Pulmonary disease among inpatient decedents: Impact of schizophrenia

OBJECTIVES: Determine the risk associated with schizophrenia for common pulmonary illness (pneumonia and chronic obstructive pulmonary disorder (COPD)) during the last year of life. METHODS: Inpatient decedents in Veterans (VA) hospitals in 2002 (N=27,798) were identified. Logistic regression modeled diagnosis of pulmonary illness in either the final year or final admission as a function of schizophrenia, smoking history and other covariates. RESULTS: Among decedents, 943 (3%) had schizophrenia, 3% were women, most were white (76%) or African-American (18%), and average age at death was 72.4 years (SD 11.5). Three-fifths received VA outpatient care in the year prior to death. Among those with schizophrenia, only two-fifths had outpatient care. Pneumonia was more common among schizophrenia patients (38% vs 31%) as was COPD (46% vs 38%). In models controlling for history of smoking and other covariates, schizophrenia was a risk factor for pulmonary disease in the last year of life (OR=1.9, 95% CI 1.6-2.2) but less so for final-stay pulmonary disease (OR=1.5, 95% CI 1.3-1.7). CONCLUSIONS: VA inpatient decedents with schizophrenia were at increased risk for pneumonia and COPD, independent of smoking indicators. Clinicians treating schizophrenia patients need to be especially alert to potential comorbid medical conditions and ensure vulnerable patients receive appropriate care.     

The utility of (11)C-arachidonate PET to study in vivo dopaminergic neurotransmission in humans

We developed a novel method to study dopaminergic neurotransmission using positron emission tomography (PET) with [1-(11)C]arachidonic acid ([1-(11)C]AA). Previous preclinical studies have shown the utility of [1-(11)C]AA as a marker of signal transduction coupled to cytosolic phospholipase A(2) (cPLA(2)). Using [1-(11)C]AA and [(15)O]water PET, we measured regional incorporation coefficients K(*) for AA and regional cerebral blood flow (rCBF), respectively, in healthy male volunteers given the D(1)/D(2) agonist (10 or 20 μg/kg subcutaneous) apomorphine. We confirmed a robust central dopaminergic response to apomorphine by observing significant increases in the serum concentration of growth hormone. We observed significant increases, as well as decreases in K(*) and increases in rCBF in response to apomorphine. These changes remained significant after covarying for handedness and apomorphine dosage. The magnitude of increases in K(*) was lower than those in our previous animal experiments, likely reflecting the smaller dose of apomorphine used in the current human study. Changes in K(*) may reflect neuronal signaling downstream of activated D(2)-like receptors coupled to cPLA(2). Changes in rCBF are consistent with previous studies showing net functional effects of D(1)/D(2) activation. [1-(11)C]AA PET may be useful for studying disturbances of dopaminergic neurotransmission in conditions such as Parkinson's disease and schizophrenia.     

Periventricular white matter hyperintensities as predictors of suicide attempts in bipolar disorders and unipolar depression

The aim of this study was to evaluate whether deep white matter hyperintensities (DWMH) and periventricular white matter hyperintensities (PVH) are associated with suicidal behavior in patients with major affective disorders. Subjects were 99 consecutively admitted inpatients (42 men; 57 women; mean age: 46.5 years [SD=15.2; Min./Max.=19/79]) with a diagnosis of major affective disorder (bipolar disorder type I, bipolar disorder type-II and unipolar major depressive disorder). 44.4% of the participants had made at least one previous suicide attempt. T2-weighted brain magnetic resonance images were rated for the presence and extension of WMH using the modified Fazekas scale. Patients were interviewed for clinical data on average 5 days after admission. Bivariate analyses, corrected for multiple-testing, and logistic regression analysis were used to test the association between suicide attempts and clinical variables. Attempters and nonattempters differed only in the presence of PVH--the former were more likely to have PVH. The logistic regression indicated that the presence of PVH was robustly associated with suicidal behaviors after controlling for age (OR: 8.08). In conclusion, neuroimaging measures may be markers of risk for suicidal attempts in patients with major affective disorders.     

