivo by indirectly inhibiting MPTP/MPP(+)-induced glial iNOS expression and/or directly inhibiting NO-induced neurotoxicity, most likely by inhibiting the phosphorylation of p38 MAPK. Thus, NO appears to play an important role in MPTP neurotoxicity. Neuroprotective tetracyclines may be effective in preventing or slowing the progression of Parkinson's and other neurodegenerative diseases.

Minocycline blocks nitric oxide-induced neurotoxicity by inhibition p38 MAP kinase in rat cerebellar granule neurons.

Minocycline, a semisynthetic second-generation tetracycline, was reported to have neuroprotective effects in models of global and focal cerebral ischemia, the R6/2 mouse model of Huntington disease, as well as glutamate-induced neurotoxicity in mixed neuronal/glial cultures. It was suggested that neuroprotective effects of minocycline resulted from inhibition of microglial/astroglial activation 'Proc. Natl. Acad. Sci. USA 95 1998 15769'. To determine whether or not minocycline is able to directly protect neurons against injury insults and to delineate its neuroprotective mechanism(s), we treated cultured rat cerebellar granule neurons (CGN) with nitric oxide (NO) in the presence or absence of minocycline. We found that minocycline protected neurons against NO-induced neuronal death in a concentration-dependent fashion. Consistent to other reports, NO was able to induce p38 MAP kinase phosphorylation at 3-6 h and such an induction could be significantly inhibited by minocycline. Furthermore, SB 203580, a p38 MAP kinase inhibitor, almost completely attenuated NO-induced neuronal death of CGN as well. These results suggest that minocycline is able to block NO-induced neurotoxicity in CGN by inhibiting NO-induced phosphorylation of p38 MAP kinase. Our finding may explain the neuroprotective mechanism of minocycline in those neurodegenerative models.

Neuroinflammation-induced acceleration of amyloid deposition in the APPV717F transgenic mouse.

It has been postulated that neuroinflammation plays a critical role in the pathogenesis of Alzheimer's disease (AD). To directly test whether an inflammatory stimulus can accelerate amyloid deposition in vivo, we chronically administered the bacterial endotoxin, lipopolysaccharide (LPS), intracerebroventricularly (i.c.v.) to 2-month-old APPV717F+/+ transgenic (TG) mice, which overexpress a mutant human amyloid precursor protein (APP 717V-F) with or without apolipoprotein E (apoE) for 2 weeks. Two weeks following central LPS administration a striking global reactive astrocytosis with increased GFAP immunoreactivity was found throughout the brains of all LPS-treated wild-type and transgenic mice including the contralateral brain hemisphere. Localized microglial activation was also evident from lectin immunostaining adjacent to the cannula track of LPS-treated mice. Quantification of thioflavine-S-positive Abeta deposits revealed a marked acceleration of amyloid deposition in LPS-treated APPV717F+/+-apoE+/+ mice compared to nontreated or vehicle-treated APPV717F+/+-apoE+/+ mice (P = 0.005). By contrast, no amyloid deposits were detected by thioflavine-S staining in LPS or vehicle-treated apoE-deficient APPV717F TG mice. Our data suggest that neuroinflammation can accelerate amyloid deposition in the APPV717F+/+ mouse model of AD and that this process requires the expression of apoE.

Statistical aspects of quantitative image analysis of beta-amyloid in the APP(V717F) transgenic mouse model of Alzheimer's disease.

Cerebral beta-amyloidosis is a central part of the neuropathology of Alzheimer's disease (AD). Quantitation of beta-amyloid plaques in the human AD brain, and in animal models of AD, is an important study endpoint in AD research. Methodologic approaches to the measurement of beta-amyloid in the brain vary between investigators, and these differences affect outcome measures. Here, one quantitative approach to the measurement of beta-amyloid plaques in brain sections was analyzed for sources of variability due to sampling. Brain tissue was from homozygous APP(V717F) transgenic male mice. Sampling variables were at the mouse and microscopic slide and field levels. Results indicated that phenotypic variability in the mouse sample population was the largest contributor to the standard error of the analyses. Within each mouse, variability between slides or between fields within slides had smaller effects on the error of the analyses. Therefore, when designing studies of adequate power, in this and in other similar models of cerebral beta-amyloidosis, sufficient numbers of mice per group must be included in order for change in mean plaque burden attributable to an experimental variable to outweigh phenotypic variability.

Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease.

Active immunization with the amyloid beta (A beta) peptide has been shown to decrease brain A beta deposition in transgenic mouse models of Alzheimer's disease and certain peripherally administered anti-A beta antibodies were shown to mimic this effect. In exploring factors that alter A beta metabolism and clearance, we found that a monoclonal antibody (m266) directed against the central domain of A beta was able to bind and completely sequester plasma A beta. Peripheral administration of m266 to PDAPP transgenic mice, in which A beta is generated specifically within the central nervous system (CNS), results in a rapid 1,000-fold increase in plasma A beta, due, in part, to a change in A beta equilibrium between the CNS and plasma. Although peripheral administration of m266 to PDAPP mice markedly reduces A beta deposition, m266 did not bind to A beta deposits in the brain. Thus, m266 appears to reduce brain A beta burden by altering CNS and plasma A beta clearance.

Dyspnea and the affective response during exercise training in obstructive pulmonary disease.

BACKGROUND: Dyspnea (SOB), dyspnea-related anxiety (DA), and exercise performance have been shown to improve after exercise training in patients with Chronic Obstructive Pulmonary Disease (COPD). However, there are no published descriptions of the changes in dyspnea intensity or dyspnea-related anxiety during or across the exercise training sessions. OBJECTIVES: To describe and compare the differences in the patterns of change in SOB, DA, and exercise performance during 12 exercise training sessions with and without nurse coaching. METHODS: Forty-five dyspnea-limited patients with COPD were randomly assigned to nurse-monitored (ME) or nurse-coached exercise (CE). SOB and DA were rated on a 200 mm VAS every 2 minutes during each of 12 treadmill training sessions. RESULTS: Warm-up, peak, cool-down, mean SOB, and peak SOB/stage remained constant over the exercise sessions, with increasing exercise performance for both groups over the 12 sessions (p < .001). There was a significant difference in the pattern of mean SOB over time between the ME and CE group (p < . 05). Mean, peak DA, and peak DA/stage showed a rapid decrease within the first 4 sessions (p < . 05) with no significant differences between the groups. Warm-up and cool-down DA remained constant. There were large intra- and inter-subject variations in the rating of dyspnea and dyspnea-related anxiety within and across sessions. CONCLUSIONS: As theoretically proposed, both groups significantly decreased their DA over the training sessions. This decrease was early in the sessions and was not accompanied by a decrease in the SOB. In contrast, subjects maintained a nearly constant mean and peak SOB with increasing exercise performance, suggesting that people may have a dyspnea threshold above which they are unable to tolerate greater dyspnea. Description of the changes in dyspnea and the affective response during training need to be expanded, while studying the type and timing of strategies to enhance the improvement in dyspnea and dyspnea-related anxiety.