World psychiatric association section of old age psychiatry consensus statement on ethics and capacity in older people with mental disorders.

The World Psychiatric Association (WPA) Section of Old Age Psychiatry, since 1997, has developed Consensus Statements relevant to the practice of Old Age Psychiatry. Since 2006 the Section has worked to develop a Consensus Statement on Ethics and Capacity in older people with mental disorders, which was completed in Prague, September 2008, prior to the World Congress in Psychiatry. This Consensus meets one of the goals of the WPA Action Plan 2008-2011, "to promote the highest ethical standards in psychiatric practice and advocate the rights of persons with mental disorders in all regions of the world". This Consensus Statement offers to mental health clinicians caring for older people with mental disorders, caregivers, other health professionals and the general public the setting out of and discourse in ethical principles which can often be complex and challenging, supported by practical guidance in meeting such ethical needs and standards, and to encouraged good clinical practice.

Delayed wound repair and impaired angiogenesis in mice lacking syndecan-4.

The syndecans make up a family of transmembrane heparan sulfate proteoglycans that act as coreceptors with integrins and growth factor tyrosine kinase receptors. Syndecan-4 is upregulated in skin dermis after wounding, and, in cultured fibroblasts adherent to the ECM protein fibronectin, this proteoglycan signals cooperatively with beta1 integrins. In this study, we generated mice in which the syndecan-4 gene was disrupted by homologous recombination in embryonic stem cells to test the hypothesis that syndecan-4 contributes to wound repair. Mice heterozygous or homozygous for the disrupted syndecan-4 gene are viable, fertile, and macroscopically indistinguishable from wild-type littermates. Compared with wild-type littermates, mice heterozygous or homozygous for the disrupted gene have statistically significant delayed healing of skin wounds and impaired angiogenesis in the granulation tissue. These results indicate that syndecan-4 is an important cell-surface receptor in wound healing and angiogenesis and that syndecan-4 is haplo-insufficient in these processes.

Tumorigenicity of herpesvirus-transformed cells correlates with production of plasminogen activator.

Our studies first demonstrated that established hamster cell lines transformed in vitro by herpesviruses activate plasminogen more effectively than normal hamster fibroblasts. This ability is probably due to increased levels of the enzyme plasminogen activator (PA). In the studies described here, the 333-8-9 cell line, originally transformed by herpes simplex virus type 2 strain 333, was used to derive subclonal lines that maintained stable PA phenotypes over the course of long in vitro passage. We were interested in correlating tumor formation by the subclones with their fibrinolytic capacity. Cells were, therefore, single-cell subcloned twice, and resulting cultures were tested for ability to activate plasminogen in vitro. PA activity was then quantitated by [125I]fibrin lysis assay, and high- and low-activity subclones were isolated; these retained high- or low-activity phenotypes. Syngeneic newborn hamsters were inoculated with these subclones and observed for the appearance of palpable tumors. A strong correlation between enzyme activity and tumor formation was observed in four separate trials; animals receiving high-PA subclones developed tumors more rapidly than those inoculated with the parental cell line. Tumors were also excised from test animals, and the cell lines established from the tumors were tested in vitro at different passages for their ability to activate plasminogen. These tumor cells were then reinoculated into syngeneic animals to confirm the tumorigenicity of cell lines with high fibrinolytic activity. In these experiments, the positive correlation between PA production and tumorigenicity was confirmed.

Reciprocal antagonism between estrogen receptor and NF-kappaB activity in vivo.

