Suicide risk around the world: a meta-analysis of longitudinal studies.

PURPOSE: Suicidal thoughts and behaviors (STBs) have been a persistent problem worldwide. Identifying risk factors for STBs across distinct areas of the world may help predict who or where requires the greatest attention. However, risk factors for STBs are infrequently explored cross-nationally. The present study examined whether psychopathology prospectively predicts STBs across different areas of the world, and whether certain country-level factors moderate the degree of risk conferred. METHODS: We conducted a meta-analysis of 71 longitudinal studies from 30 different countries that featured psychopathology-related variables predicting STB outcomes. Meta-regression was used to evaluate whether the following country-level factors modified risk: geographic region, income level, and degree of mental health structural stigma. RESULTS: Over 90% of studies had been conducted in North America and Europe. When assessed by country income level, it was found that only one longitudinal study on psychopathology and STB was conducted outside of a high-income country. Moreover, less than 10% of studies were conducted in high structural stigma contexts. Meta-regression findings revealed that the variation in risk effect sizes across studies was not explained by models including country-level factors. CONCLUSIONS: Our findings show critical underrepresentation of low- and middle-income countries, which account for a large proportion of global suicide deaths. This reveals a need to broaden the scope of longitudinal research on STB risk, such that countries across more regions, income levels, and degrees of structural stigma are fully accounted for. Such lines of research will improve generalizability of findings, and more precisely inform prevention efforts worldwide.

Psychosis as a risk factor for suicidal thoughts and behaviors: a meta-analysis of longitudinal studies.

BACKGROUND: Research has long noted higher prevalence rates of suicidal thoughts and behaviors among individuals with psychotic symptoms. Major theories have proposed several explanations to account for this association. Given the differences in the literature regarding the operationalization of psychosis and sample characteristics, a quantitative review is needed to determine to what extent and how psychosis confers risk for suicidality. METHODS: We searched PsycInfo, PubMed, and GoogleScholar for studies published before 1 January 2016. To be included in the analysis, studies must have used at least one psychosis-related factor to longitudinally predict suicide ideation, attempt, or death. The initial search yielded 2541 studies. Fifty studies were retained for analysis, yielding 128 statistical tests. RESULTS: Suicide death was the most commonly studied outcome (43.0%), followed by attempt (39.1%) and ideation (18.0%). The median follow-up length was 7.5 years. Overall, psychosis significantly conferred risk across three outcomes, with weighted mean ORs of 1.70 (1.39-2.08) for ideation, 1.36 (1.25-1.48) for attempt, and 1.40 (1.14-1.72) for death. Detailed analyses indicated that positive symptoms consistently conferred risk across outcomes; negative symptoms were not significantly associated with ideation, and were protective against death. Some small moderator effects were detected for sample characteristics. CONCLUSIONS: Psychosis is a significant risk factor for suicide ideation, attempt, and death. The finding that positive symptoms increased suicide risk and negative symptoms seemed to decrease risk sheds light on the potential mechanisms for the association between psychosis and suicidality. We note several limitations of the literature and offer suggestions for future directions.

Biological risk factors for suicidal behaviors: a meta-analysis.

Prior studies have proposed a wide range of potential biological risk factors for future suicidal behaviors. Although strong evidence exists for biological correlates of suicidal behaviors, it remains unclear if these correlates are also risk factors for suicidal behaviors. We performed a meta-analysis to integrate the existing literature on biological risk factors for suicidal behaviors and to determine their statistical significance. We conducted a systematic search of PubMed, PsycInfo and Google Scholar for studies that used a biological factor to predict either suicide attempt or death by suicide. Inclusion criteria included studies with at least one longitudinal analysis using a biological factor to predict either of these outcomes in any population through 2015. From an initial screen of 2541 studies we identified 94 cases. Random effects models were used for both meta-analyses and meta-regression. The combined effect of biological factors produced statistically significant but relatively weak prediction of suicide attempts (weighted mean odds ratio (wOR)=1.41; CI: 1.09-1.81) and suicide death (wOR=1.28; CI: 1.13-1.45). After accounting for publication bias, prediction was nonsignificant for both suicide attempts and suicide death. Only two factors remained significant after accounting for publication bias-cytokines (wOR=2.87; CI: 1.40-5.93) and low levels of fish oil nutrients (wOR=1.09; CI: 1.01-1.19). Our meta-analysis revealed that currently known biological factors are weak predictors of future suicidal behaviors. This conclusion should be interpreted within the context of the limitations of the existing literature, including long follow-up intervals and a lack of tests of interactions with other risk factors. Future studies addressing these limitations may more effectively test for potential biological risk factors.

