It is unknown whether the Somali population in the US is likely to participate in HPV vaccination. We aimed to determine whether Somali girls living in a US community are following the recommendations for HPV vaccination.
Materials and Methods
We conducted a study of HPV vaccination among Somali girls seen at Mayo Clinic, Rochester, Minnesota. Each Somali subject was matched by year of birth to white/non-Hispanic subjects in a 1:3 ratio. We abstracted information between August 1, 2006 and December 31, 2009 related to HPV vaccine series initiation and completion. Initiation and completion frequencies were compared between study groups using the Chi-squared test.
A total of 251 Somali and 727 white/non-Hispanic girls were identified using the Rochester Epidemiology Project who met all inclusion criteria for final analysis. 114 Somali girls (45%) and 334 white/non-Hispanic girls (46%) initiated the series (odds ratio, 0.98; 95% CI, 0.73–1.31), but only 59 Somali girls (52%) completed the vaccination series, compared with 240 (72%) of the white/non-Hispanic girls (odds ratio, 0.42; 95% CI, 0.27–0.65).
We found Somali girls to be generally accepting of initiating the HPV vaccine series, but less likely to complete the series as compared to white non-Hispanic girls of the same age.
Papillomavirus Vaccines; Uterine Cervical Neoplasms; Somalia; Emigrants and Immigrants; Sexually Transmitted Diseases
As part of the NIH-sponsored Glucosamine/Chondroitin Sulfate Arthritis Intervention Trial (GAIT) our objective here was to examine 1) the pharmacokinetics (PK) of glucosamine (GlcN) and chondroitin sulfate (CS) when taken separately or in combination as a single dose in normal individuals (n=29) and 2) the PK of GlcN and CS when taken as a single dose after 3 months daily dosing with GlcN, CS or GlcN+CS, in patients with symptomatic knee pain (n=28).
The concentration of GlcN in the circulation was determined by established fluorophore-assisted carbohydrate electrophoresis (FACE) methods. The hydrodynamic size and disaccharide composition of CS chains in the circulation and dosage samples was determined by Superose 6 chromatography and FACE.
We show that circulating levels of CS in human plasma are about 20ug/ml. Most significantly, the endogenous concentration and CS disaccharide composition were not detectably altered by ingestion of CS, when the CS was taken alone or in combination with GlcN. On the other hand, the Cmax (single dose study) and AUC values (multiple dose study) for ingested GlcN were significantly reduced by combination dosing with CS, relative to GlcN dosing alone.
We conclude that pain relief perceived following ingestion of CS probably does not depend on simultaneous or prior intake of GlcN. Further, such effects on joint pain, if present, probably do not result from ingested CS reaching the joint space but may result from changes in cellular activities in the gut lining or in the liver, where concentrations of ingested CS, or its breakdown products, could be substantially elevated following oral ingestion. Moreover, since combined dosing of GlcN with CS was found to reduce the plasma levels seen with GlcN dosing alone, any improved pain relief by combination dosing cannot be explained by higher circulating concentrations of GlcN.
Drug detoxification and long-term drug treatment utilization is lower for drug-dependent minorities than Whites. Log-binomial regression was used to assess discrimination and neighborhood-level factors on past 6-month drug treatment utilization among 638 New York City (NYC) drug users between 2006 and 2009. Drug-use discrimination was positively associated with detoxification and long-term treatment. Participants in higher concentrated Black neighborhoods were less likely to attend long-term treatment. Significantly fewer Blacks versus Whites and Hispanics reported drug-use discrimination, which may systematically filter drug users into treatment. More research is needed to understand social forms of discrimination and drug treatment.
