Fibroblasts as sentinel cells: role of the CDcd40-CDcd40 ligand system in fibroblast activation and lung inflammation and fibrosis.
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CD40 Ligand↗
Biomedical subjects
J Kaufman
Publications and source records attributed to J Kaufman.
A case-crossover analysis of particulate matter air pollution and out-of-hospital primary cardiac arrest.
Numerous epidemiologic studies have reported increases in the daily incidence of cardiovascular mortality and morbidity associated with increases in daily levels of particulate matter air pollution. We studied the association between the incidence of primary cardiac arrest and two daily measures of particulate matter using a case-crossover study of 362 cases of out-of-hospital cardiac arrest. All cases were attended by paramedics and had no history of clinically recognized heart disease or life-threatening comorbidities. We compared particulate matter levels at index times with particulate matter levels from referent days matched on day of week within strata defined by month and year. The estimated relative risk at a lag of 1 day for an interquartile range (IQR) change in nephelometry (0.51 x 10(-1) km(-1)) was 0.893 (95% CI = 0.779-1.024). The estimated relative risk at a lag of 1 day for an IQR change in PM10 (19.3 microg m(-3)) was 0.868 (95% CI = 0.744-1.012). Other lag periods gave similar results. We did not find evidence of confounding by carbon monoxide or sulfur dioxide. Analysis of effect modification by individual-level variables did not reveal any susceptible subgroups. These findings do no support an association between particulate matter and increased risk of primary cardiac arrest among persons without clinically recognized heart disease. The null results of this study may result from several factors, including the highly selected nature of this case series and the relatively low particulate matter levels in the Seattle metropolitan area.
Adult↗
The CD40-CD40 ligand system: a potential therapeutic target in atherosclerosis.
Atherosclerosis is a leading cause of cardiovascular disease in the westernized world. This review highlights emerging evidence linking atherosclerosis to the CD40-CD40 ligand (CD154) pathway. Recently, atherosclerosis has been associated with chronic inflammation, linking it to the immune system. This novel viewpoint may serve as an additional target for therapeutic intervention. CD40 and CD154 are highly expressed in atherosclerotic human plaques. Recent data from preclinical animal models of atherosclerosis show that disruption of the CD40-CD154 pathway can prevent atherosclerotic progression and may reverse established lesions. Blockade of the CD40-CD154 pathway by biologicals or small molecules may prove valuable in the treatment of atherosclerosis.
Animals↗
Therapeutic strategies for localized prostate cancer.
Prostate-specific antigen determinations for prostate cancer screening have led to a dramatic increase in the number of men who are diagnosed with organ-confined and therefore potentially curable prostate cancer. Advances in predicting outcomes with artificial neural networks may help to recommend one therapy over another. Less invasive forms of treatment, such as high-intensity focused ultrasound, may ultimately give patients additional options for treatment. Furthermore, attempts to better define the role of both neoadjuvant hormonal therapy and chemotherapy may give higher-risk patients better outcomes than with current treatments. These advances as well as continued research will likely lead to a day when more and more men with organ-confined disease will be cured.
Journal Article↗
Low growth hormone response to growth hormone-releasing hormone in child depression.
BACKGROUND: This study examined growth hormone (GH) response to growth hormone-releasing hormone (GHRH) in a large sample of depressed children compared with normal control children. Within-subject comparisons were also performed in control subjects to examine test-retest reliability and in depressed children comparing episode versus clinical recovery. METHODS: The sample included depressed children (n = 82) and normal control children (n = 55) group-matched for age, gender, and pubertal status; the mean ages were 11.2 +/- 1.7 and 11.2 +/- 1.8 years, respectively. We gave GHRH (0.1 mcg/Kg) at 9 AM, and serum GH levels were determined every 15 min from -30 min through +90 min of the GHRH infusion. A subgroup of normal control subjects (n = 11) repeated the protocol for test-retest reliability within a 2-month interval. A subgroup of depressed children (n = 20) were restudied off all medications following full clinical remission from depression. RESULTS: The mean GH response to GHRH was significantly lower in the depressed group (8.7 ng/mL +/- SEM 0.9) compared with normal control children [12.2 ng/mL +/- SEM 1.3; t(135) = 2.59, p =.01 effect size 0.44]. The test-retest reliability of GH response to GHRH was stable (intraclass correlation =.93 for mean post-GH). The GH response to GHRH remained low in subjects restudied during clinical remission from depression. CONCLUSIONS: Depressed children show low GH response to GHRH. The measure appears to be reliable, and the low GH response continues following clinical remission. Further studies are needed to explore the mechanism and relative specificity of this finding.
Child↗
Effects of early adverse experiences on brain structure and function: clinical implications.
