Modeling anorexia nervosa: transcriptional insights from human iPSC-derived neurons.

Anorexia nervosa (AN) is a complex and multifactorial disorder occurring predominantly in women. Despite having the highest mortality among psychiatric conditions, it still lacks robust and effective treatment. Disorders such as AN are most likely syndromes with multiple genetic contributions, however, genome-wide studies have been underpowered to reveal associations with this uncommon illness. Here, we generated induced pluripotent stem cells (iPSCs) from adolescent females with AN and unaffected controls. These iPSCs were differentiated into neural cultures and subjected to extensive transcriptome analysis. Within a small cohort of patients who presented for treatment, we identified a novel gene that appears to contribute to AN pathophysiology, TACR1 (tachykinin 1 receptor). The participation of tachykinins in a variety of biological processes and their interactions with other neurotransmitters suggest novel mechanisms for how a disrupted tachykinin system might contribute to AN symptoms. Although TACR1 has been associated with psychiatric conditions, especially anxiety disorders, we believe this report is its first association with AN. Moreover, our human iPSC approach is a proof-of-concept that AN can be modeled in vitro with a full human genetic complement, and represents a new tool for understanding the elusive molecular and cellular mechanisms underlying the disease.

Altered neuronal network and rescue in a human MECP2 duplication model.

Increased dosage of methyl-CpG-binding protein-2 (MeCP2) results in a dramatic neurodevelopmental phenotype with onset at birth. We generated induced pluripotent stem cells (iPSCs) from patients with the MECP2 duplication syndrome (MECP2dup), carrying different duplication sizes, to study the impact of increased MeCP2 dosage in human neurons. We show that cortical neurons derived from these different MECP2dup iPSC lines have increased synaptogenesis and dendritic complexity. In addition, using multi-electrodes arrays, we show that neuronal network synchronization was altered in MECP2dup-derived neurons. Given MeCP2 functions at the epigenetic level, we tested whether these alterations were reversible using a library of compounds with defined activity on epigenetic pathways. One histone deacetylase inhibitor, NCH-51, was validated as a potential clinical candidate. Interestingly, this compound has never been considered before as a therapeutic alternative for neurological disorders. Our model recapitulates early stages of the human MECP2 duplication syndrome and represents a promising cellular tool to facilitate therapeutic drug screening for severe neurodevelopmental disorders.

Mode of cembranoid action on embryonic muscle acetylcholine receptor.

The mechanism of eupalmerin acetate (EUAC) actions on the embryonic muscle nicotinic acetylcholine receptor (nAChR) in BC3H-1 cells was studied by using whole-cell and single-channel patch-clamp current measurements. With whole-cell currents, EUAC did not act as an agonist on this receptor. Coapplication of 30 microM EUAC with 50 microM, 100 microM, or 500 microM carbamoylcholine (CCh) reversibly inhibited the current amplitude, whereas, with 20 microM CCh, current was increased above control values in the presence of EUAC. EUAC concentration curves (0.01-40 microM) obtained with 100 microM and 500 microM CCh displayed slope coefficients, n(H), significantly smaller than one, suggesting that EUAC bound to several sites with widely differing affinities on the receptor molecule. The apparent rate of receptor desensitization in the presence of EUAC and CCh was either slower than or equal to that obtained with CCh alone. The major finding from single-channel studies was that EUAC did not affect single-channel conductance or the ability of CCh to interact with the receptor. Instead, EUAC acted by increasing the channel closing rate constant. The results are not consistent with the competitive model for EUAC inhibition, with the sequential open-channel block model, or with inhibition by increased desensitization. The data are best accounted for by a model in which EUAC acts by closed-channel block at low concentrations, by positive modulation at intermediate concentrations, and by negative allosteric modulation of the open channel at high concentrations.

[Acute myocardial infarction associated to the Sildenafil consumption. A case report and review of the literature]. / Infarto agudo de miocardio asociado al consumo de sildenafil. Aportación de caso y revisión de la literatura.

Erectile dysfunction affects more than 30 million men in The United States. Since the FDA approved the use of Sildenafil, prescription of this medication has been raising. Adverse events of Sildenafil includes: fatigue, dyspnea, and hypotension. Reported adverse cardiac events associated with the medication use include myocardial infarction, ventricular tachycardia, angina and death, raising concerns about the safety of this agent in patients with coronary artery disease. Published guidelines regarding the management of cardiac patients with erectile dysfunction suggest that Sildenafil may be hazardous in patients with ischemic heart disease. In patients using Sildenafil, myocardial infarctions have been reported to the Food and Drug Administration. Now, we report a patient with myocardial infarction after taking 100 mg of Sildenafil without sexual activity.

The MOS 36-Item Short Form Health Survey: reliability, validity, and preliminary findings in schizophrenic outpatients.

OBJECTIVES: The authors test the reliability and validity of the Medical Outcomes Study Short Form 36-Item Health Survey (SF-36) as a written, self-administered survey in outpatients with chronic schizophrenia. METHODS: Thirty-six schizophrenic outpatients completed a written and oral form of the SF-36. A psychiatrist rated the patients using the Brief Psychiatric Rating Scale to determine severity of psychopathology. Cognitive functioning and academic achievement were also assessed. Internal consistency, test-retest reliability, concurrent and discriminative validity of the oral and written versions were determined. RESULTS: The SF-36 in both forms was shown to have good internal consistency, stability, and concurrent validity. The mental health SF-36 subscales had poor discriminant validity, compared with the physical functioning scale that demonstrated good discriminant validity. CONCLUSIONS: The validity of using the written form of the SF-36 on a sample of patients with chronic mental illness was demonstrated. The SF-36 appears to be an appropriate outcome measure for changes in physical and role functioning in consumers of outpatient mental health programs.