Self-injurious thoughts and behaviors as risk factors for future suicide ideation, attempts, and death: a meta-analysis of longitudinal studies.

BACKGROUND: A history of self-injurious thoughts and behaviors (SITBs) is consistently cited as one of the strongest predictors of future suicidal behavior. However, stark discrepancies in the literature raise questions about the true magnitude of these associations. The objective of this study is to examine the magnitude and clinical utility of the associations between SITBs and subsequent suicide ideation, attempts, and death. METHOD: We searched PubMed, PsycInfo, and Google Scholar for papers published through December 2014. Inclusion required that studies include at least one longitudinal analysis predicting suicide ideation, attempts, or death using any SITB variable. We identified 2179 longitudinal studies; 172 met inclusion criteria. RESULTS: The most common outcome was suicide attempt (47.80%), followed by death (40.50%) and ideation (11.60%). Median follow-up was 52 months (mean = 82.52, s.d. = 102.29). Overall prediction was weak, with weighted mean odds ratios (ORs) of 2.07 [95% confidence interval (CI) 1.76-2.43] for ideation, 2.14 (95% CI 2.00-2.30) for attempts, and 1.54 (95% CI 1.39-1.71) for death. Adjusting for publication bias further reduced estimates. Diagnostic accuracy analyses indicated acceptable specificity (86-87%) and poor sensitivity (10-26%), with areas under the curve marginally above chance (0.60-0.62). Most risk factors generated OR estimates of <2.0 and no risk factor exceeded 4.5. Effects were consistent regardless of sample severity, sample age groups, or follow-up length. CONCLUSIONS: Prior SITBs confer risk for later suicidal thoughts and behaviors. However, they only provide a marginal improvement in diagnostic accuracy above chance. Addressing gaps in study design, assessment, and underlying mechanisms may prove useful in improving prediction and prevention of suicidal thoughts and behaviors.

Acute myeloid leukemia with t(8; 21)(q22; q22) preceded by breast granulocytic sarcoma / Leucemia mielóide aguda com t(8; 21)(q22; q22) precedido de sarcoma granulocítico na mama

Granulocytic sarcoma (GS) is a rare extramedullary tumor mass composed of immature cells derived from the hematopoietic myeloid series. It is usually associated with leukemia and other myeloproliferative disorders but can also occur without overt hematologic diseases. The breast has been reported to be an uncommon site of presentation. We report a case of acute myeloid leukemia preceded by GS of the breast. The immunohistochemistry revealed myeloperoxidase, CD68 and CD43 positivity, thus indicating a diagnosis of GS. Conventional cytogenetic analysis of peripheral blood cells showed t(8;21)(q22;22). Complete remission was achieved with Daunorubicin and Cytarabine induction therapy followed by three courses of high-dose Cytarabine consolidation. The patient remains in continuous complete remission at 27 months.

Sarcoma granulocítico (GS) é um raro tumor extramedular composto de células imaturas derivadas das linhagens hematopoiéticasmielóides. É geralmente associada à leucemia ou outras desordens mieloproliferativas, mas também pode ocorrer sem manifestação de doenças hematológicas. A mama tem sido relatada como local incomum de apresentação. Relatamos um caso de leucemia mielóide aguda precedida por GS da mama. A imunohistoquímica revelou mieloperoxidase, CD68 e CD43 positivos, indicando um diagnóstico da GS. A análise citogenética convencional de células de sangue periférico mostrou t(8; 21)(q22; 22). Remissão completa foi atingida com indução terapêutica com daunorubicina e citarabina, seguida de três ciclos de alta dose de citarabina. O paciente permanece em completa remissão há 27 meses.

Bacteraemia due to Stenotrophomonas maltophilia: an analysis of 45 episodes.

