Substance use disorders among armed forces veterans with gambling disorder: Insights from an inpatient treatment sample.

Armed forces veterans are especially prone to experiencing a variety of addictive disorders, including gambling disorder. Even so, gambling disorder in veterans remains understudied generally, and there remain significant gaps in the research literature with regards to how gambling disorder relates to the experience and expression of comorbid substance use disorders. The present work examines the prevalence, presentation, and clinical associations of substance use disorders in U.S. Armed Forces veterans receiving inpatient treatment for gambling disorder. Participants (N = 664) were veterans from all branches of the U.S. Armed Forces receiving inpatient treatment for gambling disorder through the Department of Veteran Affairs Healthcare System. Clinical data from the time of intake was analyzed. A substantial portion of veterans (36.1%) met current criteria for an SUD, with another 16.5% reporting a history of SUD. Alcohol use disorder was the most commonly reported SUD (76.1% of those with a current SUD), with polysubstance use disorders and stimulant use disorders each occurring in at least 25% of those with SUDs. SUD status was related to greater levels of impulsivity, but there was no evidence that SUD status was related to gambling symptom severity, gambling preferences, or further psychiatric comorbidities.

Comorbid psychiatric diagnoses and gaming preferences in US armed forces veterans receiving inpatient treatment for gambling disorder.

Armed Forces Veterans are uniquely vulnerable to problem gambling and gambling disorder. Even so, research regarding the full clinical profile of veterans with gambling problems lags. Gambling activities vary widely from each other, but most gambling activities can be understood as either strategic (i.e., involving some measure of skill and decision-making as a part of the gambling practice) or non-strategic (i.e., gambling activities that are entirely based on chance). Prior works have found that gamblers that prefer strategic gambling activities and those that prefer nonstrategic gambling activities often differ from each other in key ways, with the two preferences being linked to varying motivations for gambling, varying cognitions about gambling, and the course of gambling disorder. The present work sought to examine how preferences for strategic vs. nonstrategic gambling might be related to psychiatric comorbidities among U.S. Armed Forces Veterans receiving inpatient treatment for Gambling Disorder. Data from U.S. Armed Forces Veterans (N = 401) receiving residential treatment for GD between the years of 2010-2016 were analyzed. Results demonstrated that gamblers that preferred strategic gambling, as opposed to non-strategic gambling, were more likely to be younger, more likely to be men, less likely to have a nicotine use disorder, and less likely to have PTSD. Such findings suggest that gamblers with PTSD are likely to prefer nonstrategic games and may imply a unique vulnerability to gambling problems related to non-strategic gambling among armed forces veterans.

Syncytialization alters the extracellular matrix and barrier function of placental trophoblasts.

The human placenta is of vital importance for proper nutrient and waste exchange, immune regulation, and overall fetal health and growth. Specifically, the extracellular matrix (ECM) of placental syncytiotrophoblasts, which extends outward from the placental chorionic villi into maternal blood, acts on a molecular level to regulate and maintain this barrier. Importantly, placental barrier dysfunction has been linked to diseases of pregnancy such as preeclampsia and intrauterine growth restriction. To help facilitate our understanding of the interface and develop therapeutics to repair or prevent dysfunction of the placental barrier, in vitro models of the placental ECM would be of great value. In this study, we aimed to characterize the ECM of an in vitro model of the placental barrier using syncytialized BeWo choriocarcinoma cells. Syncytialization caused a marked change in syndecans, integral proteoglycans of the ECM, which matched observations of in vivo placental ECM. Syndecan-1 expression increased greatly and predominated the other variants. Barrier function of the ECM, as measured by electric cell-substrate impedance sensing (ECIS), increased significantly during and after syncytialization, whereas the ability of THP-1 monocytes to adhere to syncytialized BeWos was greatly reduced compared with nonsyncytialized controls. Furthermore, ECIS measurements indicated that ECM degradation with matrix metalloproteinase-9 (MMP-9), but not heparanase, decreased barrier function. This decrease in ECIS-measured barrier function was not associated with any changes in THP-1 adherence to syncytialized BeWos treated with heparanase or MMP-9. Thus, syncytialization of BeWos provides a physiologically accurate placental ECM with a barrier function matching that seen in vivo.

Unfractionated heparin displaces sFlt-1 from the placental extracellular matrix.

