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Biomedical subjects

P Cohen

Publications and source records attributed to P Cohen.

At least 91 records · Page 5Linked to original sources
PubMed2001

Selective deletion of leptin receptor in neurons leads to obesity.

Animals with mutations in the leptin receptor (ObR) exhibit an obese phenotype that is indistinguishable from that of leptin deficient ob/ob mice. ObR is expressed in many tissues, including brain, and the relative importance of leptin's effects on central versus peripheral sites has not been resolved. To address this, we generated mice with neuron-specific (ObR(SynI)KO) and hepatocyte-specific (ObR(Alb)KO) disruption of ObR. Among the ObR(SynI)KO mice, the extent of obesity was negatively correlated with the level of ObR in hypothalamus and those animals with the lowest levels of ObR exhibited an obese phenotype. The obese mice with low levels of hypothalamic ObR also show elevated plasma levels of leptin, glucose, insulin, and corticosterone. The hypothalamic levels of agouti-related protein and neuropeptide Y RNA are increased in these mice. These data indicate that leptin has direct effects on neurons and that a significant proportion, or perhaps the majority, of its weight-reducing effects are the result of its actions on brain. To explore possible direct effects of leptin on a peripheral tissue, we also characterized ObR(Alb)KO mice. These mice weigh the same as controls and have no alterations in body composition. Moreover, while db/db mice and ObR(SynI)KO mice have enlarged fatty livers, ObR(Alb)KO mice do not. In summary, these data suggest that the brain is a direct target for the weight-reducing and neuroendocrine effects of leptin and that the liver abnormalities of db/db mice are secondary to defective leptin signaling in the brain.

Animals↗
PubMed2001

Factors associated with use of mental health services for depression by children and adolescents.

OBJECTIVE: This study examined patterns of mental health service use among depressed children and adolescents and factors associated with help seeking and treatment modalities. METHODS: The sample consisted of 206 children and adolescents aged 9 to 17 years who were assessed as part of a larger survey of mental health service use in five service systems and in the community and who met DSM-III-R criteria for depressive disorders (major depression or dysthymia). RESULTS: Among the 206 children, 75 (36 percent) never received professional help for depressive symptoms. Among the 131 children who received professional help for depression, antidepressants were prescribed for 40 (31 percent) in the year before the interview. The findings indicate possible undertreatment of depression among children and adolescents, especially among African Americans. Socioeconomic factors, such as the mother's education and the child's health insurance, were not associated with receiving professional help for depressive symptoms but were associated with receiving antidepressants. Parental perception of a child's mental health service need was associated with receiving professional help but not with receiving antidepressants. Also, depressed children were more likely to receive antidepressants when they had life-threatening or severe symptoms, such as a suicide attempt or drug abuse. CONCLUSIONS: Whether a depressed child receives mental health services and the types of treatment received are influenced by different individual and family factors and by the type of symptoms exhibited. Better understanding of these factors will help in meeting the service needs of depressed children and adolescents.

Adolescent↗
PubMed2001

Transferrin is an insulin-like growth factor-binding protein-3 binding protein.

Insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) possesses both growth-inhibitory and -potentiating effects on cells that are independent of IGF action and are mediated through specific IGFBP-3 binding proteins/receptors located at the cell membrane, cytosol, or nuclear compartments and in the extracellular matrix. We have here characterized transferrin (Tf) as one of these IGFBP-3 binding proteins. Human serum was fractionated over an IGFBP-3 affinity column, and a 70-kDa protein was eluted, sequenced, and identified (through database searching and Western immunoblot) as human Tf. Tf bound IGFBP-3 but had negligible affinity to the other five IGFBPs, and iron-saturated holo-Tf bound IGFBP-3 more avidly than unsaturated Tf. Biosensor interaction analysis confirmed that this interaction is specific and sensitive, with a high association rate similar to IGF-I, and suggested that binding occurs in the vicinity of the IGFBP-3 nuclear localization site. As an independent confirmation of this interaction, using a yeast two-hybrid system, we cloned Tf from a human liver complementary DNA library as an IGFBP-3 protein partner. Tf treatment blocked IGFBP-3-induced cell proliferation in bladder smooth muscle cells, and IGFBP-3-induced apoptosis in prostate cancer cells. In summary, we have employed a combination of techniques to demonstrate that Tf specifically binds IGFBP-3, and we showed that this interaction has important physiological effects on cellular events.

Adult↗
PubMed2001

Dramatic-erratic personality disorder symptoms: I. Continuity from early adolescence into adulthood.

