Biodegradable cationic nanogels with tunable size, swelling and pKa for drug delivery.

Cationic polymers have garnered significant interest for their utility in intracellular drug delivery and gene therapy. However, due to their associated toxicities, novel synthesis approaches must be explored to develop materials that are biocompatible. The novel library of nanoparticles synthesized in this study exhibit tunable hydrodynamic diameters, composition and pH-responsive properties as a function of synthesis parameters. In addition, differences in the responsiveness of these nanoparticles under different pH conditions affords greater control over intracellular drug release.

Inheritance of pulmonary arterial pressure in Angus cattle and its correlation with growth.

Pulmonary arterial pressure (PAP) is an indicator of resistance to blood flow through the lungs and when measured at high altitude is a reliable predictor of susceptibility of an animal to brisket disease, a noninfectious cardiac pulmonary condition. (Co)-variance components for PAP, birth weight, and adjusted 205-d weaning weight were estimated from 2,305 spring-born, registered Angus cattle from a Colorado ranch at an elevation of 1,981 m. A single measure of PAP was collected after weaning on animals born from 1984 to 2003. The same licensed veterinarian measured every animal. Multitrait animal models with and without PAP maternal effects were fitted for a pedigree including 132 sires and 793 dams. The interaction of year x sex was a significant fixed effect (P <0.05) for PAP, but age of dam was not. Age at PAP testing was a significant (P <0.1) linear covariate for PAP, and scores increased 0.012 +/- 0.007 mmHg X d(-1) of age. Heritability of PAP direct was 0.34 +/- 0.05. Maternal heritability converged to a boundary at 0.0, and the model with maternal genetic effects for PAP was not significantly better than a model with only direct effects. Phenotypically, PAP was uncorrelated with birth or weaning weights. Genetically, PAP appeared to have positive, unfavorable relationships with direct effects for birth (0.49 +/- 0.12) and weaning weight (0.50 +/- 0.18). Positive correlations imply sires whose offspring exhibited resistance to brisket disease had lower weights and gains. A model that evaluated PAP in females and males as different traits had heritability estimates for each sex of 0.38 +/- 0.07 and 0.46 +/- 0.09, respectively, with a genetic correlation of 0.64 +/- 0.12 between the sexes and was not significantly better than the model assuming homogeneity by sex and a unit genetic correlation between sexes. The results suggest that PAP is moderately heritable in spring-born Angus cattle acclimatized and tested at high altitude, and selection for low PAP scores would be effective. Selection for growth at low altitude will produce cattle less suited to high altitude.

Maternal effects on docility in Limousin cattle.

The objective of this study was to quantify the role of maternal effects on docility in Limousin cattle. Docility scores were obtained at weaning while animals were restrained in a squeeze chute. Scores 1 through 6 represented a docile to aggressive temperament, respectively, and were provided by the North American Limousin Foundation. Observations with unknown age of dam, contemporary groups containing less than 10 observations, contemporary groups with no variation, and single-sire contemporary groups were removed, leaving 21,932 observations. A 2-generation pedigree file compiled from animals with observations contained 49,459 animals. Fixed effects were weaning contemporary group and age of dam (2, > or =3 yr). Six animal models encompassed combinations of random factors: direct genetic, maternal genetic, and maternal permanent environmental effects. The model D was the most basic, containing direct genetic and residual effects, and it resembled the method currently used by the North American Limousin Foundation for genetic evaluation of docility. Maternal genetic or permanent environmental effects were separately added to the model D, denoted as models DM and DC, respectively. Model DMC contained all random factors. Models DM-Zero and DMC-Zero were equivalent to models DM and DMC, respectively, but with zero direct-maternal genetic covariance. Direct heritability estimates were moderate for all models (0.29 +/- 0.02 to 0.38 +/- 0.03). Maternal heritability estimates were low, ranging from 0.01 +/- 0.01 (DM-Zero) to 0.05 +/- 0.02 (DM). Negative direct-maternal genetic correlations of -0.41 +/- 0.09 and -0.55 +/- 0.09 were estimated for models DM and DMC, respectively. The proportion of phenotypic variance accounted for by maternal permanent environmental effects was 0.03 +/- 0.01, 0.04 +/- 0.01, and 0.02 +/- 0.01 for models DC, DMC, and DMC-Zero, respectively. Likelihood ratio tests indicated that model DMC best fit the data. Although maternal genetic and maternal permanent environmental effects were significant, they accounted for only 8% (model DMC) of the phenotypic variance, and a Spearman rank correlation of 0.99 between models D and DMC showed sires did not rank differently with or without inclusion of these effects. Given these results, inclusion of maternal effects to the genetic evaluation of docility in Limousin cattle does not seem warranted.