Soluble vascular endothelial growth factor receptor-1 (sFlt-1) is an anti-angiogenic protein which is secreted by numerous cell types and acts as a decoy receptor for the angiogenic protein vascular endothelial growth factor (VEGF). Despite its physiologic importance in maintaining angiogenic balance, excess sFlt-1 levels are associated with the pathogenesis of many diseases, especially those with angiogenic imbalance, endothelial dysfunction, and hypertension. Although sFlt-1 is a soluble protein, it contains a binding site for the extracellular matrix component heparan sulfate. This allows cells to retain and localize sFlt-1 in order to prevent excessive VEGF signaling. During pregnancy, placental syncytiotrophoblasts develop a large extracellular matrix which contains significant amounts of heparan sulfate. Consequently, the placenta becomes a potential storage site for large amounts of sFlt-1 bound to extracellular heparan sulfate. Additionally, it should be noted that sFlt-1 can bind to the anticoagulant unfractionated heparin due to its molecular mimicry to heparan sulfate. However, it remains unknown whether unfractionated heparin can compete with heparan sulfate for binding of localized sFlt-1. In this study, we hypothesized that administration of unfractionated heparin would displace and solubilize placental extracellular matrix(ECM)-bound sFlt-1. If unfractionated heparin can displace this large reservoir of sFlt-1 in the placenta and mobilized it into the maternal circulation, we should be able to observe its effects on maternal angiogenic balance and blood pressure. To test this hypothesis, we utilized in vitro, ex vivo, and in vivo methods. Using the BeWo placental trophoblast cell line, we observed increased sFlt-1 in the media of cells treated with unfractionated heparin compared to controls. The increase in media sFlt-1 was found in conjunction with decreased localized cellular Flt (sFlt-1 and Flt-1) as measured by total cell fluorescence. Similar results were observed using ex vivo placental villous explants treated with unfractionated heparin. Real-time quantitative PCR of the explants showed no change in sFlt-1 or heparanase-1 mRNA expression, eliminating increased production and enzymatic cleavage of heparan sulfate as causes for sFlt-1 media increase. Timed-pregnant rats given a continuous infusion of unfractionated heparin exhibited an increased mean arterial pressure as well as decreased bioavailable VEGF compared to vehicle-treated animals. These data demonstrate that chronic unfractionated heparin treatment is able to displace matrix-bound sFlt-1 into the maternal circulation to such a degree that mean arterial pressure is significantly affected. Here we have shown that the placental ECM is a storage site for large quantities of sFlt-1, and that it should be carefully considered in future studies concerning angiogenic balance in pregnancy.

Potential Perinatally Acquired Extended Spectrum ß-Lactamase Escherichia coli Urinary Tract Infection in an Infant.

Extended-spectrum ß-lactamases (ESBL) are produced mainly by members of the Enterobacteriaceae family and confer resistance to most ß-lactam antibiotics. Because of limited treatment options, ESBL infections are typically more challenging to treat resulting in poor outcomes, increased complications, and mortality. Because ESBL-producing organisms are primarily seen in critically ill patients, along with those patients having prolonged hospital stays, extensive courses of antimicrobials, and/or use of invasive medical devices (i.e., urinary catheters, central venous lines, or endotracheal tubes), guidelines regarding the management of ESBL-producing organisms in the pediatric population are scant. A review of current recommended treatment options for infections caused by ESBL-producing organisms centers on the use of carbapenems, with some supportive literature regarding the utility/effectiveness of other non-ß-lactam therapy. We present a case report of an 8-month-old female diagnosed with a urinary tract infection due to ESBL-producing Escherichia coli successfully treated with sulfamethoxazole/trimethoprim. Multidrug resistant infections in pediatric patients without risk factors remains an important field of study because these unique infections may pose a problem when choosing an effective empiric antimicrobial therapy.

Differential regulation of sFlt-1 splicing by U2AF65 and JMJD6 in placental-derived and endothelial cells.

