Systematic review of depression and suicidality in child and adolescent (CAP) refugees
Child adversity and trauma has been shown to have incredible detrimental effects physically and mentally in the subsequent adult life. Importantly, refugee minors are especially vulnerable to trauma. Thus far there are numerous studies examining cohorts of child and adolescent refugees and their impact on mental health in general and post-traumatic stress disorder (PTSD), but none have focused specifically on depression and suicide.Â The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed for the current systematic review. 25 articles out of 2660 queried were identified to be included in the review. Overall, CAP refugees have increased risk for major depressive disorder and suicidality compared to the general population to which they have immigrated, regardless of origin. Due to the differences in the assessment tools used, it is hard to parse out if mood disturbance was secondary to major depressive disorder (MDD) or PTSD, or that suicidality is independent or a sequela of MDD/PTSD. Given the vulnerability of CAP refugees after trauma future studies are needed to further elucidate their risk of concurrent depression and suicidality, so as to facilitate appropriate treatment.
Pharmacokinetic implications leading to marked valproic acid level-drop during COVID-19 treatment [Letter]
COVID-19 Pandemic: Impact on psychiatric care in the United States
The World Health Organization declared the coronavirus outbreak a pandemic on March 11, 2020. Infection by the SARS-CoV2 virus leads to the COVID-19 disease which can be fatal, especially in older patients with medical co-morbidities. The impact to the US healthcare system has been disruptive, and the way healthcare services are provided has changed drastically. Here, we present a compilation of the impact of the COVID-19 pandemic on psychiatric care in the US, in the various settings: outpatient, emergency room, inpatient units, consultation services, and the community. We further present effects seen on psychiatric physicians in the setting of new and constantly evolving protocols where adjustment and flexibility have become the norm, training of residents, leading a team of professionals with different expertise, conducting clinical research, and ethical considerations. The purpose of this paper is to provide examples of "how to" processes based on our current front-line experiences and research to practicing psychiatrists and mental health clinicians, inform practitioners about national guidelines affecting psychiatric care during the pandemic, and inform health care policy makers and health care systems about the challenges and continued needs of financial and administrative support for psychiatric physicians and mental health systems.
Hypertensive Urgency and Emergency in Alcohol Withdrawal: A Literature Review
Objective/UNASSIGNED:To help clinicians recognize that hypertension, hypertensive urgency, and hypertensive emergency can arise in patients detoxifying from alcohol. Diagnostic and treatment implications are reviewed to help clinicians manage blood pressure in these situations. Data Sources/UNASSIGNED:PubMed was searched with no restrictions on publication date or study type in June 2019 using the terms (alcohol withdrawal) AND hypertension. Study Selection/UNASSIGNED:Of 531 studies retrieved, all were reviewed, and articles older than 20 years were excluded. Of the remaining 158 articles, all were reviewed by full-text reading, and 17 were selected based on relevance. Seven UpToDate articles and 2 older papers were also included for relevance. Data Extraction/UNASSIGNED:Various other searches were also performed; however, no relevant hits resulted when the following terms were entered: (hypertensive urgency/emergency) AND alcohol withdrawal OR detoxification; (hypertensive urgency/emergency) AND (alcohol withdrawal OR detoxification) AND treatment-resistant hypertension. Results/UNASSIGNED:Hypertension is typically self-limited in alcohol withdrawal syndrome; however, treatment is important to prevent hypertensive urgency or emergency. There is a paucity of data on how best to manage hypertension in patients withdrawing from alcohol, with treatment often individualized. Patients with underlying treatment-resistant hypertension may have more difficult-to-control blood pressure, especially in the first 24 hours of withdrawal. Conclusions/UNASSIGNED:Multiple medications may be used to treat hypertension in the setting of alcohol withdrawal, with selection based on side effect profile and the patient's other comorbidities. In patients for whom there is concern for hypertensive urgency versus emergency, full medical evaluation is indicated to identify any potential end-organ damage.