PAM-4 Signaling over VCSELs with 0.13microm CMOS Chip Technology.

We present results for VCSEL based links operating PAM-4 signaling using a commercial 0.13microm CMOS technology. We perform a complete link analysis of the Bit Error Rate, Q factor, random and deterministic jitter by measuring waterfall curves versus margins in time and amplitude. We demonstrate that VCSEL based PAM-4 can match or even improve performance over binary signaling under conditions of a bandwidth limited, 100meter multi-mode optical link at 5Gbps. We present the first sensitivity measurements for optical PAM-4 and compare it with binary signaling. Measured benefits are reconciled with information theory predictions.

Vital involvement of a natural killer cell activation receptor in resistance to viral infection.

Natural killer (NK) cells are lymphocytes that can be distinguished from T and B cells through their involvement in innate immunity and their lack of rearranged antigen receptors. Although NK cells and their receptors were initially characterized in terms of tumor killing in vitro, we have determined that the NK cell activation receptor, Ly-49H, is critically involved in resistance to murine cytomegalovirus in vivo. Ly-49H requires an immunoreceptor tyrosine-based activation motif (ITAM)-containing transmembrane molecule for expression and signal transduction. Thus, NK cells use receptors functionally resembling ITAM-coupled T and B cell antigen receptors to provide vital innate host defense.

Divalproex sodium in sex offenders with bipolar disorders and comorbid paraphilias: an open retrospective study.

BACKGROUND: This study evaluated divalproex response in sex offenders with a bipolar disorder. METHODS: We reviewed the records of all sex offenders who participated in a residential rehabilitative program who received divalproex for treatment of a bipolar disorder. Patients' mood symptoms and, when present, comorbid paraphilic symptoms, were retrospectively assessed using the CGI severity scale. RESULTS: Sex offenders displayed significant improvement in manic symptoms with divalproex treatment. However, there was no significant improvement in paraphilic symptoms in the subset of patients admitting to these symptoms. CONCLUSION: Divalproex may be effective for manic symptoms in sex offenders with a bipolar disorder. However, for bipolar sex offenders with comorbid paraphilias, the drug may not be effective for paraphilic symptoms. LIMITATIONS: This study was limited by its retrospective, open-label design, lack of systematic means of assessing manic and paraphilic symptoms, and small sample size. CLINICAL RELEVANCE: Divalproex may be a helpful adjunct in the treatment of the subset of sex offenders who have a bipolar disorder.

Rat embryo cultures for in vitro teratology.

Mammalian embryos provide a particular challenge to those who wish to study developmental processes because development takes place inside the mother's body, thus limiting the investigator's ability to directly affect and observe the embryonic stages of development. Fortunately, as this unit illustrates, methods have been developed for in vitro culture of rodent embryos during early postimplantation (gestation days 9 to 11) and early fetal (gestation days 12 to 14) stages, which are the periods during which the major systems of the embryo are established. Embryos at these stages are particularly suitable for screening studies to determine the effects of teratological agents.

Effects of peroxynitrite on pulmonary edema and the oxidative state.