Effects of WIN 55,212-2 mesylate (a synthetic cannabinoid) on the protective action of clonazepam, ethosuximide, phenobarbital and valproate against pentylenetetrazole-induced clonic seizures in mice

The aim of this study was to determine the effect of WIN 55,212-2 mesylate (WIN — a non-selective cannabinoid CB1 and CB2 receptor agonist) on the protective action of four classical antiepileptic drugs (AEDs: clonazepam [CZP], ethosuximide [ETS], phenobarbital [PB], and valproate [VPA]) in the mouse pentylenetetrazole (PTZ)-induced clonic seizure model.WIN (15 mg/kg, i.p.) significantly enhanced the anticonvulsant action of ETS, PB and VPA, but not that of CZP against PTZ-induced clonic seizures. The ED₅₀ values of ETS, PB and VPA were reduced from 148.0, 13.9 and 137.1 mg/kg to 104.0, 8.3 and 85.6 mg/kg, respectively (P < 0.05). WIN (5 and 10 mg/kg, i.p.) had no impact on the anticonvulsant action of all studied AEDs against PTZ-induced clonic seizures. WIN (15 mg/kg, i.p.) significantly elevated total brain concentrations of ETS and VPA, but not those of CZP and PB in mice. Moreover, WIN combined with CZP, ETS, PB and VPA significantly impaired motor performance, long-term memory and muscular strength in mice subjected to the chimney, passive avoidance and grip-strength tests, respectively.Pharmacodynamic enhancement of the anticonvulsant action of PB by WIN against PTZ-induced clonic seizures is favorable from a preclinical viewpoint. Advantageous effects of WIN in combination with ETS and VPA against PTZ-induced seizures were pharmacokinetic in nature. However, WIN combined with CZP, ETS, PB and VPA impaired motor coordination and long-term memory as well as reduced skeletal muscular strength in the experimental animals.     

Somato-dendritic distribution of 5-HT(1A) and 5-HT(1B) autoreceptors in the BDNF- and cAMP-differentiated RN46A serotoninergic raphe cell line

The rapid differentiating effects of brain-derived neurotrophic factor (BDNF) or dibutyryl-cAMP (dBcAMP) were characterized on RN46A, a rat raphe-derived neuronal cell line. After BDNF treatment, RN46A cells were serotonin-immunopositive and bipolar, and expressed the microtubule-associated-protein 2 (Map2). After dBcAMP treatment, the cells often became multipolar, bearing very long processes strongly immunopositive for serotonin and Map2. Under both conditions, the expression and distribution of 5-HT(1A) and 5-HT(1B) autoreceptors remained identical. 5-HT(1A) and Map2 immunolabelings were superimposable, as expected of their somato-dendritic targeting. Surprisingly, the distribution of 5-HT(1B) immunoreactivity was similar, in contrast with its usual localization in axons and nerve terminals in the brain. In conclusion, both BDNF and cAMP-differentiated RN46A cells towards a neuronal serotoninergic-like phenotype without the typical differential targeting of the 5-HT(1) autoreceptors, an interesting model to study the molecular mechanisms ensuing the targeting of 5-HT(1) autoreceptors to somas and dendrites.     