OBJECTIVE: Stenotrophomonas maltophilia is an important nosocomial pathogen and a therapeutic challenge. A ten-year review of episodes of bacteraemia due to S. maltophilia was undertaken in light of reports of an increasing frequency of infection. METHODS: A retrospective analysis of bloodstream infections due toS. maltophilia at a tertiary care hospital in Melbourne, Australia. Cases were identified via microbiology laboratory reports, and relevant clinical data were collected from the medical record of each patient. RESULTS: Eighty per cent of these 45 episodes were nosocomial. The most common characteristics in cases of bacteraemia were the presence of an indwelling central venous catheter (CVC) (38/45, 84%) and previous antibiotic therapy (33/45, 73%). There were 8 deaths (8/44, 18%) within 7 days of bacteraemia. A significant correlation was found between deaths and a failure to remove the CVC (P = 0.01) or treat with appropriate antimicrobials (P = 0.01). Antibiotic susceptibility testing revealed that isolates were most sensitive to sulphamethoxazole (80%), chloramphenicol (75.5%) and ceftazidime (64.5%). CONCLUSIONS: S. maltophilia is an important pathogen especially in the highly compromised host. Isolation of this organism from a blood culture should prompt a careful review of the patient with particular emphasis on removal of indwelling CVCs and commencement of appropriate antibiotic therapy.

Nocardia infection in heart-lung transplant recipients at Alfred Hospital, Melbourne, Australia, 1989-1998.

Nocardia infections are uncommon in recipients of heart, lung, or heart-lung transplants, but such infections are well described. Frequent episodes of rejection, high-dose prednisolone treatment, renal impairment, and prolonged respiratory support have all been shown to increase the risk of Nocardia infection in this group. In this retrospective review of 540 recipients of heart, lung, or heart-lung transplants, 10 patients developed Nocardia infection (frequency, 1.85%). Infection occurred at a mean +/- standard deviation of 13+/-14.5 months after transplantation. All patients had pulmonary disease with no evidence of extrapulmonary disease. The Nocardia infection did not contribute directly to patient deaths. Coinfection with other pathogens was present in 6 patients, and 2 patients had sequential infections. Radiological findings varied. All isolates were susceptible to trimethoprim-sulfamethoxazole, amikacin, and imipenem. Treatment regimens varied. Two (30%) of 6 patients treated with trimethoprim-sulfamethoxazole developed adverse reactions, which necessitated a change in antibiotic therapy. The optimal treatment regimen, which comprises both the antimicrobial agent and the length of treatment, is unclear.

Possible analgesic effect of vigabrin in animal experimental chronic neuropathic pain

Since anticonvulsants have been used for treating neuralgias, an interest has arisen to experimentally test vigabatrin for its gabaergic mechanism of action. For this, 41 Wistar rats were used, and in 25 of them a constractive sciatic neuropathy was induced (Bennet & Xie model). For testing pain symptoms, spontaneous (Scratching) and evoked behaviors to noxious (46 degrees Celsius) and non-noxious (40 degrees Celsius) thermal stimuli were quatified. Moreover, a comparative pharmacological study of vigabatrin with other analgesic anticonvulsant drugs was also performed. The results showed a possible dose-dependent analgesic effect of vigabatrin (gamma-vinyl-GABA) on experimental neuropathic pain, as shown vy the significant (p<0.05) decreasing effect of vigabatrin on scratching and by its significant (p>0.05) increasing effect on the latency of the right hindpaw withdrawal of the animals to noxious thermal stimulus. This was corroborated by similar findings with analgesic anticonvulsants (carbamazepine, phenytoin and valproic acid). This possible and not yet described analgesic effect of vigabatrin seems not to be opioid mediated.

The effect of baclofen on spontaneous and evoked behavioral expression of experimental neuropathic chronic pain

Baclofen (Beta-p-chlorophenyl-GABA) has been used in humans to treat spasticity, as well as trigeminal neuralgia Since GABA (gamma-aminobutyric acid) has been implicated in inhibitory and analgesic effects in the nervous system, it was of interest to study the effect of baclofen in experimental neuropathic pain. With this purpose, experiments were carried out in 17 neuropathic rats with constrictive sciatic injury, as described by Bennet and Xie (1988), taking as pain parameters scratching behaviour and the latency to the thermal nociceptive stimulus. The results showed that baclofen induces, in a dose-dependent manner, significant decrease (p<0.05) of scratching behaviour and significant increase (p<0.05) of the latency to the nociceptive thermal stimulus. The absence of antagonism of naloxone suggested a non-participation of an opioid-mediated mechanism in this analgesic effect of baclofen on experimental neuropathic pain.