discrimination; neighborhood; race/ethnicity; drug treatment; urban health
Transcranial magnetic stimulation (TMS) has shown promise as a treatment tool, with one FDA approved use. While TMS alone is able to up- (or down-) regulate a targeted neural system, we argue that TMS applied as an adjuvant is more effective for repetitive physical, behavioral and cognitive therapies, that is, therapies which are designed to alter the network properties of neural systems through Hebbian learning. We tested this hypothesis in the context of a slow motor learning paradigm. Healthy right-handed individuals were assigned to receive 5 Hz TMS (TMS group) or sham TMS (sham group) to the right primary motor cortex (M1) as they performed daily motor practice of a digit sequence task with their non-dominant hand for 4 weeks. Resting cerebral blood flow (CBF) was measured by H215O PET at baseline and after 4 weeks of practice. Sequence performance was measured daily as the number of correct sequences performed, and modeled using a hyperbolic function. Sequence performance increased significantly at 4 weeks relative to baseline in both groups. The TMS group had a significant additional improvement in performance, specifically, in the rate of skill acquisition. In both groups, an improvement in sequence timing and transfer of skills to non-trained motor domains was also found. Compared to the sham group, the TMS group demonstrated increases in resting CBF specifically in regions known to mediate skill learning namely, the M1, cingulate cortex, putamen, hippocampus, and cerebellum. These results indicate that TMS applied concomitantly augments behavioral effects of motor practice, with corresponding neural plasticity in motor sequence learning network. These findings are the first demonstration of the behavioral and neural enhancing effects of TMS on slow motor practice and have direct application in neurorehabilitation where TMS could be applied in conjunction with physical therapy.
TMS; Primary motor cortex; Motor learning; Digit sequence practice; Hebbian learning; Hyperbolic function; Motor system; Skill transfer; Motor learning network
Overexpression of SLMAP gene has been associated with diabetes and endothelial dysfunction of macro- and micro-blood vessels. In this study our primary objective is to explore the role of SLMAP gene polymorphisms in the susceptibility of type 2 diabetes (T2DM) with or without diabetic retinopathy (DR) in the Qatari population.
A total of 342 Qatari subjects (non-diabetic controls and T2DM patients with or without DR) were genotyped for SLMAP gene polymorphisms (rs17058639 C > T; rs1043045 C > T and rs1057719 A > G) using Taqman SNP genotyping assay.
SLMAP rs17058639 C > T polymorphism was associated with the presence of DR among Qataris with T2DM. One-way ANOVA and multiple logistic regression analysis showed SLMAP SNP rs17058639 C > T as an independent risk factor for DR development. SLMAP rs17058639 C > T polymorphism also had a predictive role for the severity of DR. Haplotype Crs17058639Trs1043045Ars1057719 was associated with the increased risk for DR among Qataris with T2DM.
The data suggests the potential role of SLMAP SNPs as a risk factor for the susceptibility of DR among T2DM patients in the Qatari population.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-015-0411-6) contains supplementary material, which is available to authorized users.
SLMAP; Endothelial dysfunction; Genetic susceptibility; Qatari population; Diabetic retinopathy; T2DM
Homeostatic B Cell-Attracting chemokine 1 (BCA-1) otherwise known as CXCL13 is constitutively expressed in secondary lymphoid organs by follicular dendritic cells (FDC) and macrophages. It is the only known ligand for the CXCR5 receptor, which is expressed on mature B cells, follicular helper T cells (Tfh), Th17 cells and regulatory T (Treg) cells. Aberrant expression of CXCL13 within ectopic germinal centers has been linked to the development of autoimmune disorders (e.g. Rheumatoid Arthritis, Multiple Sclerosis, Systemic Lupus Erythematosis). We, therefore, hypothesized that antibody-mediated disruption of the CXCL13 signaling pathway would interfere with the formation of ectopic lymphoid follicles in the target organs and inhibit autoimmune disease progression. This work describes pre-clinical development of human anti-CXCL13 antibody MAb 5261 and includes therapeutic efficacy data of its mouse counterpart in murine models of autoimmunity.