The functional interaction, or "cross-talk," between estrogen receptor (ER) and the proinflammatory transcription factor nuclear factor (NF)-kappaB demonstrated in vitro has been suggested to play a role in estrogen prevention of cardiovascular disease. Here, we demonstrate that this reciprocal cross-talk occurs in vivo. Ovariectomized C57BL/6 mice fed an atherogenic diet had increased hepatic levels of active NF-kappaB and numerous inflammatory genes, including MHC invariant chain (Ii), vascular cell adhesion molecule-1, tumor necrosis factor-alpha, and RANTES. Treatment with 17alpha-ethinylestradiol (EE) strongly blocked induction of these genes but had no effect on their basal expression levels. ER was required for this activity, because the antagonist ICI 182,780 completely blocked the inhibitory activity of EE. Gene activation by EE was not required for inhibition of inflammatory gene expression, because both the phytoestrogen genistein and low doses of EE were effective in blocking inflammatory gene induction without inducing marker genes such as intestinal trefoil factor (ITF) or myo-inositol-1-phosphate synthase (IPS). The in vivo transcriptional interference was reciprocal, with EE induction of ITF and IPS greatly reduced in animals fed the atherogenic diet versus chow-fed controls. This interference was specific to the liver, because diet had no effect on uterine weight increases produced by EE. Transfection experiments confirmed that the extent of inhibition of ER-mediated transcription by inflammatory stimuli correlated with the extent of NF-kappaB activation. These results suggest that the cross-talk between ER and NF-kappaB does occur in vivo and may indeed contribute significantly to the cardioprotective effects of estrogen.

Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of the cell cycle.

BACKGROUND: Although percutaneous transluminal coronary angioplasty (PTCA) is a highly effective procedure to reduce the severity of stenotic coronary atherosclerotic disease, its long-term success is significantly limited by the high rate of restenosis. Several cellular and molecular mechanisms have been implicated in the development of restenosis post-PTCA, including vascular smooth muscle cell (VSMC) activation, migration, and proliferation. Recently, our group demonstrated that rapamycin, an immunosuppressant agent with antiproliferative properties, inhibits both rat and human VSMC proliferation and migration in vitro. In the present study, we investigated (1) whether rapamycin administration could reduce neointimal thickening in a porcine model of restenosis post-PTCA and (2) the mechanism by which rapamycin inhibits VSMCs in vivo. METHODS AND RESULTS: PTCA was performed on a porcine model at a balloon/vessel ratio of 1.7+/-0.2. Coronary arteries were analyzed for neointimal formation 4 weeks after PTCA. Intramuscular administration of rapamycin started 3 days before PTCA at a dose of 0.5 mg/kg and continued for 14 days at a dose of 0.25 mg/kg. Cyclin-dependent kinase inhibitor (CDKI) p27(kip1) protein levels and pRb phosphorylation within the vessel wall were determined by immunoblot analysis. PTCA in the control group was associated with the development of significant luminal stenosis 4 weeks after the coronary intervention. Luminal narrowing was a consequence of significant neointimal formation in the injured areas. Rapamycin administration was associated with a significant inhibition in coronary stenosis (63+/-3.4% versus 36+/-4.5%; P<0.001), resulting in a concomitant increase in luminal area (1.74+/-0.1 mm2 versus 3. 3+/-0.4 mm2; P<0.001) after PTCA. Inhibition of proliferation was associated with markedly increased concentrations of the p27(kip1) levels and inhibition of pRb phosphorylation within the vessel wall. CONCLUSIONS: Rapamycin administration significantly reduced the arterial proliferative response after PTCA in the pig by increasing the level of the CDKI p27(kip1) and inhibition of the pRb phosphorylation within the vessel wall. Therefore, pharmacological interventions that elevate CDKI in the vessel wall and target cyclin-dependent kinase activity may have a therapeutic role in the treatment of restenosis after angioplasty in humans.

The role of CBP in estrogen receptor cross-talk with nuclear factor-kappaB in HepG2 cells.