Meloxicam-desmopressin drug-drug interaction producing hyponatremia [Case Report]
BACKGROUND:People with schizophrenia and medical comorbidities are often on multiple medications to manage their symptoms. Herein we present a case of drug-drug interaction (meloxicam and desmopressin), in a patient also on clozapine, that ultimately resulted in hyponatremia and seizure. METHODS:The patient provided consent to have his case published. We searched PubMed and after reviewing 321 articles, 11 were chosen for relevance. RESULTS:Meloxicam enhanced the adverse effect (hyponatremia) of desmopressin and was the likely culprit. CONCLUSIONS:In a patient with higher ADH levels, as in our patient taking desmopressin, the addition of an NSAID could further increase water retention and worsen hyponatremia; indeed, meloxicam was the only new medication added to the patient's regimen, and a drug interaction calculator supports the desmopressin-meloxicam drug-drug interaction as the culprit. We urge clinicians to avoid the use of desmopressin in patients with schizophrenia as this can lead to water intoxication. As meloxicam may worsen desmopressin-induced hyponatremia and could result in seizure, one should avoid using NSAIDs in patients with schizophrenia whom are also prescribed vasopressin/desmopressin. Serum sodium levels should be closely monitored in patients with schizophrenia whose regimen includes desmopressin.
Hypercalcemia and Psychosis: Case Report, Review of the Literature, and Management Considerations [Case Report]
The objective of this article is to help clinicians make an accurate diagnosis by considering hypercalcemia as a potential cause of psychosis. A patient case is presented, along with a review of the literature dissecting the association between calcium and psychiatric symptoms. Clinical implications and suggestions for management of hypercalcemia and psychosis in the setting of primary hyperparathyroidism are provided.
Identification of RASAL1 as a major tumor suppressor gene in thyroid cancer
BACKGROUND:RAS-coupled MAPK and PI3K pathways play a fundamental role in thyroid tumorigenesis, and classical genetic alterations upregulating these pathways are well characterized. We hypothesized that gene abnormality of negative modulators of these signaling pathways might be an important alternative genetic background for thyroid cancer. METHODS:By examining gene expression patterns of negative modulators of RAS signaling, we attempted to identify potential tumor suppressor genes. We then analyzed the methylation and mutation patterns of the identified gene in 101 thyroid tumors and tested its functions in vitro and in vivo to establish the tumor suppressor role in thyroid cancer. RESULTS:Among 13 negative modulators of the RAS pathway screened, RASAL1, encoding a RAS GTPase-activating protein, was frequently hypermethylated in thyroid cancers, which was coupled to its silencing in thyroid cancer cells. We also, for the first time, identified the presence of RASAL1 mutations, with a prevalence of 4.88% (n = 2 of 41) in follicular thyroid cancer (FTC) and 16.67% (n = 5 of 30) in anaplastic thyroid cancer (ATC). RASAL1 displayed MAPK- and PI3K-suppressing and thyroid tumor-suppressing activities, which were all impaired by the mutations. Hypermethylation and mutations of RASAL1 were mutually exclusive and collectively found in zero of 20 benign thyroid tumors, 3.22% (n = 1 of 31) of papillary thyroid cancers, 31.70% (n = 13 of 41) of FTCs, and 33.33% (n = 10 of 30) of ATCs. A rate of 20.83% (n = 5 of 24) of tumors carrying RASAL1 mutation or methylation at high levels (>50%) vs 44.16% (n = 34 of 77) of tumors carrying no RASAL1 mutation or methylation at low levels (< 50%) harbored any of the classical mutations (two-sided P = .02, Fisher exact test) in RAS, BRAF, PTEN, and PIK3CA genes in the MAPK and PI3K pathways, revealing a largely mutually exclusive relationship. CONCLUSIONS:We identified RASAL1 as a major tumor suppressor gene that is frequently inactivated by hypermethylation and mutations, providing a new alternative genetic background for thyroid cancer, particularly FTC and ATC.
The Akt-specific inhibitor MK2206 selectively inhibits thyroid cancer cells harboring mutations that can activate the PI3K/Akt pathway
CONTEXT/BACKGROUND:The phosphoinositide 3-kinase (PI3K)/Akt pathway is widely postulated to be an effective therapeutic target in thyroid cancer. OBJECTIVE:The aim of the study was to test the therapeutic potential of the novel Akt inhibitor MK2206 for thyroid cancer. DESIGN/METHODS:We examined the effects of MK2206 on thyroid cancer cells with respect to the genotypes of the PI3K/Akt pathway. RESULTS:Proliferation of thyroid cancer cells OCUT1, K1, FTC133, C643, Hth7, and TPC1, which harbored PIK3CA, PTEN, Ras, or RET/PTC mutations that could activate the PI3K/Akt pathway, was potently inhibited by MK2206 with IC(50) values mostly below or around 0.5 Î¼m. In contrast, no potent inhibition by MK2206 was seen in most of the Hth74, KAT18, SW1736, WRO, and TAD2 cells that did not harbor mutations in the PI3K/Akt pathway. The inhibition efficacy was also genetic-selective. Specifically, the average inhibition efficacies were 59.2 Â± 11.3 vs. 36.4 Â± 8.8% (P = 0.005) at 1 Î¼m MK2206 and 64.4 Â± 11.5 vs. 38.5 Â± 18.9% (P = 0.02) at 3 Î¼m MK2206 for cells with mutations vs. cells without. The SW1736 cell, lacking mutations in the PI3K/Akt pathway, had minimal response to MK2206, but transfection with exogenous PIK3CA mutants, PIK3CA H1047R and E545K, significantly increased its sensitivity to MK2206. MK2206 also completely overcame the feedback activation of Akt from temsirolimus-induced mammalian target of rapamycin suppression, and the two inhibitors synergistically inhibited thyroid cancer cell growth. CONCLUSIONS:Our study demonstrates a genetic selectivity of MK2206 in inhibiting thyroid cancer cells by targeting the PI3K/Akt pathway, supporting a clinical trial in thyroid cancer.