We developed a human IgG1 monoclonal antibody, MAb 5261 that specifically binds to human, rodent and primate CXCL13 with an affinity of approximately 5 nM and is capable of neutralizing the activity of CXCL13 from these various species in in vitro functional assays. For in vivo studies we have engineered a chimeric antibody to contain the same human heavy and light chain variable genes along with mouse constant regions. Treatment with this antibody led to a reduction in the number of germinal centers in mice immunized with 4-Hydroxy-3-nitrophenylacetyl hapten conjugated to Keyhole Limpet Hemocyanin (NP-KLH) and, in adoptive transfer studies, interfered with the trafficking of B cells to the B cell areas of mouse spleen. Furthermore, this mouse anti-CXCL13 antibody demonstrated efficacy in a mouse model of Rheumatoid arthritis (Collagen-Induced Arthritis (CIA)) and Th17-mediated murine model of Multiple Sclerosis (passively-induced Experimental Autoimmune Encephalomyelitis (EAE)).
We developed a novel therapeutic antibody targeting CXCL13-mediated signaling pathway for the treatment of autoimmune disorders.
CXCL13; Chemokine; Monoclonal antibody; Collagen-induced arthritis; Experimental autoimmune encephalomyelitis
The viral reservoir represents a critical challenge facing HIV-1 eradication strategies1–5. However, it remains unclear when and where the viral reservoir is seeded during acute infection and the extent to which it is susceptible to early antiretroviral therapy (ART). Here we show that the viral reservoir is seeded very early following mucosal SIV infection of rhesus monkeys and prior to systemic viremia. We initiated suppressive ART in groups of monkeys on days 3, 7, 10, and 14 following intrarectal SIVmac251 infection. Treatment on day 3 blocked the emergence of viral RNA and proviral DNA in peripheral blood and also substantially reduced levels of proviral DNA in lymph nodes and gastrointestinal mucosa as compared with treatment at later timepoints. In addition, treatment on day 3 abrogated the induction of SIV-specific humoral and cellular immune responses. Nevertheless, following discontinuation of ART after 24 weeks of fully suppressive therapy, virus rebounded in all animals, although animals treated on day 3 exhibited a delayed viral rebound as compared with animals treated on days 7, 10 and 14. The time to viral rebound correlated with total viremia during acute infection and with proviral DNA at the time of ART discontinuation. These data demonstrate that the viral reservoir is seeded very early following intrarectal SIV infection of rhesus monkeys, during the “eclipse” phase, and prior to viremia. This strikingly early seeding of the refractory viral reservoir raises important new challenges for HIV-1 eradication strategies.
The catalytic moiety of Pseudomonas exotoxin A (domain III or PE3) inhibits protein synthesis by ADP-ribosylation of eukaryotic elongation factor 2 (eEF2). PE3 is widely used as a cytocidal payload in receptor-targeted protein toxin conjugates. We have designed and characterized catalytically inactive fragments of PE3 that are capable of structural complementation. We dissected PE3 at an extended loop and fused each fragment to one subunit of a heterospecific coiled coil. In vitro ADP-ribosylation and protein translation assays demonstrate that the resulting fusions — supplied exogenously as genetic elements or purified protein fragments — had no significant catalytic activity or effect on protein synthesis individually, but in combination catalyzed the ADP-ribosylation of eEF2 and inhibited protein synthesis. Although complementing PE3 fragments are less efficient catalytically than intact PE3 in cell-free systems, co-expression in live cells transfected with transgenes encoding the toxin fusions inhibits protein synthesis and causes cell death comparably as intact PE3. Complementation of split PE3 offers a direct extension of the immunotoxin approach to generate bispecific agents that may be useful to target complex phenotypes.
exotoxin A; structural complementation; ADP-ribosylation; elongation factor 2; cytotoxicity
Chikungunya virus (CHIKV) and o’nyong nyong virus (ONNV) are mosquito-borne alphaviruses endemic in East Africa that cause acute febrile illness and arthritis. The objectives of this study were to measure the seroprevalence of CHIKV and ONNV in coastal Kenya and link it to demographics and other risk factors.