Functional interactions or cross-talk between ligand-activated nuclear receptors and the proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) may play a major role in ligand-mediated modification of diseases processes. In particular, the cardioprotective effects of estrogen replacement therapy are thought to be due in part to the ability of ligand-bound estrogen receptor (ER) to inhibit NF-kappaB function. In the current study 17beta-estradiol-bound ERalpha interfered with cytokine-induced activation of a NF-kappaB reporter in HepG2 cells. The estrogen metabolite, 17alpha-ethinyl estradiol, and the phytoestrogen, genistein, were also effective inhibitors of NF-kappaB activation, whereas tamoxifen, 4-hydroxytamoxifen, and raloxifene were inactive. This inhibition was reciprocal, as NF-kappaB interfered with the trans-activation properties of ERalpha. Ligand-bound ERalpha did not inhibit NF-kappaB binding to DNA, but it did decrease the histone acetyltransferase activity required for NF-kappaB transcriptional activity. Coexpression of the transcription coactivator CREB binding protein (CBP), but not steroid receptor coactivator 1a, reversed the ERalpha-mediated inhibition of NF-kappaB activity. Mammalian two-hybrid experiments also revealed that ligand-bound ERalpha can interact functionally with CBP-NF-kappaB complexes. We suggest that CBP targeting by ERalpha results in the inhibition of NF-kappaB and may occur through formation of transcriptionally inert multimeric complexes that are dependent upon the nature of the ERalpha ligand.

Obstructive sleep apnea in association with posterior fossa neurologic disease.

Sleep apnea in association with neurologic disease is uncommon, and its documentation with nocturnal polysomnography (PSG) is rare. Two patients with posterior fossa neurologic disease had obstructive and central sleep apnea on PSG. The first was a 40-year-old woman who experienced a respiratory arrest ten days after neurosurgical decompression of a cervical syrinx associated with syringobulbia. Nocturnal PSG demonstrated obstructive sleep apnea. Tracheostomy was performed and a second nocturnal PSG showed no sleep apnea. The second patient was a 76-year-old woman with daytime hypersomnolence, nocturnal choking spells, progressive spastic paraparesis, and left-sided cerebellar tremor. Neurologic evaluation led to the diagnosis of olivopontocerebellar degeneration. Nocturnal PSG showed multiple episodes of central and obstructive apnea. These cases support the hypothesis that central and obstructive sleep apnea can originate from a central mechanism.

Cholesteryl ester cycle in cultured hepatoma cells.

The existence of a cholesteryl ester cycle in cultured Fu5AH hepatoma cells was documented and factors affecting the rate of turnover of the cholesteryl ester cycle in this cell line were explored. The influence of the physical state of the lipid inclusion in which the cholesteryl esters are stored could be addressed in this cell line because these cells can be induced to store cholesteryl esters in anisotropic (liquid-crystalline) cytoplasmic inclusions by exposure to free cholesterol-rich phospholipid dispersions or in isotropic (liquid) inclusions by addition of oleic acid to the phospholipid dispersions. To examine the relative rates of turnover of the cholesteryl ester cycle in the cells with the two types of inclusions, the fraction of cholesteryl linolenate, a cholesteryl ester present in low amounts in these inclusions, was examined after cells were exposed to medium containing linolenate. After 12 h, cells with anisotropic inclusions contained 17.5% cholesteryl linolenate and cells with isotropic inclusions contained 29.8% cholesteryl linolenate, suggesting an approximately 2-fold difference in turnover of the cholesteryl ester pool. To determine whether this difference was due to a differential rate of cholesteryl ester hydrolysis, the acyl CoA: cholesterol acyl transferase arm of the cholesteryl ester cycle was blocked using a specific inhibitor, Sandoz 58-035. In the presence of this compound, cholesteryl ester was hydrolysed twice as fast in cells with isotropic inclusions as compared to that in cells with anisotropic inclusions. The difference in rate of turnover of the cholesteryl ester cycle was shown to be related to the rate of hydrolysis of cholesteryl ester which, in turn, is related to the physical state of the stored cholesteryl ester.

Echocardiographic differentiation of a cystic and a solid tumor of the heart.

A hydatid cyst in the ventricular septum was diagnosed with echocardiography in a child with abdominal echinococcosis. The finding was confirmed with cardiac catheterization, cineangiography and surgical removal and pathologic examination of the cyst. The echocardiographic features of the fluid-filled hydatid cyst are contrasted with those of solid left ventricular tumor (rhabdomyoma) in a newborn.

Psychological effects of dopamine beta-hydroxylase inhibition: a failure to replicate.