IQGAP1 plays an important role in the invasiveness of thyroid cancer
PURPOSE/OBJECTIVE:This study was designed to explore the role of IQGAP1 in the invasiveness of thyroid cancer and its potential as a novel prognostic marker and therapeutic target in this cancer. EXPERIMENTAL DESIGN/METHODS:We examined IQGAP1 copy gain and its relationship with clinicopathologic outcomes of thyroid cancer and investigated its role in cell invasion and molecules involved in the process. RESULTS:We found IQGAP1 copy number (CN) gain â‰¥ 3 in 1 of 30 (3%), 24 of 74 (32%), 44 of 107 (41%), 8 of 16 (50%), and 27 of 41 (66%) of benign thyroid tumor, follicular variant papillary thyroid cancer (FVPTC), follicular thyroid cancer (FTC), tall cell papillary thyroid cancer (PTC), and anaplastic thyroid cancer, respectively, in the increasing order of invasiveness of these tumors. A similar tumor distribution trend of CN â‰¥ 4 was also seen. IQGAP1 copy gain was positively correlated with IQGAP1 protein expression. It was significantly associated with extrathyroidal and vascular invasion of FVPTC and FTC and, remarkably, a 50%-60% rate of multifocality and recurrence of BRAF mutation-positive PTC (P = 0.01 and 0.02, respectively). The siRNA knockdown of IQGAP1 dramatically inhibited thyroid cancer cell invasion and colony formation. Coimmunoprecipitation assay showed direct interaction of IQGAP1 with E-cadherin, a known invasion-suppressing molecule, which was upregulated when IQGAP1 was knocked down. This provided a mechanism for the invasive role of IQGAP1 in thyroid cancer. In contrast, IQGAP3 lacked all these functions. CONCLUSIONS:IQGAP1, through genetic copy gain, plays an important role in the invasiveness of thyroid cancer and may represent a novel prognostic marker and therapeutic target for this cancer.
Identification and functional characterization of isocitrate dehydrogenase 1 (IDH1) mutations in thyroid cancer
Mutations in the genes for isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) have been recently identified in glioblastoma. In the present study, we investigated IDH1 and IDH2 mutations in follicular thyroid cancer (FTC) and anaplastic thyroid cancer (ATC), with the latter, like glioblastoma, having a rapidly aggressive and lethal clinical course. By direct genomic DNA sequencing, we analyzed exon 4 of the IDH1 and IDH2 genes that harbored the mutation hot spots codon 132 and 172 of the two genes in glioblastoma, respectively, in 12 thyroid cancer cell lines, 20 FTC, and 18 ATC tumor samples. A novel homozygous G367A IDH1 mutation, resulting in a G123R amino acid change in codon 123, was identified in a case of ATC. A previously described IDH1 V71I mutation was found in a case of FTC and a case of ATC and no mutations were found in the cell lines. The overall prevalence of mutations was thus 1/20 (5%) in FTC and 2/18 (11%) in ATC. We did not find mutation in the IDH2 gene in these thyroid cancer cell lines and tumor samples. Sequence alignment analysis of 16 species revealed that the novel IDH1 G123R mutation was located in a highly conserved region, raising the possibility of a serious functional consequence as could also be predicted by the occurrence of a positively charged amino acid from this mutation. To test this, we created a G123R mutant by site-directed mutagenesis and demonstrated a decreased enzymatic activity of IDH1, similar to the expected reduction in the enzymatic activity of the previously described R132H IDH1 mutant measured as a control. Thus, functionally relevant IDH1 mutations can also occur in thyroid cancer, particularly ATC, suggesting a potential tumorigenic role of the IDH1 system that could represent a new therapeutic target for thyroid cancer.