Predicting short-term suicidal thoughts in adolescents using machine learning: developing decision tools to identify daily level risk after hospitalization.

BACKGROUND: Mobile technology offers unique opportunities for monitoring short-term suicide risk in daily life. In this study of suicidal adolescent inpatients, theoretically informed risk factors were assessed daily following discharge to predict near-term suicidal ideation and inform decision algorithms for identifying elevations in daily level risk, with implications for real-time suicide-focused interventions. METHODS: Adolescents (N = 78; 67.9% female) completed brief surveys texted daily for 4 weeks after discharge (n = 1621 observations). Using multi-level classification and regression trees (CARTSs) with repeated 5-fold cross-validation, we tested (a) a simple prediction model incorporating previous-day scores for each of 10 risk factors, and (b) a more complex model incorporating, for each of these factors, a time-varying person-specific mean over prior days together with deviation from that mean. Models also incorporated missingness and contextual (study week, day of the week) indicators. The outcome was the presence/absence of next-day suicidal ideation. RESULTS: The best-performing model (cross-validated AUC = 0.86) was a complex model that included ideation duration, hopelessness, burdensomeness, and self-efficacy to refrain from suicidal action. An equivalent model that excluded ideation duration had acceptable overall performance (cross-validated AUC = 0.78). Models incorporating only previous-day scores, with and without ideation duration (cross-validated AUC of 0.82 and 0.75, respectively), showed relatively weaker performance. CONCLUSIONS: Results suggest that specific combinations of dynamic risk factors assessed in adolescents' daily life have promising utility in predicting next-day suicidal thoughts. Findings represent an important step in the development of decision tools identifying short-term risk as well as guiding timely interventions sensitive to proximal elevations in suicide risk in daily life.

Overview of the preclinical pharmacological properties of Nigella sativa (black seeds): a complementary drug with historical and clinical significance.

Nigella sativa (N. sativa, black seeds; or sometimes known by many other names such as the blessed seed by the Arabs, black cumin in the Holy Bible, black caraway and Kalonji in South Asia) has been traditionally used for many years not only as a food but also as complementary drug. It is the objective of this communication to review the evidence-based pre-clinical pharmacological actions of N. sativa as a basis of its existing and potential new human clinical uses. Primary PubMed literature searches and secondary Medline searches were conducted to define N. sativa pre-clinical pharmacological and toxicological actions using a retrospective narrative review of the published studies. The ground seeds, its oil and its various extracts exhibit very broad pharmacological actions in laboratory studies, which are predictive of human clinical efficacy. In laboratory studies, N. sativa possesses anti-inflammatory, analgesic, anti-diabetic, anti-hyperlipidemic, anti-convulsant, anti-microbial, anti-ulcer, anti-hypertensive, anti-asthmatic and anti-cancer activities. Its mode of action is mediated via several mechanisms, which include anti-oxidant, immunomodulating, cytoprotective and an inhibitory effect on some mediators of inflammation. Although the seeds contain many chemical components, thymoquinone and alpha-hederin are proven to be pharmacologically active. Despite N. sativa broad and worldwide pharmacological characterization, only limited non-clinical safety studies were reported. N. sativa has many potentially important therapeutic applications. The black seeds clearly warrant formal preclinical drug development consideration to investigate the pharmacology of its components, to standardize the contents of the dosage forms, to define the methods of the pharmaceutical preparation, to determine its pharmacokinetics characteristics and its safety profile. It is our opinion that N. sativa should be considered for clinical development initially for unmet therapeutic uses, especially in the fields of oncology, neurology, rheumatology, pulmonary medicine, infectious diseases and endocrinology.

Extensive Fetal Congenital Subcutaneous Mixed Venous Lymphatic Lesion: Prenatal Diagnosis and Postnatal Management.

Vascular lesions may be categorized as proliferative tumors, such as hemangiomas, or nonproliferative malformations that include capillary, lymphatic, venous, arterial, or mixed lesions. Lymphatic malformations are benign localized congenital malformations of the lymphatic system. They may be microcystic or macrocystic lesions or a combination of both. The lesions may also be uniseptate or multiseptate, and are more commonly located in the head and neck or axillary region. Prenatal diagnosis is based on ultrasound and magnetic resonance imaging. Postnatal management largely depends on the size and location of the lesion. This is the first case report of prenatally diagnosed extensive subcutaneous macrocystic venous lymphatic malformation involving the fetal thorax, back, pelvis, and lower extremities. Prenatal course and postnatal management are described. This report will aid other specialists in the field of prenatal diagnosis and postnatal surgery in the evaluation and management of these patients.

A comprehensive analysis of the human placenta transcriptome.