2-DPMP (desoxypipradrol, 2-benzhydrylpiperidine, 2-phenylmethylpiperidine) and D2PM (diphenyl-2-pyrrolidin-2-yl-methanol,diphenylprolinol): A preliminary review

2-DPMP (desoxypipradrol, 2-benzhydrylpiperidine, 2-phenylmethylpiperidine) and D2PM (diphenyl-2-pyrrolidin-2-yl-methanol, diphenylprolinol) are psychoactive substances, sold primarily over the Internet and in ‘head’ shops as ‘legal highs’, ‘research chemicals’ or ‘plant food’. Originally developed in the 1950s for the treatment of narcolepsy and ADHD, 2-DPMP's use soon became very limited. Recreational use of 2-DPMP and D2PM appears to have started in March 2007, but only developed slowly. However, in the UK their popularity grew in 2009, increasing rapidly during summer 2010. At this time, there were many presentations to UK Emergency Departments by patients complaining of undesirable physical and psychiatric effects after taking 2-DPMP. In spring 2011 there were similar presentations for D2PM. Recreational use of these drugs has been reported only occasionally in on-line user fora. There is little scientifically-based literature on the pharmacological, physiological, psychopharmacological, toxicological and epidemiological characteristics of these drugs. Here we describe what is known about them, especially on their toxicity, including what we believe to be the first three deaths involving the use of 2-DPMP in August 2010. There are no international controls imposed on 2-DPMP or D2PM. However, a ban on their UK importation was imposed in November 2011 and they became Class C drugs on 13 June 2012. It is critical that any other cases, including non-fatal overdoses, are documented so that a scientific evidence-base can be established for them.     

Association study between obsessive-compulsive disorder and serotonergic candidate genes

BACKGROUND: To date, research examining the relationship between serotonergic genes and obsessive-compulsive disorder (OCD) has yielded conflicting results. The purpose of this study is to investigate the association between four serotonergic polymorphisms (STin2 VNTR and 5-HTTLPR of the SLC6A4 gene, and A-1438G (rs6311) and T102C (rs6313) of the HTR2A gene) and OCD. METHODS: 99 OCD patients, 456 non-OCD psychiatric patients, and 420 healthy controls from a homogeneous Spanish Caucasian population were genotyped using standard methods. RESULTS: All groups showed Hardy-Weinberg equilibrium for the analyzed genetic variability. A-1438G and T102C polymorphisms were in complete linkage disequilibrium. OCD patients showed an excess of STin2.12 carriers (12/12, 12/10, and 12/9 genotypes) compared with healthy controls (chi(2) (1)=7.21, corrected p=0.021; OR=3.38, 95% CI=1.32-8.62) and non-OCD psychiatric patients (chi(2) (1)=6.70, corrected p=0.030; OR=3.24, 95% CI=1.27-8.26). However, no differences were found between non-OCD patients and healthy controls (chi(2) (1)=0.05, corrected p>1; OR=1.04, 95% CI=0.72-1.51). No significant differences were found with respect to A-1438G and 5-HTTLPR polymorphisms. CONCLUSIONS: Our data provide supporting evidence of an association between the STin2 VNTR polymorphism of the SLC6A4 gene and OCD.     

A genetic schizophrenia-susceptibility region located between the ANKK1 and DRD2 genes

Background

The gene coding for the D2 dopamine receptor (DRD2) is considered to be one of the most pertinent candidate genes in schizophrenia. However, genetic studies have yielded conflicting results whereas the promising TaqIA variant/rs1800497 has been mapped in a novel gene, ANKK1.

Methods

We investigated eleven single nucleotide polymorphisms (SNPs) spanning the DRD2 and ANKK1 genes, using both a case–control association study comparing 144 independent patients to 142 matched healthy subjects, and a transmission disequilibrium test in 108 trios. This classical genetic study was coupled with a cladistic phylogeny-based association test of human variants, and with an interspecies evolution study of ANKK1.

Results

Case–control study, followed by a 108 trios family-based association analysis for replication, revealed an association between schizophrenia and the ANKK1 rs1800497 (p = 0.01, Odds Ratio = 1.5, 95% Confidence Interval = 1.1–2.2), and the intergenic rs2242592 (p = 2 · 10^− 4, OR = 1.8, 95%CI = 1.3–2.5). A significant SNP–SNP interaction was also found (p < 10^− 5, OR = 2.0, 95%CI = 1.6–2.5). The phylogeny-based association test also identified an association between both these polymorphisms and schizophrenia. Finally, interspecies comparison of the sequences from chimpanzee, orangutan, rhesus macaque and human species suggested specific involvement of ANKK1 in the human lineage.