Child abuse is associated with markedly elevated rates of major depression and other psychiatric disorders in adulthood. This article reviews preclinical studies examining the effects of early stress, factors that modify the impact of these experiences, and neurobiological changes associated with major depression. Preclinical studies demonstrate that early stress can alter the development of the hypothalamic-pituitary-adrenal axis, hypothalamic and extrahypothalamic corticotropin releasing hormone, monoaminergic, and gamma-aminobutyric acid/benzodiazepine systems. Stress has also been shown to promote structural and functional alterations in brain regions similar to those seen in adults with depression. Emerging data suggest, however, that the long-term effects of early stress can be moderated by genetic factors and the quality of the subsequent caregiving environment. These effects also can be prevented or reversed with various pharmacologic interventions. Preclinical studies of early stress can provide valuable insights in understanding the pathophysiology and treatment of major depression. They also can provide an important tool to use to investigate interactions between genes and environments in determining an individual's sensitivity to stress. More research is needed to understand how inherent factors interact with experiences of abuse and other psychosocial factors to confer vulnerability to develop depression.
Age Factors↗
The simple chicken major histocompatibility complex: life and death in the face of pathogens and vaccines.
In contrast to the major histocompatibility complex (MHC) of well-studied mammals such as humans and mice, the particular haplotype of the B-F/B-L region of the chicken B locus determines life and death in response to certain infectious pathogens as well as to certain vaccines. We found that the B-F/B-L region is much smaller and simpler than the typical mammalian MHC, with an important difference being the expression of a single class I gene at a high level of RNA and protein. The peptide-binding specificity of this dominantly expressed class I molecule in different haplotypes correlates with resistance to tumours caused by Rous sarcoma virus, while the cell-surface expression level correlates with susceptibility to tumours caused by Marek's disease virus. A similar story is developing with class II beta genes and response to killed viral vaccines. This apparently suicidal strategy of single dominantly expressed class I and class II molecules may be due to coevolution between genes within the compact chicken MHC.
Animals↗
HIV-2 protease is inactivated after oxidation at the dimer interface and activity can be partly restored with methionine sulphoxide reductase.
Human immunodeficiency viruses encode a homodimeric protease that is essential for the production of infectious virus. Previous studies have shown that HIV-1 protease is susceptible to oxidative inactivation at the dimer interface at Cys-95, a process that can be reversed both chemically and enzymically. Here we demonstrate a related yet distinct mechanism of reversible inactivation of the HIV-2 protease. Exposure of the HIV-2 protease to H(2)O(2) resulted in conversion of the two methionine residues (Met-76 and Met-95) to methionine sulphoxide as determined by amino acid analysis and mass spectrometry. This oxidation completely inactivated protease activity. However, the activity could be restored (up to 40%) after exposure of the oxidized protease to methionine sulphoxide reductase. This treatment resulted in the reduction of methionine sulphoxide 95 but not methionine sulphoxide 76 to methionine, as determined by peptide mapping/mass spectrometry. We also found that exposure of immature HIV-2 particles to H(2)O(2) led to the inhibition of polyprotein processing in maturing virus particles comparable to that demonstrated for HIV-1 particles. Thus oxidative inactivation of the HIV protease in vitro and in maturing viral particles is not restricted to the type 1 proteases. These studies indicate that two distinct retroviral proteases are susceptible to inactivation after a very minor modification at residue 95 of the dimer interface and suggest that the dimer interface might be a viable target for the development of novel protease inhibitors.
Amino Acid Sequence↗
Growth hormone secretion in children and adolescents at high risk for major depressive disorder.
BACKGROUND: Decreased growth hormone (GH) response to pharmacologic stimulation has been found in children and adolescents during an episode of major depressive disorder and after recovery. In this study, we sought to determine whether GH secretion is similarly altered in children and adolescents who had never experienced depression but were at high risk of developing depression. METHODS: Subjects were 8 through 16 years of age and selected for high- and low-risk status according to familial loading for mood disorders. Sixty-four high-risk and 55 low-risk healthy subjects participated in the study, which assessed the following GH measures: (1) GH before growth hormone-releasing hormone (GHRH) infusion, every 15 minutes for 30 minutes; (2) GH response after intravenous infusion of GHRH (0.1 microg/kg), every 15 minutes for 90 minutes; and (3) nocturnal GH every 20 minutes from 9 PM until morning awakening. RESULTS: After stimulation with GHRH, the high-risk subjects secreted significantly less GH compared with the low-risk healthy controls (effect sizes for mean and peak GH, 0.52 [P =.007] and 0.40 [P =.04], respectively). In contrast, there were no between-group differences in the pre-GHRH and nocturnal GH secretion levels. Exposure to recent stressors was not associated with GH secretion. CONCLUSIONS: Taken together with previous evidence of decreased GH after GHRH infusion in acutely depressed and recovered children, these results indicate that the decreased GH response found in high-risk subjects may represent a trait marker for depression in children and adolescents.