As the conduit for nutrients and growth signals, the placenta is critical to establishing an environment sufficient for fetal growth and development. To better understand the mechanisms regulating placental development and gene expression, we characterized the transcriptome of term placenta from 20 healthy women with uncomplicated pregnancies using RNA-seq. To identify genes that were highly expressed and unique to the placenta we compared placental RNA-seq data to data from 7 other tissues (adipose, breast, hear, kidney, liver, lung, and smooth muscle) and identified several genes novel to placental biology (QSOX1, DLG5, and SEMA7A). Semi-quantitative RT-PCR confirmed the RNA-seq results and immunohistochemistry indicated these proteins were highly expressed in the placental syncytium. Additionally, we mined our RNA-seq data to map the relative expression of key developmental gene families (Fox, Sox, Gata, Tead, and Wnt) within the placenta. We identified FOXO4, GATA3, and WNT7A to be amongst the highest expressed members of these families. Overall, these findings provide a new reference for understanding of placental transcriptome and can aid in the identification of novel pathways regulating placenta physiology that may be dysregulated in placental disease.

Prostaglandins and brain-gut axis.

Prostaglandins (PGs) have well documented physiological and pharmacological actions on the gastrointestinal (GI) tract. This communication reviews the evidence for peripheral and central nervous system (CNS) physiological actions of PGs in order to determine their role in the brain-gut axis, if any. PGs are widely distributed in nearly all cells peripherally and centrally. Laboratory and clinical evidence indicate that there is a direct relationship between altered GI physiological functions and peripheral PGs biosynthesis. Either local or parenteral administration of natural E-series PGs alters GI physiological functions particularly those relating to mucosal defense. Furthermore, the cyclooxygenase enzymes (COX), which are responsible for the PGs biosynthesis, have been localized in the brain as well as peripherally. However, increased levels of PGs in the brain have been associated with pathological processes such as inflammation, pain, fever and addiction. Although PGs have been shown to modulate CNS effects of catecholaminergic, serotoninergic and cholinergic neurons, there is no meaningful information concerning their direct central effect on GI function. The evidence for a clear physiological role of central PGs on the GI tract is not convincing. At this time, we conclude that PGs primarily manifest their activity on the GI tract by peripheral rather than by central mechanisms.

High incidence of Klebsiella pneumoniae clinical isolates to extended-spectrum B-lactam drugs in intensive care units.

A prospective study conducted among Jordanian ICU patients in 1997 using Etest identified resistance rates among isolates of E. coli (25%-44%), Enterobacter spp. (54%-62%), and Klebsiella spp. (30%-80%) to extended-spectrum B-lactams (ESBLs): ceftazidime, cefotaxime, ceftriaxone, and aztreonam. All these isolates were susceptible to imipenem and showed low resistance rate to ciprofloxacin (5%-19%) and amikacin (13%-18%). Higher and significant resistance rates of Klebsiella isolates to ceftazidime (80%) and aztreonam (65%) were observed in 1997 compared with a previous study performed in 1994. The majority of Klebsiella pneumoniae (70%) express different ESBL phenotypes that were almost resistant to aztreonam and ceftazidime but susceptible or resistant to cefotaxime and/or ceftriaxone. This prospective study strongly suggests that ESBL production of Klebsiella pneumoniae isolates have been highly disseminated among ICU patients during 1997.

1',1'-Dimethylheptyl-delta-8-tetrahydrocannabinol-11-oic acid: a novel, orally effective cannabinoid with analgesic and anti-inflammatory properties.

1',1'-Dimethylheptyl-Delta-8-tetrahydrocannabinol-11-oic acid (CT-3) is a novel cannabinoid that is under development by Atlantic Pharmaceuticals as an anti-inflammatory and analgesic drug. The objective of the study was to investigate the effects of CT-3 on overt symptom complex (Irwin's test), nociception, gastrointestinal (GI) ulceration, and pharmacological availability after intragastric (i.g.) and intraperitoneal (i.p.) administration. Analgesic studies were assessed in the hot-plate (55 degrees C) and the tail clip tests in mice and in the tail clip test in rats. In addition, pharmacological interaction of CT-3 with the solvent dimethyl sulfoxide (DMSO) was investigated in rats. In mice, CT-3 decreased spontaneous motor activity and induced dose-dependent, analgesic activity in the tail clip and hot-plate tests, with potency similar to morphine sulfate after i.g. and i.p. administration. However CT-3 showed more prolonged duration of analgesic action than morphine. In rats, CT-3 showed marked analgesia in the tail clip test and had similar i.p. and i.g. median effective dose (ED(50) values; 5 mg/kg). CT-3 was devoid of GI ulceration when administered with DMSO either acutely at doses below 100 mg/kg or chronically at a dosage of 30 mg/kg/day for 5 days. In contrast, indomethacin induced GI ulceration and deaths. The concurrent use of DMSO with CT-3 decreased its analgesic action, increased its adverse central nervous system effects, and induced GI ulceration. The evidence indicates that CT-3 exhibits a large dissociation between its anti-inflammatory/analgesic effects and its ulcerogenic actions. CT-3 warrants clinical development as a novel anti-inflammatory and analgesic drug.

Effects of tolcapone, a catechol-O-methyltransferase inhibitor, and Sinemet on intestinal electrolyte and fluid transport in conscious dogs.