Experimental HTLV-1 infection and associated myelopathy

HTLV-I infection and associated myelopathy has been reproduced experimentally in vitro and in vivo and these studies have shown the possibility of creating several lines of infective cells and of detecting minor and major clinical expressions of HTLV-I associated myelopathy in rabbits and rats.

Stability of association of 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine with liposomes is composition dependent.

The ether lipid, 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET-18-OCH3), has anticancer activity, but it has serious side-effects, including hemolysis, which prevent its optimal use. We surmised if ET-18-OCH3 could be stably associated with liposomes, less free ET-18-OCH3 would be available for lytic interaction with red cells. Liposome composition variables investigated included acyl chain saturation, phospholipid head group and mole ratio of Chol and ET-18-OCH3. It was found that attenuation of hemolysis was strongly liposome composition dependent. Some ET-18-OCH3 liposome compositions were minimally hemolytic. For example, whereas the HI5 (drug concentration required to cause 5% human red cell lysis) was 5-6 microM for free ET-18-OCH3, it was approximately 250 microM for DOPC (dioleoylphosphatidylcholine):Chol (cholesterol):DOPE-GA (glutaric acid derivatized DOPE):ET-18-OCH3, (4:3:1:2) and 640 microM for DOPE (dioleyolphosphatidylethanolamine):Chol:DOPE-GA:ET-18-OCH3 (4:3:1:2) liposomes. Efflux of carboxyfluorescein (CF) from liposomes and Langmuir trough determinations of mean molecular area of lipids in monolayers (MMAM) were used as indicators of membrane packing and stability. Incorporation of ET-18-OCH3 in liposomes reduced the MMAM. Reduction in CF permeation was correlated with reduction in hemolysis. The most stable liposomes included components, such as cholesterol, DOPC and DOPE, which have complementary shapes to ET-18-OCH3.

The release and detection of endotoxin from liposomes.

Incorporation of lipopolysaccharide (LPS) into liposomes dramatically reduces its ability to coagulate Limulus amebocyte lysate (LAL). The coagulation of LAL is commonly used to signal the presence of endotoxin in vitro. This study demonstrates a simple method to release masked endotoxin from liposomal dispersions using moderate amounts of detergent to form mixed micelles containing lipid, detergent, and LPS. Several parameters were found to affect the degree of liposome solubilization and/or the sensitivity of the LAL assay. These included detergent type and concentration, temperature for solubilization, lipid composition, liposome morphology, and time for test incubation. The nonionic detergent polyoxyethylene 10 lauryl ether (C12E10) proved to be unique in its ability to solubilize liposomes and minimally interfere with endotoxin detection. The LAL endotoxin detection limit for samples dispersed in C12E10 varied with the phospholipid component; the sensitivity decreased in the order DSPC > DPPC = EPC >> DMPC. Cholesterol lowered the solubility limit of the liposomes, but did not appear to affect the LAL assay sensitivity once the liposomes were completely solubilized. The presence of negatively charged phospholipids, DSPG and Pops, also lowered the solubility limit. Pops, but not DSPG, at 10 mol% further decreased the LAL endotoxin detection limit. This detergent-solubilization method should be useful in liposomal LPS immunological studies or in other situations where accurate determination of endotoxin concentration is important.

Combination of antitumor ether lipid with lipids of complementary molecular shape reduces its hemolytic activity.