Despite years of study, the gestational disorder preeclampsia (PE) remains poorly understood. One proposed mechanism of PE development is increased soluble VEGF receptor-1 (sFlt-1), ultimately causing angiogenic imbalance and endothelial dysfunction. The soluble protein is an alternative splice variant of FLT1, which also encodes for the full-length receptor Flt-1. The mechanism of the alternative splicing, and the reason for its inappropriate increase in preeclampsia, is not well understood. U2 auxiliary factor 65 (U2AF65) and jumonji C domain-containing protein 6 (JMJD6) have been implicated in the splicing of sFlt-1. Using siRNA knockdown and plasmid overexpression in immortalized placental trophoblasts (BeWo) and primary endothelial cells (HUVECs), we examined the role these proteins play in production of sFlt-1. Our results showed that U2AF65 has little, if any, effect on sFlt-1 splicing, and JMJD6 may enhance sFlt-1 splicing, but is not necessary for splicing to occur. Utilizing a hypoxic environment to mimic conditions of the preeclamptic placenta, as well as examining placentae in the reduced uterine perfusion pressure (RUPP) model of PE, which exhibits increased circulating sFlt-1, we found increased expression of JMJD6 in both hypoxic cells and placental tissue. Additionally, we observed a potential role for U2AF65 and JMJD6 to regulate the extracellular matrix enzyme heparanase, which may be involved in the release of sFlt-1 protein from the extracellular matrix. It will be important to study the role of these proteins in different tissues in the future, as changes in expression had differential effects on sFlt-1 splicing in the different cell types studied here.

Biopolymer-Delivered, Maternally Sequestered NF-κB (Nuclear Factor-κB) Inhibitory Peptide for Treatment of Preeclampsia.

Preeclampsia is a hypertensive disorder of pregnancy that causes significant acute and long-term risk to the mother and the baby. The multifaceted maternal syndrome is driven by overproduction of circulating anti-angiogenic factors, widespread inflammation, and endothelial dysfunction. Nuclear factor-κB (NF-κB) is a transcription factor that plays a central role in the inflammatory response. Its activity is increased in the preeclamptic placenta, and it promotes the systemic endothelial dysfunction present in preeclampsia. There is an acute need for new therapeutics targeted to the causative pathways of preeclampsia. Our group has developed a drug delivery system based on the bioengineered protein ELP (elastin-like polypeptide) that is capable of stabilizing therapeutics in the maternal circulation and preventing their placental transfer. Here we used the ELP carrier system to deliver a peptide known to inhibit the NF-κB pathway. This polypeptide, containing a cell-penetrating peptide and an NF-κB inhibitory peptide derived from the p50 nuclear localization sequence (abbreviated SynB1-ELP-p50i), blocked NF-κB activation and prevented TNF-α (tumor necrosis factor alpha)-induced endothelin production in vitro. Fusion of the p50i peptide to the SynB1-ELP carrier slowed its plasma clearance and prevented its placental transfer in pregnant rats, resulting in increased deposition in the maternal kidney, liver, and placenta relative to the free peptide. When administered in a rat model of placental ischemia, SynB1-ELP-p50i partially ameliorated placental ischemia-induced hypertension and reduced placental TNF-α levels with no signs of toxicity. These data support the continued development of ELP-delivered NF-κB inhibitors as maternally sequestered anti-inflammatory agents for preeclampsia therapy.

Heparanase regulation of sFLT-1 release in trophoblasts in vitro.

INTRODUCTION: Preeclampsia is a common pregnancy disorder which is characterized by new onset hypertension and endothelial dysfunction. Despite efforts to determine the causal factors of this disease, little progress has been made in discerning the etiology. The hypoxic and ischemic placenta, however, is generally accepted as the source for secreted factors in the maternal circulation, such as sFLT-1, which drive the maternal syndrome. METHODS: Using BeWo placental trophoblast cells, we measured the role of hypoxia on sFLT-1 mRNA as well as protein production. We also exposed the cells to treatment with heparin and heparanase inhibitor OGT-2115. RESULTS: We found that under hypoxic conditions mRNA levels of sFLT-1 were unchanged compared to normoxic controls. Although the message level did not differ under hypoxic conditions, the sFLT-1 release into the media was significantly greater in hypoxia. Additionally, we found that sFLT-1 is able to bind heparan strands in the extracellular matrix with its heparin binding site. These heparan strands can be cleaved by the extracellular enzyme heparanase. We found that heparanase expression was significantly increased in hypoxia, and inhibiting the actions of heparanase attenuated the release of sFLT-1 into the media. DISCUSSION: While the placenta remains a source of sFLT-1, the mechanism of increased circulating sFLT-1 may differ than simple upregulation of the protein. These data demonstrate the potential importance of the role heparanase may play in releasing previously made sFLT-1 into the maternal circulation.