Tolcapone (T) is a novel catechol-O-methyltransferase (COMT) inhibitor recently introduced for the treatment of Parkinson's disease. In clinical efficacy studies, T has been associated with a low incidence of diarrhea. The objectives of the study were to examine whether T and its adjunctive drug Sinemet (S) could influence intestinal fluid and electrolyte transport as a possible cause for the diarrhea. The studies were conducted in conscious dogs surgically prepared with Thiry-Vella loops constructed from a 40-cm jejunal segment. A physiologically buffered test solution was perfused into the orad stoma and collected from the caudad stoma. Secretions were collected at 15-min intervals and analyzed for volume, electrolytes, lipid phosphorus, and protein. The acute oral administration of T (10 and 30 mg/kg doses) was well tolerated. Concurrent acute administration of S (25 mg/kg) with T (30 mg/kg) was also well tolerated. The acute oral administration of T induced a dose-dependent efflux of intestinal fluid and electrolytes (sodium, potassium, chloride, and bicarbonate) secretion (P < 0.05). The oral coadministration of S (25 mg/kg) with T (30 mg/kg) accelerated the onset of the stimulation of intestinal secretion. Despite the significant stimulation of intestinal secretion, none of the dogs developed diarrhea, indicating the importance of intestinal compensatory mechanisms. Neither T nor T&S affected calcium, lipid, or protein efflux rates, suggesting that the stimulated secretion was not a consequence of intestinal mucosal injury. The chronic (seven-day) administration of T and T&S was associated with reduced intestinal secretory responses when compared with the acute administration of the same drugs; S enhanced the T-induced tolerance development. The basis for such tolerance is unknown. In conclusion, the stimulatory systemic actions of tolcapone on intestinal secretion may, under certain conditions, contribute to the induction of diarrhea in susceptible patients.

Effects of maternal exercise on fetal activity in late gestation.

In order to test the effects of maternal exercise in late gestation on fetal biophysical activities as measured by fetal breathing, shoulder movement, and kick response, these parameters were monitored by ultrasound in ten healthy pregnant women at 35 weeks of gestation before and after 20 minutes of aerobic dance and before and after 20 minutes of rest. A randomized crossover design between exercise (sequence A) and rest (sequence B) that used each pregnant woman as her own control was used in this study. Cumulative means for each fetal activity were compared. Results indicated a significant decrease in fetal breathing after maternal exercise and no significant change in shoulder movements or kick response.

Dopamine DRD2/Cys311 is not associated with chronic schizophrenia.

A mutation in the DRD2 receptor gene has been reported in association with schizophrenia in Japanese and Caucasian populations. The variation, Ser to Cys at codon 311, occurs in the third intracellular loop of the receptor and is therefore putatively functional. We report the results of screening US Caucasian schizophrenic and nonschizophrenic populations. We detected the occurrence of the DRD2 Cys311 variant in both schizophrenics and controls. Our data demonstrates no significant difference between the frequency of Cys311 in Caucasian schizophrenic and non-schizophrenic populations, indicating no association with schizophrenia.

Interleukin-6 does not stimulate rat myometrial contractions in an in vitro model.

PROBLEM: Interleukin-6 (IL-6) increases in culture-positive amniotic fluid in women with preterm labor. IL-6 stimulates the production of prostaglandins leading to increased uterine activity. METHODS: We tested the hypothesis that IL-6 increases myometrial activity through release of uterotonic mediators. We studied the effect of IL-6 on uterine contractions in the absence and presence of fetal membranes to determine if the effect was on myometrium alone or was mediated through fetal membranes/decidua. IL-6 in concentrations of 100, 10, 0.1 or 0 ng/ml was added to the maternal side of the dual chamber-fetal membrane-uterine muscle in vitro model. RESULTS: We found that 10 ng/ml of IL-6 alone, without fetal membranes, caused a significant decrease in uterine contractions over time (P < or = 0.01). This decrease was not observed with the addition of term, nonlabored fetal membranes. CONCLUSIONS: IL-6 in the presence or absence of membranes, over a four log fold dose range, did not stimulate uterine contractions.

Effect of mitogenic and hormonal stimulation on zinc transport in mixed lymphocyte cultures.

Human mixed lymphocyte cultures (hMLC) were used to examine the relationship between mitogenic stimuli (MITO), synthetic human calcitonin (hCT), and human insulin (hINS) on zinc (Zn) transport kinetics. Lymphocytes were isolated using a Ficoll density gradient. The hMLCs were labeled by incubation with 65Zn in either control or MITO-containing media. 65Zn release to equilibrium was then measured in unstimulated and mitogen-stimulated cells treated with hCT and hINS. hCT and hINS were added only during this final incubation due to the rapid response to peptide hormones. Bidirectional transmembrane flux coefficients were calculated using a closed two-compartment model. The hMLCs subjected to MITO stimulation demonstrated a 25% decrease in the fractional efflux coefficient (Kcm) and a 69% increase in the fractional influx coefficient (Kmc) compared with controls. Acute exposure to hINS resulted in a marked increase in Kmc with no significant change in Kcm. Acute exposure to hCT had effects qualitatively similar to those of MITO alone. Neither hormone significantly altered the transport of 65Zn when compared with stimulation with MITO alone.