Excess nitric oxide (NO) generation in the presence of superoxide anion (O2-) leads to the formation of peroxynitrite which may result in lung injury. Oxidant-mediated lung injury has a critical role in pulmonary diseases. We therefore determined whether peroxynitrite causes lung fluid accumulation, lipid peroxidation, and formation of nitrotyrosine using an isolated perfused rat lung model. The lung weight gain during bolus peroxynitrite infusion increased in a dose-dependent manner over a range of 3 to 30 mumole. Concomitantly, bronchoalveolar lavage Ficoll also increased, indicative of increased endothelial permeability. Peroxynitrite increased the production of thiobarbituric acid reactive substances, an index of lipid peroxidation. Furthermore, nitrotyrosine levels in lung tissue rose with increased concentration of peroxynitrite, as determined by Western blot using antinitrotyrosine antibodies. These results suggest that peroxynitrite, formed from NO and O2-, leads to increased pulmonary fluid accumulation, possibly through lipid peroxidation and/or nitration of cell membrane proteins.

Effects of pre- and postnatal cysteamine exposure on renal function in the rat.

The safety of cysteamine after renal transplantation and during pregnancy is an important issue, since girls with cystinosis are in better health on cysteamine therapy and thus more likely to become pregnant. In the first study, cysteamine was given to pregnant rats on days 6.5-18.5 post conception in oral doses of 0, 37.5, 75, 100, and 150 mg/kg per day. The dams were sacrificed on day 20.5, the fetal kidneys removed and prepared for histological examination. In the second study, cysteamine was given to dams on days 6.5-19.5 post conception in oral doses of 0, 37.5, 50, and 75 mg/kg per day. Dams were allowed to give birth naturally and pups were given cysteamine on days 4-21 to yield the same oral doses of cysteamine given to the dam. Renal function was evaluated on day 35. Histological examination of fetal kidneys revealed no changes even in kidneys from fetuses with growth retardation and malformations. Furthermore, there were no alterations in renal function in offspring on day 35. These findings demonstrate that cysteamine therapy does not affect renal development in the rat. Further investigations will be required to prove whether cysteamine therapy has the potential to affect renal development in the human.

Expression of cysteine proteases in extraembryonic tissues during mouse embryogenesis.

The expression of cathepsin B- and L-specific mRNAs as well as active forms of the enzymes was determined in mouse placenta and visceral yolk sac from 7.5 through 17.5 days postconception, a period marked by major anatomic transitions in the mouse conceptus. The level of specific mRNA was determined relative to the 28S ribosomal RNA in a series of multiprobe ribonuclease protection assays using high-specific-activity antisense cathepsin B and L riboprobes. The molecular forms of active cysteine proteases present in the tissues at the time of extraction were detected using a membrane-permeant radiolabeled active site-specific inhibitor, Fmoc-[(125)I(2)]Tyr-Ala-CHN(2). The results of this study show that the expression of active cathepsin L relative to active cathepsin B is significantly higher in visceral yolk sac than in placenta, consistent with a higher proteolytic requirement for the former tissue. Active cathepsin L was highest at Day 9.5 in visceral yolk sac, a stage at which it has been shown that proteolysis in this organ is required for production of amino acids for embryonic protein synthesis. Cathepsin L mRNA was also elevated in the Day 9.5 placenta, but paradoxically this did not result in an increase in cellular active enzyme. An unknown protein, termed p14, highly expressed in placenta, also reacted with the inhibitor. Expression of this protein was highest early during gestation in the ectoplacental cone, suggesting that p14 may be important in the implantation process.

Activation of the erythropoietin receptor is not required for internalization of bound erythropoietin.

Erythropoietin (EPO) is required for the survival and expansion of red blood cell progenitor cells and supports continued differentiation of these committed progenitors to mature red blood cells. After binding to its cognate receptor, EPO promotes receptor homodimerization, activation of receptor-associated JAK2, subsequent receptor tyrosine phosphorylation, and transduction of signal. EPO is also internalized and degraded in lysosomes. The contribution of EPO-induced receptor internalization to modulation of EPO signals has not been determined. To examine this question, we generated a panel of hematopoietic cell lines containing progressively truncated isoforms of the erythropoietin receptor (EPO-R) and determined the rate and extent of EPO internalization and receptor downregulation. We demonstrated that a membrane-proximal domain of the cytoplasmic tail of the EPO-R was the minimal region required for EPO-induced receptor internalization. This cytoplasmic domain is also the minimal domain required for activation of JAK2, a cytosolic tyrosine kinase essential for the function of the EPO-R. However, neither EPO activation of cytosolic JAK2 tyrosine kinase activity nor tyrosine phosphorylation of the EPO-R cytoplasmic tail was required for EPO-induced receptor downregulation. Both functional and nonfunctional cell surface receptor isoforms were internalized equally. These results suggest that, for downregulation of cell surface ligand occupied EPO-R and possibly for signaling receptors of the cytokine receptor superfamily in general, internalization of cell surface ligand occupied receptors may follow a pathway distinct from signaling receptors of the receptor tyrosine kinase (RTK) family.