Adolescent↗
Comorbidity of mood and anxiety disorders.
This article reviews data on the prevalence of panic, social phobia, generalized anxiety, and posttraumatic stress disorder, and research documenting the comorbidity of these disorders with major depression (MDD). These anxiety disorders are frequently comorbid with MDD, and 50-60% of individuals with MDD report a lifetime history of one or more of these anxiety disorders. The anxiety disorders are also highly correlated with one another, and approximately one-quarter to one-half of individuals with each of the anxiety disorders report a lifetime history of an alcohol or substance use disorder. Anxiety disorders rarely exist in isolation, with several studies reporting that over 90% of individuals with anxiety disorders have a lifetime history of other psychiatric problems. Implications for research are discussed, including the potential benefit of using combined categorical and dimensional rating scale approaches in future genetic, biochemical, neuroimaging, and treatment studies. The clinical implications of the findings are also discussed, and the results of recent clinical trials summarized. Available data suggests selective serotonin reuptake inhibitors are the first-line pharmacological treatment for these disorders, and that newer serotonin and norepinephrine reuptake inhibitors show significant promise, especially for comorbid cases. Comorbidity among depression and anxiety disorders is associated with greater symptom severity, and a considerably higher incidence of suicidality. Increased public awareness about these disorders and the availability of effective treatments is sorely needed.
Antidepressive Agents↗
Screen for Child Anxiety-Related Emotional Disorders (SCARED): convergent and divergent validity.
The purpose of this study was to examine the Screen for Child Anxiety-Related Emotional Disorders' (SCARED) divergent and convergent validity and its ability to identify anxious children. The SCARED, the Child Behaviour Checklist (CBCL), and the State-Trait Anxiety Inventory for Children (STAIC) were administered to children, adolescents (n = 295), and their parents attending an outpatient mood and anxiety disorders clinic. DSM-IIIR/IV diagnoses were made using a semistructured interview (n = 130) or a symptom checklist (n = 165). The Multi-Trait Multi-Method Matrix was used to assess construct validity, and Receiver Operating Curve analysis was used to assess the sensitivity and specificity of the SCARED, CBCL, and STAIC. The SCARED correlated significantly better with the CBCL's internalizing factors than with the externalizing factors. In addition, parent and child forms of the SCARED correlated significantly with the trait and state subscales of the STAIC. Children with an anxiety disorder scored significantly higher on the SCARED than children with depression only or disruptive disorders only (P < 0.05), thus demonstrating the discriminant validity of the SCARED. The SCARED is a reliable and valid screening tool for clinically referred children and adolescents with anxiety disorders.
Adolescent↗
Angiogenic therapy for the chronically ischemic lower limb in a rabbit model.
The purpose of this study was to evaluate the long-term effectiveness of basic fibroblast growth factor (bFGF) in achieving neovascularization following ischemia from arterial ligation and to determine an optimal dosage level. We used an Ameroid constrictor to produce progressive occlusion of the left femoral artery of rabbits. At 2 weeks, the rabbits were randomized to receive intravenous injection of vehicle (group A, n = 15); 3 microg/kg/day bFGF (group B, n = 12); 10 microg/kg/day bFGF (group C, n = 12); or 16 microg/kg/day bFGF (group D, n = 15) for 3 days. At 1 to 37 days after surgery, we assessed limb neovascularization by transcutaneous oximetry (TCPO(2)), angiography, heart rate, arterial pressure, peripheral vascular resistance (PRU), and muscle blood flow (MBF) during steady-state intra-arterial infusion of saline (basal), acetylcholine, papaverine, or serotonin under anesthesia and capillary density (cap/mm(2)) and capillary per muscle fiber ratio (cap/F). Groups B and C showed significantly greater change in TCPO(2) over time than groups A and D (P < 0.0001). Group D showed the lowest TCPO(2) values from days 14 to 37 and group C the highest. Groups B and C showed a higher number of vessels filled with contrast agent than groups A and D (P < 0.0001). Calf cap/mm(2) and cap/F were significantly higher in groups B and C than groups A and D (P < 0.0001). Calf basal MBF values were higher in groups B and C than in groups A and D, but were not statistically significant. Group D showed the highest level in basal PRU. There were no significant differences in heart rate or blood pressure among the groups. These results show (1) treatment with bFGF has no adverse hemodynamic effects, (2) bFGF enhances angiogenesis and circulation at moderate doses, and these effects persist at least several weeks, and (3) high doses of bFGF may inhibit angiogenesis and collateral circulation.
Animals↗
Expression of cyclooxygenase-2 and prostaglandins by B-1 cells and B-CLL cells.
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Animals↗
The major and a minor class II beta-chain (B-LB ) gene flank the Tapasin gene in the B-F /B-L region of the chicken major histocompatibility complex.