Because the therapeutic use of the antitumor ether lipid 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphorylcholine (ET-18-OCH3) is restricted by its hemolytic activity we explored the use of lipid packing parameters to reduce this toxicity by creating structurally optimized ET-18-OCH3 liposomes. We postulated that combination of ET-18-OCH3, which is similar in structure to lysophosphatidylcholine, with lipid molecules of complementary molecular shape (opposite headgroup/chain volume) would likely yield a stable lamellar phase from which ET-18-OCH3 exchange to red blood cell membranes would be curtailed. To quantitate the degree of shape complementarity, we used a Langmuir trough and measured the mean molecular area per molecule (MMAM) for monolayers comprised of ET-18-OCH3, the host lipids, and binary mixtures of varying mole percentage ET-18-OCH3. The degree of complementarity was taken as the reduction in MMAM from the value expected based on simple additivity of the individual components. The greatest degree of shape complementarity was observed with cholesterol: the order of complementarity for the ET-18-OCH3-lipid mixtures examined was cholesterol >> DOPE > POPC approximately DOPC. Phosphorus NMR and TLC analysis of aqueous suspensions of ET-18-OCH3 (40 mol%) with the host lipids revealed them to all be lamellar phase. For ET-18-OCH3 at 40 mol% in liposomes, the hemolytic activity followed the trend of the reduction in MMAM and was least for the ET-18-OCH3/cholesterol system (H50 = 661 microM ET-18-OCH3) followed by ET-18-OCH3/DOPE (H50 = 91 microM) and mixtures with POPC and DOPC which were comparable at H50 = 26 microM and 38 microM, respectively: the H50 concentration for free ET-18-OCH3 was 16 microM. This experimental strategy for designing optimized liposomes with a reduction in exchange, and hence toxicity, may be useful for other amphipathic/lipophilic drugs that are dimensionally compatible with lipid bilayers.

Association and release of prostaglandin E1 from liposomes.

PGE1-lipid interactions were studied in several liposome systems. Data from both circular dichroic (CD) measurements and differential scanning calorimetry (DSC) indicated that PGE1 in the protonated form seeks the less polar environment of the lipid bilayer. CD measurements made on PGE1 in solution showed that the wavelength of maximum absorbance red shifted approximately 8 nm with decreasing solvent polarity. The CD spectrum of liposomal PGE1 prepared in pH 4.5 but not pH 7.2 buffer was also red shifted. There was no red shift in the CD spectrum of PGE1 detected at pH 4.5 in the absence of phospholipid. DSC measurements on DSPC bilayers prepared with 5 mol% PGE1 at pH 4.5 but not pH 7.2 revealed an almost complete loss of the pre-transition as well as broadening of the main phase transition. The amount of 3H-PGE1 initially associated with EPC, POPC or DSPC liposomes was determined using size exclusion filters and centrifugation. This amount was found to be dependent on the pH of the buffer (pH 4.5 >> pH 7.2) and fluidity of the bilayer (EPC = POPC > DSPC), but independent of the lamellarity of the liposome. In all cases, addition of cholesterol reduced the amount of PGE1 associated with the liposome. The time-dependent release of PGE1 from the liposomes was determined by rapidly diluting the sample 100-fold into pH 7.2 buffer. Lipid saturation was a key factor influencing this release. Gel-phase liposomes of DSPC showed a rapid initial release (t(1/2) < 2 min) of PGE1, corresponding to the amount in the outer monolayer, followed by a very slow, almost negligible release of the remaining PGE1. A rapid initial release also occurred in fluid-phase membranes, followed by a more gradual release of the remaining PGE1 over several hours. This release rate could be slowed by increasing the lamellarity of these liposomes, or adding cholesterol to decrease the fluidity of the membrane.

Enhanced therapeutic effects of liposome-associated 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine.

The ether-lipid 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET-18-OCH3) has anticancer activity, but systemic toxicity has restricted its therapeutic use. In this report "free" ET-18-OCH3 and a stable, well-characterized, liposome-based formulation of ET-18-OCH3 (ELL-12) were compared for in vivo toxicity in normal mice and for therapeutic efficacy in three mouse tumor model systems. The entrapment of ET-18-OCH3 in liposomes decreased the acute toxicity of ET-18-OCH3 after i.v. administration. The maximum tolerated dose for a single i.v. dose of free ET-18-OCH3 was found to be approximately 25 mg/kg, whereas the maximum tolerated dose for ELL-12 was approximately 200 mg/kg. ELL-12 was much less hemolytic in vivo than ET-18-OCH3. The therapeutic efficacy of free ET-18-OCH3 and ELL-12 was investigated against i.p. P388 leukemia, Lewis lung cancer lung metastases, and B16/F10 melanoma (lung tumor nodules) in mice. Although ET-18-OCH3 had some anticancer activity, it was found that ELL-12 was more effective than ET-18-OCH3 in all three tumor models at lower and nontoxic dose schedules. These results suggest that association of ET-18-OCH3 in stable, well-characterized liposomes transforms it into an effective antitumor agent.