Predicting Gambling Situations: The Roles of Impulsivity, Substance Use, and Post-Traumatic Stress.

Gambling disorder and symptoms of post-traumatic stress are highly comorbid. Numerous studies suggest that the presence of one (either disordered gambling or post-traumatic stress) substantially increases the odds of later developing the other. However, little is known about the etiological links between these two domains or the nuances of the comorbidity. Past research has suggested that symptoms of post-traumatic stress might be related to unique motivations for and beliefs about gambling. The present work sought to examine whether or not symptoms of post-traumatic stress might also be related to specific situational vulnerabilities to gambling behaviors. Using a large cross-sectional sample of Internet-using adults in the United States who were primarily recreational gamblers (N = 743; 46% men, Mage = 36.0, SD = 11.1), as well as an inpatient sample of US Armed Forces veterans seeking treatment for gambling disorder (N = 332, 80% men, Mage = 53.5, SD = 11.5), the present work tested whether or not symptoms of post-traumatic stress were uniquely related to a variety of gambling situations. Results in both samples revealed that even when controlling for potentially confounding variables (eg, substance use and trait impulsivity), symptoms of post-traumatic stress were uniquely related to gambling in response to negative affect, gambling in response to social pressure, and gambling due to a need for excitement. These findings are consistent with recent work suggesting that individuals with post-traumatic stress symptoms are more likely to engage in gambling behaviors for unique reasons that differ from gamblers without such symptoms.

PARTIAL HOSPITALIZATION: AN INTERVENTION FOR YOUTH WITH POORLY CONTROLLED DIABETES MELLITUS.

Objective: To examine the efficacy of an integrated medical/psychiatric partial hospitalization program (PHP) to improve glycemic control in youth with both diabetes mellitus and mental health disorders. Methods: This retrospective chart review is of patients admitted to a PHP between 2005-2015 with concerns about diabetes mellitus care. Clinical characteristics, laboratory data, diabetic ketoacidosis hospitalizations, and outpatient clinic visit frequency were collected from the year prior to the year after PHP admission. Results: A total of 43 individuals met inclusion criteria: 22 (51%) were female, 40 (93%) had type 1 diabetes, the mean age was 15.2 ± 2.3 years, and the mean diabetes mellitus duration was 4.6 ± 3.6 years. Of those individuals, 35 of these patients had hemoglobin A1c (HbA1c) data available at baseline, 6 months, and 1 year after PHP. The average HbA1c before PHP admission was 11.3 ± 2.3% (100.5 ± 25 mmol/mol), and decreased to 9.2 ± 1.3% (76.7 ± 14.8 mmol/mol) within 6 months of PHP admission (P<.001). The average HbA1c 1 year after PHP was 10.7 ± 1.7 % (93.3 ± 19.1 mmol/mol). Overall, 24 patients (68%) had lower HbA1c, and 75% of those with improvement maintained an HbA1c reduction of ≥1% (≥10 mmol/mol) at 1 year compared to before PHP. Conclusion: Most patients demonstrated improved glycemic control within 6 months of PHP admission, and many of those maintained a ≥1% (≥10 mmol/mol) reduction in HbA1c at 1 year following PHP admission. This program may represent a promising intervention that could serve as a model for intensive outpatient management of youth with poorly controlled diabetes mellitus. Abbreviations: ADA = American Diabetes Association; DKA = diabetic ketoacidosis; EMR = electronic medical record; HbA1c = hemoglobin A1c; ICD-9 = International Classification of Diseases, 9th revision; PHP = partial hospitalization program.

NAA10 polyadenylation signal variants cause syndromic microphthalmia.