This longitudinal study examined dramatic-erratic personality disorder symptoms (histrionic, borderline, and narcissistic symptoms) in a community sample of 407 adolescents to assess whether this diagnostic construct is meaningful in young people. Based on latent variable models and dimensional symptom scales, these so-called Cluster B symptoms were highly stable across an eight-year interval from early adolescence to early adulthood. Furthermore, when compared with internalizing and externalizing symptoms, dramatic-erratic symptoms were more stable over time than these well-established Axis I symptom clusters. Based on high correlations with co-occurring internalizing and externalizing symptoms, Cluster B symptoms clearly reflect emotional distress during adolescence. These analyses reinforce recent efforts to establish personality disorders as a clinically significant and valid diagnostic construct in young people.

Adolescent↗
PubMed2001

Dramatic-erratic personality disorder symptoms: II. Developmental pathways from early adolescence to adulthood.

This study examined the relationship over time between Cluster B personality disorder symptoms (borderline, histrionic, and narcissistic symptoms) and comorbid internalizing and externalizing symptoms in a community sample of 407 adolescents. Cross-lagged longitudinal models tested (a) the hypothesis that Cluster B symptoms reflect primary disturbances that give rise to co-occurring internalizing and externalizing symptoms; and (b) the alternative hypothesis that these Axis I symptom clusters reflect primary problems that interfere with normal personality development. Internalizing and externalizing symptoms each predicted subsequent Cluster B symptoms in girls, although these effects occurred only at specific developmental stages. Cluster B symptoms in boys and girls at ages 10 to 14 years predicted externalizing symptoms two years later. Instead of clearly supporting one hypothesis over the other, longitudinal models suggested gender-specific developmental effects that were partially consistent with both hypotheses.

Adolescent↗
PubMed2001

Insulin-like growth factor binding protein-3 mediates 1 alpha,25-dihydroxyvitamin d(3) growth inhibition in the LNCaP prostate cancer cell line through p21/WAF1.

PURPOSE: We determined that insulin-like growth factor binding protein 3 (IGFBP-3) induction by 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) is a necessary component of 1,25-(OH)(2)D(3) mediated growth inhibition of the LNCaP human prostate cancer cell line. In addition, induction of the cyclin dependent kinase inhibitory protein p21/WAF/CIP1 by 1,25-(OH)(2)D(3) is mediated by IGFBP-3. MATERIALS AND METHODS: Induction of IGFBP-3 by 1,25-(OH)(2)D(3) was determined by enzyme-linked immunosorbent assay for IGFBP-3 protein and by Northern blot analysis for IGFBP-3 messenger (m) RNA. Growth assays for LNCaP cells were determined by measuring DNA content. The contribution of IGFBP-3 toward 1,25-(OH)(2)D(3) mediated growth inhibition was determined by adding either antisense oligonucleotides or immuno-neutralizing antibodies to culture media of growth assays. Regulation of p21/WAF/CIP1 was determined by Western blot analysis. RESULTS: Adding 1,25-(OH)(2)D(3) to LNCaP prostate cancer cells demonstrated that 1,25-(OH)(2)D(3) significantly up-regulated IGFBP-3 at the mRNA and protein levels in these cells approximately 3-fold over control levels. Also, adding IGFBP-3 protein to LNCaP cell growth medium inhibited LNCaP cell growth. Interestingly adding IGFBP-3 antisense oligonucleotides or antibodies directed toward IGFBP-3 abolished the growth inhibitory actions of 1,25-(OH)(2)D(3), indicating that this effect is IGFBP-3 dependent. Furthermore, to connect the mechanisms of IGFBP-3 and 1,25-(OH)(2)D(3) mediated growth inhibition we demonstrated that IGFBP-3 up-regulates the expression of p21/WAF1 protein to approximately 2-fold over the control level. Adding an IGFBP-3 immuno-neutralizing antibody completely prevented the 1,25-(OH)(2)D(3) induced up-regulation of p21/WAF1. CONCLUSIONS: 1,25-(OH)(2)D(3) up-regulates IGFBP-3 in the LNCaP cell line at the mRNA and protein levels. The growth inhibitory action of 1,25-(OH)(2)D(3) on LNCaP cells depends on active IGFBP-3, as evidenced by the loss of growth inhibition induced by IGFBP-3 antisense oligonucleotide and immuno-neutralization experiments. A possible connection between IGFBP-3 and 1,25-(OH)(2)D(3) lies in the cyclin dependent kinase inhibitory protein p21/WAF1 since IGFBP-3 and 1,25-(OH)(2)D(3) each up-regulate this protein and both inhibit LNCaP cell growth. Therefore, we hypothesize that the mechanism of action by which IGFBP-3 and 1,25-(OH)(2)D(3) induce growth inhibition is the induction of p21/WAF1 because IGFPB-3 immuno-neutralizing antibodies completely abrogate the 1,25-(OH)(2)D(3) mediated up-regulation of p21/WAF1 and growth inhibition.