Conclusions

Intergenic rs2242592 appears to be involved in the genetic vulnerability to schizophrenia, whereas the ANKK1 rs1800497 appears to have a modifying rather than causative effect. Finally, ANKK1 may be a specific human lineage-trait involved in a specific human disease, schizophrenia.     

Intravenous and oral administrations of DD2 [7-Amino-2-(sulfanylmethyl)heptanoic acid] produce thrombolysis through inhibition of plasma TAFIa in rats with tissue factor-induced microthrombosis

Thrombin-activatable fibrinolysis inhibitor (TAFI) is a plasma zymogen that is activated by thrombin in plasma. In fibrinolytic processes, carboxy-terminal lysine (Lys) residues in partially degraded fibrin are important sites for plasminogen binding and activation, and an active form of TAFI (TAFIa) inhibits fibrinolysis by eliminating these residues proteolytically. We synthesized DD2 [7-Amino-2-(sulfanylmethyl)heptanoic acid], a Lys analogue containing sulfur, as an inhibitor of TAFIa and investigated its pharmacological profile and pathophysiological role in thrombolysis via in vitro and in vivo studies. DD2 specifically inhibited plasma TAFIa activity with an apparent IC₅₀ (50% inhibitory concentration) value of 3.4 × 10^- 8 M under the present experimental condition and enhanced tissue plasminogen activator-mediated clot lysis in a concentration-dependent manner. In order to study tissue factor (TF)-induced microthrombosis in an animal model, rats were given intravenous injection (2.5 mg/kg and higher) or oral administration (10 mg/kg and higher) of DD2. This attenuated TF-induced glomerular fibrin deposition and increased the plasma levels of fibrin degradation products and D-dimer in a dose-dependent manner. A DD2 dose approximately 4X higher than the dose used in intravenous injections was required to achieve an equivalent thrombolytic effect to that seen following oral administration. Moreover, the oral absorption efficiency of DD2 into the vasculature was 29.8%. These results indicate that both intravenous and oral administration of DD2 enhanced endogenous fibrinolysis and reduced thrombi in a TF-induced microthrombosis model.     

N-(quinolin-2-ylmethyl)butane-1,4-diamine,a polyamine analogue,attenuated injury in in vitro and in vivo models of cerebral ischemia

It has been widely recognized that glutamate (Glu)-induced cytotoxicity, intracellular calcium overload and excessive free radical production are the key players in the development and progression of ischemic brain injury. Since MK-801, an antagonist of N-methyl-d-aspartate (NMDA) receptor, showed many adverse reactions that hampered its clinical applications, development of safe and effective agent for the treatment of cerebral ischemia is eagerly required. This study was to investigate the effects of N¹-(quinolin-2-ylmethyl)butane-1,4-diamine (QMA), a polyamine analogue, on the in vitro and in vivo models of cerebral ischemic damage. The results revealed that pretreatment with QMA could attenuate Glu, putrescine (Put) and oxygen-glucose deprivation (OGD)-induced cell death, lipid peroxidation as well as the elevation of reactive oxygen species (ROS) and intracellular [Ca²⁺]_i in pheochromocytoma (PC12) cells and in rat primary cortical neurons. The results also demonstrated that QMA could inhibit NMDA-mediated intracellular [Ca²⁺]_i accumulation in rat primary cortical neurons and reduce brain infarct volume in middle cerebral artery occlusion (MCAO) rats. The present report suggested that polyamines played a crucial role in the pathological processes of cerebral ischemic damage and that QMA or other novel polyamine analogues could be promising therapeutic candidates for stroke by virtue of their anti-hypoxia and antioxidation property.