BACKGROUND: A single variant in NAA10 (c.471+2T>A), the gene encoding N-acetyltransferase 10, has been associated with Lenz microphthalmia syndrome. In this study, we aimed to identify causative variants in families with syndromic X-linked microphthalmia. METHODS: Three families, including 15 affected individuals with syndromic X-linked microphthalmia, underwent analyses including linkage analysis, exome sequencing and targeted gene sequencing. The consequences of two identified variants in NAA10 were evaluated using quantitative PCR and RNAseq. RESULTS: Genetic linkage analysis in family 1 supported a candidate region on Xq27-q28, which included NAA10. Exome sequencing identified a hemizygous NAA10 polyadenylation signal (PAS) variant, chrX:153,195,397T>C, c.*43A>G, which segregated with the disease. Targeted sequencing of affected males from families 2 and 3 identified distinct NAA10 PAS variants, chrX:g.153,195,401T>C, c.*39A>G and chrX:g.153,195,400T>C, c.*40A>G. All three variants were absent from gnomAD. Quantitative PCR and RNAseq showed reduced NAA10 mRNA levels and abnormal 3' UTRs in affected individuals. Targeted sequencing of NAA10 in 376 additional affected individuals failed to identify variants in the PAS. CONCLUSION: These data show that PAS variants are the most common variant type in NAA10-associated syndromic microphthalmia, suggesting reduced RNA is the molecular mechanism by which these alterations cause microphthalmia/anophthalmia. We reviewed recognised variants in PAS associated with Mendelian disorders and identified only 23 others, indicating that NAA10 harbours more than 10% of all known PAS variants. We hypothesise that PAS in other genes harbour unrecognised pathogenic variants associated with Mendelian disorders. The systematic interrogation of PAS could improve genetic testing yields.

Post-traumatic stress and gambling related cognitions: Analyses in inpatient and online samples.

Individuals with gambling disorder (GD) report much higher rates of post-traumatic stress symptoms and post-traumatic stress disorder (PTSS/D) than the general population, and individuals with both PTSS/D and GD often report much greater distress and impairment in daily life in comparison to individuals with GD alone (Grubbs, Chapman, Milner, Gutierrez, & Bradley, 2018). Despite these associations, little is known about the specific ways in which PTSS/D and GD might influence each other. To address this gap in research, the present work sought to examine how PTSD might be related to the expression and experience of gambling related cognitions. Specifically, it was hypothesized that individuals with PTSD or symptoms of PTSD (i.e., subclinical levels of post-traumatic stress) would demonstrate greater cognitive distortions and erroneous beliefs about gambling. To test these hypotheses, we analyzed data from two samples, an inpatient sample of U.S. Armed Forces veterans seeking treatment for gambling disorder (n = 332) and an online sample of largely recreational gambling U.S. adults (n = 589). Results consistently revealed that, in both samples, individuals with PTSD or symptoms of PTSD were likely to report greater gambling related cognitions. These findings persisted, even when gambling symptom severity and trait neuroticism were held constant. Collectively, these results suggest that PTSD is uniquely associated with greater cognitive distortions and erroneous beliefs about gambling behaviors. These findings bear distinct implications for current understandings of how PTSS/D and GD are related, as well as for treatment of individuals with dealing with this comorbidity.

Acute Hypoxia and Chronic Ischemia Induce Differential Total Changes in Placental Epigenetic Modifications.

Preeclampsia is a common obstetrical complication, hallmarked by new-onset hypertension. Believed to result from placental insufficiency and chronic placental ischemia, the symptoms of preeclampsia are caused by release of pathogenic factors from the placenta itself, although the mechanisms of their regulation are in many cases unknown. One potential mechanism is through changes in placental epigenetic chromatin modifications, particularly histone acetylation and DNA methylation. Here, we determined the effects of chronic ischemia on global epigenetic modifications in the rodent placenta in vivo and acute hypoxia in BeWo placental trophoblast cells in vitro. Placental insufficiency via uterine artery restriction increased maternal blood pressure and fetal demise while decreasing placental and fetal mass. Global placental histone H3 acetylation levels were significantly decreased at H3 K9, K14, K18, K27, and K56. Interestingly, when BeWo-immortalized placental trophoblast cells were cultured in oxygen concentrations mimicking healthy and ischemic placentas, there was a significant increase in acetylated at K9, K18, K27, and K56. This was associated with a small but significant decrease in placental acetyl-CoA, suggesting depletion in the source of acetyl group donors. Finally, while global methylation of cytosine from placental DNA was low in both groups of animals (<1%), there was ∼50% increase in 5-mC in response to chronic ischemia. This suggests acute hypoxia and chronic ischemia induce differential global changes in histone acetylation in the placenta and that chronically altered metabolic profiles could affect histone acetylation in the placenta, thereby regulating production of pathogenic factors from the placenta during preeclampsia.