In a previous investigation of whether reduced dopamine-beta-hydroxylase (DBH) might play a role in schizophrenia, we studied the effects of DBH inhibition for a few hours in normal subjects. This initial study showed positive effects, i.e., unusual subjective psychological reports confirmed by psychiatric rating scales, in subjects given the DBH inhibitor fusaric acid. The present study attempted to replicate these findings using a more detailed battery of tests and an additional control situation. Each subject underwent the following four treatment conditions at 1-week intervals: fusaric acid plus L-dopa; L-dopa alone; d-amphetamine; placebo. The present results did not confirm those of the first study. A few interesting results were found that were chiefly attributable to amphetamine effects. No effect could be definitely attributed to fusaric acid.

Head injury in partner-abusive men.

Research into etiology of marital aggression has focused primarily on psychosocial, political, and cultural factors, to the exclusion of physiological influences. Fifty-three partner abusive men, 45 maritally satisfied, and 32 maritally discordant, nonviolent men were evaluated for past history of head injury, by a physician who was not informed of group membership and aggression history. Logistic regressions confirmed that head injury was a significant predictor of being a battered. The implications of these findings for both marital aggression and post-head injury rehabilitation are discussed.

Europium-152 as a potential substitute for cobalt-60 in radiation therapy.

Construction has begun of prototype europium-152 sources, with the principal goal of providing cost-effective teletherapy for emergent nations where prices for cobalt-60 are excessive, owing to replacement needs, and the use of linacs is economically prohibitive and technologically unfeasible. 152Eu sources (T1/2 = 13.4y vs T1/2 = 5.26y for 60Co) are designed for absorbed dose rates > 1.5 Gy/min at 1 m, with specific activities > 5 TBq/gm, allowing substitution into existing irradiators. Costs of 152Eu compare favorably with 60Co, taking account of extended useful lifetime.

The scale for treatment integration of the dually diagnosed (STIDD): an instrument for assessing intervention strategies in the pharmacotherapy of mentally ill substance abusers.

The authors developed a series of 15 multiple-choice vignettes which pose common dilemmas in the pharmacotherapy of patients suffering from psychoactive substance use disorders coexisting with other mental disorders. Fourteen judges standardized the treatment options along a 'treatment integration continuum'. The authors surveyed 112 psychiatrists with the vignettes and 3 subscales of the Substance Abuse Attitude Survey. Ten of the 15 vignettes were taken to form the normally distributed Scale for Treatment Integration of the Dually Diagnosed (STIDD), which is described in terms of its reliability, validity and potential use as a teaching and research tool.

In vitro antioxidant effects of estrogens with a hindered 3-OH function on the copper-induced oxidation of low density lipoprotein.

Estrogens with some bulky alkyl substituents in both the 2- and 4-positions have been synthesized and evaluated for the ability to inhibit the in vitro oxidation of low density lipoprotein as determined by the thiobarbituric reactive substances method. The present compounds with bulky groups in either the 2- or the 4-position (but not both the 2- and 4-) were especially effective as antioxidants, having IC50 values lower than either estradiol or probucol; however, they do not bind to the estrogen receptor with any great affinities (RBA < 0.1 versus estradiol). This separation of antioxidant efficacy from estrogenicity may allow these compounds to serve as useful probes for ascertaining the relative importance of these effects in the cardioprotective role played by estrogens.

Pharmacotherapeutic management strategies for mentally ill substance abusers.

In order to determine psychiatrists' strategies for managing the pharmacotherapy and treatment of mentally ill substance abusers, the authors constructed a series of standardized clinical vignettes, each with five multiple-choice treatment interventions. The vignettes, based on clinical experience, depict difficult dilemmas involving the use of medication in the treatment of a variety of dually diagnosed patients. The authors surveyed a heterogeneous reference group of 112 psychiatrists with these vignettes. The psychometric properties of the resultant Scale for Treatment Integration of the Dually Diagnosed (STIDD) are briefly described. The ten vignettes and the treatment interventions chosen by the reference group are described in detail. The results indicate that most clinicians favor an integrated treatment approach which attempts to address both diagnoses.

Hepatic cyst associated with Peutz-Jeghers syndrome.