Calcitriol↗
PubMed2001

Localized neurological necrotizing vasculitides. Three cases with isolated mononeuritis multiplex.

Localized vasculitic neuropathies are increasingly reported. We describe 3 cases of peripheral neuropathy with necrotizing vasculitis confined to nerves and muscles without systemic involvement. These neuropathies were severe and relapsing, in contrast to a usually benign prognosis. Our cases appear to be isolated vasculitic neuropathies, with vasculitis strictly limited to the peripheral neuromuscular system without nonspecific clinical and/or biological systemic involvement.

Aged↗
PubMed2001

Hydroxyethyl starch-induced renal insufficiency after plasma exchange in a patient with polymyositis and liver cirrhosis.

Hydroxyethyl starch (HES) is a macromolecular preparation that has been used as a volume expander since 1991. Renal toxicity of high-dose HES is now well recognized but potential renal toxicity of low-dose HES is poorly documented. Acute renal toxicity of cyclosporin A (CyA) may be responsible for osmotic nephrosis-like lesions. We report here the case of a 30-year-old male who developed cirrhosis due to hepatitis B and delta viruses and polymyositis. Polymyositis was treated with CyA, prednisone and plasma exchanges using low-dose HES as the replacement fluid. Renal insufficiency occurred with biopsy-proven osmotic nephrosis-like lesions, considered to be secondary to HES infusions and/or CyA.

Adult↗
PubMed2001

Antigen inhalation as a triggering factor in systemic small-sized-vessel vasculitis. Four cases.

In order to identify small-sized-vessel vasculitis occurring immediately after massive inhalation of particles which could be considered antigenic, we performed a retrospective review of patients who consulted our Department of Internal Medicine between 1980 and 1998 and were diagnosed as having small-vessel vasculitis that developed immediately after massive exposure to inhaled particles. Four patients, 27 to 55 years old, presented with small-sized-vessel vasculitis (one with Wegener's granulomatosis and three with Churg-Strauss syndrome) which developed after massive inhalation of particles. Clinical manifestations occurred from a few hours to 10 days after inhalation of diesel fumes, cereal dust, flour or cereal dust and/or pigeon droppings. Three patients remain disease-free 8, 9 and 18 years after discontinuing treatment. One patient remains well after 3 years on low-dose corticosteroids and cyclophosphamide therapy. Our data suggest that primary antigens can cause small-sized-vessel vasculitides. Identifying such etiological factors could improve our understanding of the pathogenesis of systemic vasculitides and prevent relapses due to similar antigenic exposure.

Adult↗
PubMed2001

Optimization for the blockade of epidermal growth factor receptor signaling for therapy of human pancreatic carcinoma.

We determined the optimal administration schedule of a novel epidermal growth factor receptor (EGFR) protein tyrosine kinase inhibitor (PKI), PKI 166 (4-(R)-phenethylamino-6-(hydroxyl)phenyl-7H-pyrrolo[2.3-d]-pyrimidine), alone or in combination with gemcitabine (administered i.p.) for therapy of L3.6pl human pancreatic carcinoma growing in the pancreas of nude mice. Seven days after orthotopic implantation of L3.6pl cells, the mice received daily oral doses of PKI 166. PKI 166 therapy significantly inhibited phosphorylation of the EGFR without affecting EGFR expression. EGFR phosphorylation was restored 72 h after cessation of therapy. Seven days after orthotopic injection of L3.6pl cells, groups of mice received daily or thrice weekly oral doses of PKI 166 alone or in combination with gemcitabine. Treatment with PKI 166 (daily), PKI 166 (3 times/week), or gemcitabine alone produced a 72%, 69%, or 70% reduction in the volume of pancreatic tumors in mice, respectively. Daily oral PKI 166 or thrice weekly oral PKI 166 in combination with injected gemcitabine produced 97% and 95% decreases in volume of pancreatic cancers and significant inhibition of lymph node and liver metastasis. Daily oral PKI 166 produced a 20% decrease in body weight, whereas treatment 3 times/week did not. Decreased microvessel density, decreased proliferating cell nuclear antigen staining, and increased tumor cell and endothelial cell apoptosis correlated with therapeutic success. Collectively, our results demonstrate that three weekly oral administrations of an EGFR tyrosine kinase inhibitor in combination with gemcitabine are sufficient to significantly inhibit primary and metastatic human pancreatic carcinoma.