Examining links between posttraumatic stress and gambling motives: The role of positive gambling expectancies.

Problem gambling and gambling disorder (GD) are associated with a range of mental health concerns that extend beyond gambling behaviors alone. Prior works have consistently linked gambling disorder with symptoms of posttraumatic stress disorder (PTSD), both cross-sectionally and over time. However, very little work has examined the specific relationships between these 2 disorders. The present work postulated that symptoms of PTSD are likely associated with unique beliefs about gambling behaviors and unique motivations to gamble. Using 2 samples-an inpatient sample of U.S. Armed Forces veterans (N = 332) seeking treatment for GD and a Web-sample of gambling adults (N = 589)-we examined these ideas. Results from both samples indicated that symptoms of PTSD were related to positive gambling expectancies and coping motivations for gambling. Additionally, in both samples, positive gambling expectancies were associated with greater coping motivations for gambling. Structural equation models revealed that positive gambling expectancies were consistently associated with coping motivations for gambling. The findings indicate that symptoms of PTSD are likely associated with unique beliefs about and motivations for gambling behaviors. Given the high comorbidity between symptoms of PTSD and GD, these specific relationships are likely of clinical interest in populations seeking treatment for either PTSD or for problems with gambling behaviors. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Gsx transcription factors control neuronal versus glial specification in ventricular zone progenitors of the mouse lateral ganglionic eminence.

The homeobox gene Gsx2 has previously been shown to inhibit oligodendroglial specification in dorsal lateral ganglionic eminence (dLGE) progenitors of the ventral telencephalon. The precocious specification of oligodendrocyte progenitor cells (OPCs) observed in Gsx2 mutants, however, is transient and begins to normalize by late stages of embryogenesis. Interestingly, this normalization correlates with the expansion of Gsx1, a close homolog of Gsx2, in a subset of progenitors in the Gsx2 mutant LGE. Here, we interrogated the mechanisms underlying oligodendroglial specification in Gsx2 mutants in relation to Gsx1. We found that Gsx1/2 double mutant embryos exhibit a more robust expansion of Olig2+ cells (i.e. OPCs) in the subventricular zone (SVZ) of the dLGE than Gsx2 mutants. Moreover, misexpression of Gsx1 throughout telencephalic VZ progenitors from E15 and onward resulted in a significant reduction of cortical OPCs. These results demonstrate redundant roles of Gsx1 and Gsx2 in suppressing early OPC specification in LGE VZ progenitors. However, Gsx1/2 mutants did not show a significant increase in adjacent cortical OPCs at later stages compared to Gsx2 mutants. This is likely due to reduced proliferation of OPCs within the SVZ of the Gsx1/2 double mutant LGE, suggesting a novel role for Gsx1 in expansion of migrating OPCs in the ventral telencephalon. We further investigated the glial specification mechanisms downstream of Gsx2 by generating Olig2/Gsx2 double mutants. Consistent with the known essential role for Olig2 in OPC specification, ectopic production of cortical OPCs observed in Gsx2 mutants disappeared in Olig2/Gsx2 double mutants. These mutants, however, maintained the expanded expression of gliogenic markers Zbtb20 and Bcan in the VZ of the LGE similarly to Gsx2 single mutants, suggesting that Gsx2 suppresses gliogenesis via Olig2-dependent and -independent mechanisms.

Medical Considerations in Children and Adolescents with Eating Disorders.

Eating disorders are a group of psychiatric disorders with potentially fatal medical complications. Early integrated care including the family as well as pediatric medicine, nutrition, psychology and psychiatry is critical for improving prognosis and limiting negative outcomes. Mental health services are a critical component of treatment; timely weight restoration maximizes efficacy. Despite being relatively common, there are many misperceptions about eating disorders, their severity, and the associated morbidity and mortality. Opportunities exist within the medical and psychiatric communities for a better understanding of the complexity of diagnosing and treating patients with eating disorders.

A Maternally Sequestered, Biopolymer-Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia.