A solitary hepatic cyst, associated with Peutz-Jeghers syndrome, is described. To our knowledge, this association has not been previously reported. A developmental anomaly or hamartomatous nature of this lesion is suggested. Knowledge of this association may be helpful in the clinical diagnosis of this benign entity.

Effect of sirolimus on the cholesterol content of aortic arch in ApoE knockout mice.

Chronic inflammatory responses involving the immune system have been implicated in the process of atherosclerosis. Sirolimus (Rapamycin, Rapamune), a potent immunosuppressant used to prevent rejection of transplanted kidneys, has also proven effective at inhibiting restenosis in humans when eluted from implanted stents. The aim of this study was to evaluate the effect of sirolimus treatment on the development of atherosclerosis in the aortic arch of apo E-/- mice fed a high-fat (Western) diet. Following 12 weeks of treatment with sirolimus (4 mg/kg/d), the cholesterol content of the arch was reduced by 36% compared to untreated control mice fed the Western diet only. Although the murine model is not comparable to the human situation, the results of this study suggest that sirolimus may exert beneficial effects on atherosclerosis in transplant patients.

Prognosis of uncorrected biliary atresia: an update.

In order to provide a baseline for comparison with the results of the Kasai hepatic portoenterostomy, follow-up information was obtained for 89 infants who underwent surgical exploration alone for biliary atresia from 1956 through 1975. Of these patients, one is apparently cured, one is alive with liver failure, three are lost to follow-up and 84 are dead. The rate of apparent cure among patients with follow-up was 1.1%. The average age at death was 12 mo, the mean 10 mo. During this same period, nine patients were operated upon for neonatal biliary obstructions other than biliary atresia, and five are apparently cured. Reported apparent cure rates after the Kasai procedure or one of its variations, while not good, still compare favorably with the cure rate of unoperated patients.

Bochdalek hernias in infants: factors determining mortality.

From 1950 through 1974, 76 infants with Bochdalek hernias have been surgically repaired. Mortality has been confined to those admitted at under 30 hr of age, and the highest mortality has been among those infants admitted within the first 8 hr of life. A recent increase in mortality is explained by the arrival of a new group of infants who arrived intubated, had large diaphragmatic defects, required postoperative ventilatory assistance, and had hypoplastic lungs at autopsy. Six infants might have benefited from an early intervention to hasten closure of their patent ductus arteriosus. Since we cannot be positive that intubation of these infants prior to arrival will not have a deleterious effect, we urge great discretion in choosing which infants to intubate.

Prenatal diagnosis of congenital cystic adenomatoid malformation and its postnatal presentation, surgical indications, and natural history.

BACKGROUND/PURPOSE: Regression of a cystic adenomatoid malformation (CAM) in a fetus is well described. Little, however, is known about the postnatal course of these infants. This study attempts to correlate the prenatal course of CAMs with postnatal symptoms, radiological manifestations, and need for surgery. METHODS: The clinical course of patients with a CAM diagnosed prenatally were retrospectively reviewed. Inclusion in the study required a prenatal ultrasound scan documenting a CAM. RESULTS: Over 10 years, 14 patients with a CAM were diagnosed prenatally. Six (43%) showed a partial in utero regression. Four patients were symptomatic at birth and underwent a resection as newborns. Ten patients were asymptomatic at birth, and eight of these had normal chest x-rays. Elective resection has been performed in 3 of these 10, and two additional children are scheduled to undergo an excision near 1 year of age. The remaining five patients have undergone follow-up nonoperatively for a mean of 36 +/- 15 months. Of the seven asymptomatic patients not undergoing immediate surgery, only one has shown a slight postnatal regression, despite five of these showing regression in utero. None have become symptomatic. CONCLUSIONS: The results suggest that regression of a CAM on prenatal ultrasound scan is common, but this process does not continue after birth. A normal chest x-ray does not indicate complete regression of a CAM; a computed tomography (CT) scan is required to evaluate such patients, and will generally demonstrate a CAM. Asymptomatic patients with a CAM may be followed up nonoperatively with no apparent adverse effects. The decision and timing of an excision in an asymptomatic patient remains controversial among pediatric surgeons.