Pharmacotherapy to prevent the complications of allergic rhinitis.

Allergic rhinitis is an immunologic disease with effects that extend beyond the symptoms that occur subsequent to allergen exposure. A reduced quality of life and medical conditions such as asthma, sinusitis and otitis media are well recognized complications of allergic rhinitis. Craniofacial abnormalities, nasal ployps, and respiratory infections have been linked to allergic rhinitis, but the evidence is conflicting. This article reviews the complications of allergic rhinitis, their prevalences, possible mechanisms for their relationship to allergic rhinitis, and the prevention of these complications via pharmacologic treatment of allergic rhinitis.

Psychiatric features of 36 men convicted of sexual offenses.

BACKGROUND: To increase understanding of the relationship between sexual violence and mental illness, the authors assessed the legal histories and psychiatric features of 36 males convicted of sexual offenses. METHOD: Thirty-six consecutive male sex offenders admitted from prison, jail, or probation to a residential treatment facility received structured clinical interviews for DSM-IV Axis I and II disorders. The participants' legal histories, histories of sexual and physical abuse, and family histories of psychiatric disorders were also assessed. RESULTS: The participants' mean +/- SD age was 33+/-8 years. They had been convicted a mean of 1.8+/-1.4 times (range, 1-9 times) for sexual offenses and incarcerated a mean of 8+/-6 years (range, 0-22 years). Participants displayed high rates of lifetime DSM-IV Axis I disorders: 30 (83%) had a substance use disorder; 21 (58%), a paraphilia; 22 (61%), a mood disorder (13 [36%] with a bipolar disorder); 14 (39%), an impulse control disorder; 13 (36%), an anxiety disorder; and 6 (17%), an eating disorder. Participants also displayed high rates of Axis II disorders, with 26 (72%) meeting DSM-IV criteria for antisocial personality disorder. In addition, subjects reported experiencing high rates of sexual (but not physical) abuse and high rates of Axis I disorders, especially substance use and mood disorders, in their first-degree relatives. Compared with subjects without paraphilias, subjects with paraphilias displayed statistically significantly higher rates of mood, anxiety, and eating disorders, as well as significantly higher rates of childhood sexual abuse. CONCLUSION: Recognition and treatment of major psychiatric disorders among sex offenders may increase chances for successful rehabilitation, reduce recidivism and public victimization, and produce significant public health and economic benefits. More studies in this area appear warranted to search for more effective interventions for this severe public health problem.

Evaluation of the reproductive and developmental safety of cysteamine in the rat: effects on female reproduction and early embryonic development.