Administration, Oral↗
PubMed2001

Deflazacort versus prednisone in patients with giant cell arteritis: effects on bone mass loss.

OBJECTIVE: To compare bone mass loss due to deflazacort versus prednisone in longterm treatment of patients with giant cell arteritis (GCA) in a randomized double blind comparative trial. METHODS: Seventy-four patients were included in a prospective multicenter study. Half received deflazacort (DFZ) and the other half prednisone (PR) for a minimum of 12 months. Calcium and vitamin D supplements were also provided to all subjects. Our intent was (1) to evaluate bone mineral density, using dual energy x-ray absorptiometry, at baseline and comparatively at 3, 6, and 12 mo; vertebral fractures by Meunier score and size variations after 12 mo treatments were also analyzed; (2) to assess calcium/phosphate metabolism modifications in both groups at baseline and after 12 mo. RESULTS: No significant difference was observed between the 2 groups in terms of treatment efficacy. Patients taking PR were slightly older on average versus the DFZ group (74 vs 70 yrs). Bone mass loss between entry and month 12 was not statistically different in the PR group (-0.026 +/- 0.007 g/cm2) compared to the DFZ group (-0.03 +/- 0.005 g/cm2). No significant difference was found in Meunier score variations (0.77 and 1.18 in the PR and DFZ groups, respectively; p = 0.3), nor in vertebral size variations (-0.4 and -0.2 in the PR and DFZ groups, respectively; p = 0.4). There was no difference in calcium/phosphate metabolism evaluations at month 12. CONCLUSION: In older patients taking longterm glucocorticoids who are at risk of osteoporosis, deflazacort did not result in less bone loss than prednisone.

Absorptiometry, Photon↗
PubMed2001

Child abuse and neglect and the development of mental disorders in the general population.

Child abuse and neglect have repeatedly been shown to be risks for psychiatric and personality disorders. However, much of this evidence is based on retrospective reports of adults. In addition, little is known about the developmental course of psychopathology among those exposed to child maltreatment. In this study, we report mental disorders assessed from early childhood to adulthood in those later identified as victims of abuse or neglect by official or self-report. Findings show elevated rates of mental disorders and symptoms in each of four groups relative to the normative sample. Groups included those who had been victims of physical abuse or neglect according to official report and those who had been victims of physical or sexual abuse by self-report. As expected, the maltreated groups were quite different demographically from the community comparison sample, especially those with official reports. The group with retrospective self-reports of physical abuse differed only modestly from the comparison group on the symptom and disorder measures, while the sexually abused group showed the most consistently elevated patterns, even after controls for demographic differences were taken into account. The disorder and symptom patterns differed both by group and by age: neglect cases showed a partial remission in adulthood, while official physical abuse cases showed an increasingly consolidated pattern of antisocial and impulsive behavior.

Adolescent↗
PubMed2000

Serine 727 phosphorylation and activation of cytosolic phospholipase A2 by MNK1-related protein kinases.

We have previously reported that in thrombin-stimulated human platelets, cytosolic phospholipase A(2) (cPLA2) is phosphorylated on Ser-505 by p38 protein kinase and on Ser-727 by an unknown kinase. Pharmacological inhibition of p38 leads to inhibition of cPLA2 phosphorylation at both Ser-505 and Ser-727 suggesting that the kinase responsible for phosphorylation on Ser-727 is activated in a p38-dependent pathway. By using Chinese hamster ovary, HeLa, and HEK293 cells stably transfected with wild type and phosphorylation site mutant forms of cPLA2, we show that phosphorylation of cPLA2 at both Ser-505 and Ser-727 and elevation of Ca(2+) leads to its activation in agonist-stimulated cells. The p38-activated protein kinases MNK1, MSK1, and PRAK1 phosphorylate cPLA2 in vitro uniquely on Ser-727 as shown by mass spectrometry. Furthermore, MNK1 and PRAK1, but not MSK1, is present in platelets and undergo modest activation in response to thrombin. Expression of a dominant negative form of MNK1 in HEK293 cells leads to significant inhibition of cPLA2-mediated arachidonate release. The results suggest that MNK1 or a closely related kinase is responsible for in vivo phosphorylation of cPLA2 on Ser-727.

Animals↗
PubMed2000

Synergistic activation of stress-activated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7.

Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7. Here we report that MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183) in three SAPK1/JNK1 isoforms tested (JNK1 alpha 1, JNK2 alpha 2 and JNK3 alpha 1). For this reason, MKK4 and MKK7 together produce a synergistic increase in the activity of each SAPK1/JNK isoform in vitro. The MKK7 beta variant, which is several hundred-fold more efficient in activating all three SAPK1/JNK isoforms than is MKK7 alpha', is equally specific for Thr-183. MKK7 also phosphorylates JNK2 alpha 2 at Thr-404 and Ser-407 in vitro, Ser-407 being phosphorylated much more rapidly than Thr-183 in vitro. Thr-404/Ser-407 are phosphorylated in unstimulated human KB cells and HEK-293 cells, and phosphorylation is increased in response to an osmotic stress (0.5 M sorbitol). However, in contrast with Thr-183 and Tyr-185, the phosphorylation of Thr-404 and Ser-407 is not increased in response to other agonists that activate MKK7 and SAPK1/JNK, suggesting that phosphorylation of these residues is catalysed by another protein kinase, such as CK2, which also phosphorylates Thr-404 and Ser-407 in vitro. MKK3, MKK4 and MKK6 all show a strong preference for phosphorylation of the tyrosine residue of the Thr-Gly-Tyr motifs in their known substrates SAPK2a/p38, SAPK3/p38 gamma and SAPK4/p38 delta. MKK7 also phosphorylates SAPK2a/p38 at a low rate (but not SAPK3/p38 gamma or SAPK4/p38 delta), and phosphorylation occurs exclusively at the tyrosine residue, demonstrating that MKK7 is intrinsically a 'dual-specific' protein kinase.

Animals↗
PubMed2000

Association between cigarette smoking and anxiety disorders during adolescence and early adulthood.

CONTEXT: Cigarette smoking is associated with some anxiety disorders, but the direction of the association between smoking and specific anxiety disorders has not been determined. OBJECTIVE: To investigate the longitudinal association between cigarette smoking and anxiety disorders among adolescents and young adults. DESIGN: The Children in the Community Study, a prospective longitudinal investigation. SETTING AND PARTICIPANTS: Community-based sample of 688 youths (51% female) from upstate New York interviewed in the years 1985-1986, at a mean age of 16 years, and in the years 1991-1993, at a mean age of 22 years. MAIN OUTCOME MEASURE: Participant cigarette smoking and psychiatric disorders in adolescence and early adulthood, measured by age-appropriate versions of the Diagnostic Interview Schedule for Children. RESULTS: Heavy cigarette smoking (>/=20 cigarettes/d) during adolescence was associated with higher risk of agoraphobia (10.3% vs 1.8%; odds ratio [OR], 6.79; 95% confidence interval [CI], 1.53-30.17), generalized anxiety disorder (20.5% vs 3.71%; OR, 5.53; 95% CI, 1.84-16.66), and panic disorder (7.7% vs 0.6%; OR, 15.58; 95% CI, 2.31-105.14) during early adulthood after controlling for age, sex, difficult childhood temperament; alcohol and drug use, anxiety, and depressive disorders during adolescence; and parental smoking, educational level, and psychopathology. Anxiety disorders during adolescence were not significantly associated with chronic cigarette smoking during early adulthood. Fourteen percent and 15% of participants with and without anxiety during adolescence, respectively, smoked at least 20 cigarettes per day during early adulthood (OR, 0.88; 95% CI, 0.36-2.14). CONCLUSION: Our results suggest that cigarette smoking may increase risk of certain anxiety disorders during late adolescence and early adulthood. JAMA. 2000;284:2348-2351.

Adolescent↗
PubMed2000

Direct functional interactions between insulin-like growth factor-binding protein-3 and retinoid X receptor-alpha regulate transcriptional signaling and apoptosis.

Insulin-like growth factor-binding protein (IGFBP)-3 regulates apoptosis in an IGF-independent fashion and has been shown to localize to nuclei. We cloned the nuclear receptor retinoid X receptor-alpha(RXR-alpha) as an IGFBP-3 protein partner in a yeast two-hybrid screen. Multiple methodologies showed that IGFBP-3 and RXR-alpha bind each other within the nucleus. IGFBP-3-induced apoptosis was abolished in RXR-alpha-knockout cells. IGFBP-3 and RXR ligands were additive in inducing apoptosis in prostate cancer cells. IGFBP-3 enhanced RXR response element and inhibited RARE signaling. Thus, RXR-alpha-IGFBP-3 interaction leads to modulation of the transcriptional activity of RXR-alpha and is essential for mediating the effects of IGFBP-3 on apoptosis.

Amino Acid Sequence↗