We have identified the major histocompatibility complex class II beta-chain (B-LB) genes present in the B-F/B-L region of the B complex of nine well-characterized lines of chickens and have cleared up much of the confusion concerning numbers and location of B-LB genes in this region. By amplifying DNA sequences between adjacent genes, we found two B-LB genes that lie on either side of Tapasin. The dominantly expressed 'major' B-LB gene in all haplotypes lies between Tapasin and RING-3, and belongs to the B-LBII family of class II beta-chain genes. The poorly expressed 'minor' B-LB gene in all haplotypes lies between B-lec1 and Tapasin, and belongs either to the B-LBII family or to the previously unmapped B-LBVI family of class II beta-chain genes. The data suggest that the B-LBII and B-LBVI genes are two lineages of B-LB genes and we propose that they all be termed B-LB genes. The location of a third B-LB gene in the B12 haplotype (and possibly other haplotypes as well) has yet to be determined. The structural organization and expression of the class II beta-chain genes in the B-F/B-L region is similar to that of chicken class I (B-F) genes, one functional result of which is differential resistance to disease and response to vaccines.
Animals↗
Intracavernous alprostadil alfadex is more efficacious, better tolerated, and preferred over intraurethral alprostadil plus optional actis: a comparative, randomized, crossover, multicenter study.
OBJECTIVES: To compare the efficacy, safety, and patient preference of intracavernously administered alprostadil alfadex and intraurethrally administered alprostadil. METHODS: A crossover, randomized, open-label multicenter study of 111 patients with erectile dysfunction of at least 6 months' duration compared the efficacy, safety, and patient preference of intracavernosal alprostadil (EDEX/Viridal) with MUSE plus optional ACTIS. All patients underwent an in-office dose titration with either drug before undertaking an at-home treatment phase. The most frequently used doses during the at-home phase were 40 microg (44.1% of men) and 1000 microg (86.8% of men) for EDEX and MUSE, respectively; the mean doses were 26.1 microg and 922.5 microg for EDEX and MUSE, respectively. RESULTS: More EDEX than MUSE administrations resulted in an erection sufficient for sexual intercourse (82.5% versus 53.0%); significantly more patients using EDEX achieved at least one erection sufficient for sexual intercourse (92.6% versus 61.8%; P <0.0001); and EDEX use resulted in a significantly greater percentage of patients attaining at least 75% of erections sufficient for sexual intercourse (75% versus 36.8%; P <0.0001). Penile pain was the most common side effect for both medications: 20.0% versus 30.5% (in-office) and 33.8% versus 25.0% (at-home) for EDEX and MUSE, respectively. Similar numbers of adverse events were reported with either treatment during the at-home phase. Patient and partner satisfaction was greater with EDEX, and more patients preferred this therapy, choosing to continue it during a patient preference period at the end of the study. CONCLUSIONS: Since intracavernous injection therapy was more efficacious, better tolerated, and preferred by the patients and their partners, it should be offered as the first-choice treatment if oral therapy fails or is contraindicated.
Adult↗
Intracavernous alprostadil alfadex (EDEX/VIRIDAL) is effective and safe in patients with erectile dysfunction after failing sildenafil (Viagra).
OBJECTIVES: Sildenafil (Viagra), an oral treatment for erectile dysfunction, has proved popular since its introduction in 1998. However, not all patients respond to this form of therapy. Consequently, this study investigated the efficacy of intracavernous alprostadil alfadex (EDEX/VIRIDAL) treatment in patients not responding to sildenafil. METHODS: In an open-label, multicenter study, patients with erectile dysfunction were treated with sildenafil for 4 weeks. The initial dose was 50 mg, which was increased to 100 mg if no response was achieved. Patients not responding to treatment, measured using the International Index of Erectile Function (IIEF) questionnaire, entered an alprostadil alfadex in-office titration phase, to determine the optimal dose, up to 40 microgram. A 6-week alprostadil alfadex at-home treatment phase followed. RESULTS: In 67 patients who did not respond satisfactorily to sildenafil, the alprostadil alfadex at-home therapy resulted in improvements in questions 3 and 4 of the IIEF in 60 (89.6%) and 57 (85.1%) patients, respectively. The mean improvement in IIEF score for these patients was 2.75 and 2.63 for questions 3 and 4, respectively. The most common side effect was penile pain in 25 (29. 4%) of 85 patients treated with alprostadil alfadex in-office and at home. CONCLUSIONS: Alprostadil alfadex therapy can be used effectively and safely in men who fail initial therapy with sildenafil.
Administration, Oral↗
Sorting out the role of air pollutants in asthma initiation.
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Air Pollutants↗
K-SADS-PL.
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Attention Deficit Disorder with Hyperactivity↗