Cystinosis is an autosomal recessive metabolic disease in which the amino acid cystine accumulates in lysosomes due to a defect in lysosomal cystine transport. Cystinosis in infancy is associated with poor growth, muscle wastage, and death at about age 10 due to kidney failure. Treatment with cysteamine and kidney transplantation enables cystinotic girls to reach reproductive age and to be healthy enough to permit pregnancy. It is not known whether exposure to cysteamine will have adverse effects on reproduction in the human. It is also possible that some of the complications seen in cystinotic children could be avoided if a pregnant woman carrying a cystinotic fetus were given cysteamine. However, this treatment is not likely to occur until therapeutic exposures to cysteamine are judged to present no increased risk to the human fetus. As part of a larger investigation assessing the reproductive and developmental safety of cysteamine (as phosphocysteamine) using the rat, the two studies reported herein were performed. The first, a dose-finding study, led to the selection of 150 mg/kg/day as the highest dose of cysteamine used for the second and primary focus of this report. The second study involved the exposure of female rats to cysteamine from premating through day 6.5 postconception and assessment of female fertility and early embryonic development. Cysteamine was administered orally in doses of 0, 37.5, 75, 100, or 150 mg/kg/day. There were no clinical signs of maternal toxicity during the exposures of 2 to 5 weeks before successful mating. Animals in the 150 mg/kg/day group experienced a nonsignificant decrease in body weight gain during pregnancy to day 6.5 postconception, a significant increase in liver and spleen weights, and a significant increase in days to coitus--suggesting that a low level of toxicity was manifested. However, there were no adverse effects on reproductive performance with respect to conception and early embryonic development.

Developmental toxicity of cysteamine in the rat: effects on embryo-fetal development.

The reproductive and developmental safety of cysteamine has become an important issue to children with cystinosis because renal transplants and treatment with cysteamine reduce the complications associated with cystinosis and increase the lifespan of the affected children. In addition, there is the potential to decrease the severity or the incidence of renal Fanconi syndrome with administration of cysteamine to pregnant women carrying fetuses with cystinosis, and to ease significantly the burden of this disease throughout their lives. If cysteamine increases significantly the risk of fetal death, growth retardation or birth defects at doses used to treat women with cystinosis, treatment of the affected female should cease during pregnancy and would not be considered for fetal treatment. The goal of this study was to assess the developmental safety of exposure in utero to cysteamine in the rat. Pregnant rats were given cysteamine (as phosphocysteamine) from day 6.5 through day 18.5 postconception and fetuses were assessed for survival, growth, and structural abnormalities on day 20.5. Cysteamine was administered orally in doses of 0, 37.5, 75, 100, or 150 mg/kg/day. Cysteamine produced dose-dependent developmental toxicity with an apparent no adverse effect observed level of 75 mg/kg/day. Specific malformations were associated with this effect (cleft palate, kyphosis), as well as intrauterine growth retardation and fetal death at 100-150 mg/kg/day, without signs of maternal toxicity. Investigations continue into the mechanism for the developmental toxicity of cysteamine.

DSM-IV intermittent explosive disorder: a report of 27 cases.

BACKGROUND: The authors' objective was to provide data regarding the demographic, phenomenological, course of illness, associated psychiatric and medical comorbidity, family history, and psychiatric treatment response characteristics of rigorously diagnosed subjects who met DSM-IV criteria for intermittent explosive disorder. METHOD: Twenty-seven subjects meeting DSM-IV criteria for a current or past history of intermittent explosive disorder were given structured diagnostic interviews. The subjects' medical histories, family histories of psychiatric disorders, and responses to psychiatric treatments were also assessed. RESULTS: Most subjects described their intermittent explosive disorder symptoms as very distressing and/or highly problematic. All 27 subjects described aggressive impulses prior to their aggressive acts. Of 24 subjects who were systematically queried, 21 (88%) experienced tension with the impulses; 18 (75%), relief with the aggressive acts; and 11 (48%), pleasure with the acts. Most subjects stated that their aggressive impulses and acts were also associated with affective symptoms, particularly changes in mood and energy level. Twenty-five (93%) subjects had lifetime DSM-IV diagnoses of mood disorders; 13 (48%), substance use disorders; 13 (48%), anxiety disorders; 6 (22%), eating disorders; and 12 (44%), an impulse-control disorder other than intermittent explosive disorder. Subjects also displayed high rates of comorbid migraine headaches. First-degree relatives displayed high rates of mood, substance use, and impulse-control disorders. Twelve (60%) of 20 subjects receiving monotherapy with an antidepressant or a mood stabilizer reported moderate or marked reduction of their aggressive impulses and/or episodes. CONCLUSION: Intermittent explosive disorder appears to be a bona fide impulse-control disorder that may be related to mood disorder and may represent another form of affective spectrum disorder.