Molecular flexibility demonstrated by paramagnetic enhancements of nuclear relaxation. Application to alamethicin: a voltage-gated peptide channel.

A nitroxide spin label attached to the C-terminus of the channel forming peptide alamethicin produces an enhancement of the nuclear spin-lattice relaxation rates of peptide protons as a result of both intermolecular and intramolecular magnetic dipole-dipole interactions. The intermolecular contribution provides evidence that alamethicin monomers collide preferentially in a C-terminal-to-N-terminal configuration in methanol. From the intramolecular paramagnetic enhancement of nuclear spin-lattice relaxation times, effective distances between the unpaired electron on the nitroxide at the C-terminus of alamethicin and protons along the peptide backbone were calculated. These distances are much shorter than distances based on the reported crystal structure of alamethicin, and cannot be accounted for by motion in the bonds that attach the nitroxide to the peptide. In addition, the differences between distances deduced from the nuclear spin relaxation and the distances seen in the crystal structure increase toward the N-terminal end of the peptide. The simplest explanation for these data is that the alamethicin backbone suffers large structural fluctuations that yield shorter effective distances between the C-terminus and positions along the backbone. This finding can be interpreted in terms of a molecular mechanism for the voltage-gating of the alamethicin channel. When the distances between a paramagnetic center and a nucleus fluctuate, paramagnetic enhancements are expected to yield distances that are weighted by r-6, and distances calculated using the Solomon-Bloembergen equations may more nearly represent a distance of closest approach than a time average distance. Therefore, the use of paramagnetic centers such as spin labels or metal ions with long electron T1 values provides a distance measurement that reflects a dynamically averaged structure where the averaging process heavily weights short distances. The results of such measurements, when combined with other structural information, may provide particularly clear evidence for the magnitude of structural fluctuations involving distances greater than 10 A.

Structure of micelle-associated alamethicin from 1H NMR. Evidence for conformational heterogeneity in a voltage-gated peptide.

Alamethicin is a 20 amino acid peptide that produces a voltage-dependent conductance in membranes. To understand the mechanism by which this peptide becomes voltage-gated, the structure of alamethicin bound to micelles was examined using high-resolution 1H nuclear magnetic resonance (NMR). Two-dimensional correlation and nuclear Overhauser effect spectroscopy (NOESY) were carried out on alamethicin incorporated into perdeuterated sodium dodecyl sulfate (SDS) micelles, and the 1H NMR spectrum of the peptide in micelles was assigned. The intensities of the HN-HN(i,i+1), H alpha-HN(i,i+1), H alpha-NH(i,i+3), H alpha-H beta (i,i+3), and H alpha-NH(i,i+4) cross peaks in the NOESY spectrum suggest that the N-terminal half of the peptide is predominantly alpha-helical, while the C-terminal half has a less regular or more flexible structure. The exposure of micelle bound alamethicin to the aqueous solution was determined by examining the effect of aqueous paramagnetic reagents on the line widths of the peptide protons. These measurements suggest that alamethicin is buried in the micelle. A set of restraints consisting of 175 distances (derived from NOESY spectra), five dihedral angles, and two hydrogen bond distances were used in a simulated annealing procedure that yielded structures for micelle associated alamethicin. The structures that were generated with simulated annealing were largely helical from residues 4-9 and 12-16. A limited number of structural forms were obtained. The main difference among forms involved the backbone conformations of MeA10, Gly11, and Leu12 and resulted in structures that were straight or had different amounts of bend. The structural forms could be easily interconverted by rotation of the psi and phi angles of residues 10-12. The rotational freedom at or near MeA10 may be a result of Pro14, which would be the normal hydrogen-bonding position for the peptide carbonyl of MeA10. These results suggest that conformation rearrangements at or near MeA10 may play a role in the voltage-gating of alamethicin.