BACKGROUND: Preeclampsia is a hypertensive syndrome that complicates 3% to 5% of pregnancies in the United States. Preeclampsia originates from an improperly vascularized and ischemic placenta that releases factors that drive systemic pathophysiology. One of these factors, soluble fms-like tyrosine kinase-1, is believed to sequester vascular endothelial growth factor (VEGF), leading to systemic endothelial dysfunction and hypertension. With the goal of targeting soluble fms-like tyrosine kinase-1 while simultaneously preventing fetal exposure to VEGF, we fused VEGF to elastin-like polypeptide, a biopolymer carrier that does not cross the placental barrier (ELP-VEGF). METHODS AND RESULTS: ELP-VEGF restored in vitro endothelial cell tube formation in the presence of plasma from placental ischemic rats. Long-term administered ELP-VEGF in pregnant rats accumulated in maternal kidneys, aorta, liver, and placenta, but the protein was undetectable in the pups when administered at therapeutic doses in dams. Long-term administration of ELP-VEGF in a placental ischemia rat model achieved dose-dependent attenuation of hypertension, with blood pressure equal to sham controls at a dose of 5 mg/kg per day. ELP-VEGF infusion increased total plasma soluble fms-like tyrosine kinase-1 levels but dramatically reduced free plasma soluble fms-like tyrosine kinase-1 and induced urinary excretion of nitrate/nitrite, indicating enhanced renal nitric oxide signaling. ELP-VEGF at up to 5 mg/kg per day had no deleterious effect on maternal or fetal body weight. However, dose-dependent adverse events were observed, including ascites production and neovascular tissue encapsulation around the minipump. CONCLUSIONS: ELP-VEGF has the potential to treat the preeclampsia maternal syndrome, but careful dosing and optimization of the delivery route are necessary.

Reliability, Validity, and Classification Accuracy of the DSM-5 Diagnostic Criteria for Gambling Disorder and Comparison to DSM-IV.

The DSM-5 was published in 2013 and it included two substantive revisions for gambling disorder (GD). These changes are the reduction in the threshold from five to four criteria and elimination of the illegal activities criterion. The purpose of this study was to twofold. First, to assess the reliability, validity and classification accuracy of the DSM-5 diagnostic criteria for GD. Second, to compare the DSM-5-DSM-IV on reliability, validity, and classification accuracy, including an examination of the effect of the elimination of the illegal acts criterion on diagnostic accuracy. To compare DSM-5 and DSM-IV, eight datasets from three different countries (Canada, USA, and Spain; total N = 3247) were used. All datasets were based on similar research methods. Participants were recruited from outpatient gambling treatment services to represent the group with a GD and from the community to represent the group without a GD. All participants were administered a standardized measure of diagnostic criteria. The DSM-5 yielded satisfactory reliability, validity and classification accuracy. In comparing the DSM-5 to the DSM-IV, most comparisons of reliability, validity and classification accuracy showed more similarities than differences. There was evidence of modest improvements in classification accuracy for DSM-5 over DSM-IV, particularly in reduction of false negative errors. This reduction in false negative errors was largely a function of lowering the cut score from five to four and this revision is an improvement over DSM-IV. From a statistical standpoint, eliminating the illegal acts criterion did not make a significant impact on diagnostic accuracy. From a clinical standpoint, illegal acts can still be addressed in the context of the DSM-5 criterion of lying to others.

Synergistic defects of different molecules in the cytotoxic pathway lead to clinical familial hemophagocytic lymphohistiocytosis.

Several molecules (LYST, AP3, RAB27A, STX11, STXBP2, MUNC13-4, and PRF1) have been associated with the function of cytotoxic lymphocytes. Biallelic defects in all of these molecules have been associated with familial hemophagocytic lymphohistiocytosis (FHL). We retrospectively reviewed the genetic and immunology test results from 2701 patients with a clinically suspected diagnosis of hemophagocytic lymphohistiocytosis and found 28 patients with single heterozygous mutations in 2 FHL-associated genes. Of these patients, 21 had mutations within PRF1 and a degranulation gene, and 7 were found to have mutations within 2 genes involved in the degranulation pathway. In patients with combination defects involving 2 genes in the degranulation pathway, CD107a degranulation was decreased, comparable to patients with biallelic mutations in one of the genes in the degranulation pathway. This suggests a potential digenic mode of inheritance of FHL as a result of a synergistic function effect within genes involved in cytotoxic lymphocyte degranulation.