Demographic and exposure questionnaires were administered to 1,848 participants recruited from two village clusters (Milalani-Nganja and Vuga) in 2009. Sera were tested for alphavirus exposure using standardized CHIKV IgG ELISA protocols and confirmed with plaque reduction neutralization tests (PRNT). Logistic regression models were used to determine the variables associated with seropositivity. Weighted K test for global clustering of houses with alphavirus positive participants was performed for distance ranges of 50–1,000 meters, and G* statistic and kernel density mapping were used to identify locations of higher seroprevalence.
486 (26%) participants were seropositive by IgG ELISA. Of 443 PRNT confirmed positives, 25 samples (6%) were CHIKV+, 250 samples (56%) were ONNV+, and 168 samples (38%) had high titers for both. Age was significantly associated with seropositivity (OR 1.01 per year, 95% C.I. 1.00–1.01); however, younger adults were more likely to be seropositive than older adults. Males were less likely to be seropositive (p<0.05; OR 0.79, 95% C.I. 0.64–0.97). Adults who owned a bicycle (p<0.05; OR 1.37, 95% C.I. 1.00–1.85) or motor vehicle (p<0.05; OR 4.64, 95% C.I. 1.19–18.05) were more likely to be seropositive. Spatial analysis demonstrated hotspots of transmission within each village and clustering among local households in Milalani-Nganja, peaking at the 200–500m range.
Alphavirus exposure, particularly ONNV exposure, is common in coastal Kenya with ongoing interepidemic transmission of both ONNV and CHIKV. Women and adults were more likely to be seropositive. Household location may be a defining factor for the ecology of alphaviral transmission in this region.
Alphaviruses, such as chikungunya and o’nyong nyong viruses, are likely important causes of human disease in endemic regions, but are often misdiagnosed as malaria in the acute care setting. Our objective was to uncover the burden of alphavirus exposure in our study region, rural coastal Kenya. Of 1848 participants tested, 26% were seropositive by screening ELISA, demonstrating intense transmission to humans in this area. Surprisingly, confirmatory PRNT testing revealed that the majority of alphavirus exposures were due to o’nyong nyong virus, rather than chikungunya virus. Both CHIKV and ONNV antibodies were confirmed in young children, demonstrating undocumented and ongoing transmission in this region. Of the examined risk factors, older age and female gender were associated with alphavirus seropositivity.
A first analysis of the genome sequence of the common marmoset (Callithrix jacchus), assembled using traditional Sanger methods and Ensembl annotation, has permitted genomic comparison with apes and that old world monkeys and the identification of specific molecular features a rapid reproductive capacity partly due to may contribute to the unique biology of diminutive The common marmoset has prevalence of this dizygotic primate. twins. Remarkably, these twins share placental circulation and exchange hematopoietic stem cells in utero, resulting in adults that are hematopoietic chimeras.
We observed positive selection or non-synonymous substitutions for genes encoding growth hormone / insulin-like growth factor (growth pathways), respiratory complex I (metabolic pathways), immunobiology, and proteases (reproductive and immunity pathways). In addition, both protein-coding and microRNA genes related to reproduction exhibit rapid sequence evolution. This New World monkey genome sequence enables significantly increased power for comparative analyses among available primate genomes and facilitates biomedical research application.
Surgical safety checklists (SSCs) are designed to improve team communication and consistency in care, ultimately avoiding complications. In Colorado, hospitals reported that use of SSCs was standard practice, but a statewide survey indicated that SSC use was inconsistent. The purpose of this project was to directly observe the compliance with the SSC in Colorado hospitals, through direct observation of the perioperative checklist process.
Ten hospitals participated in a quality improvement initiative. Trained team members recorded compliance with each of the components of the SSC. Data analysis was performed using a chi-squared test or ANOVA, depending on the number of categorical variables, with p < 0.05 determining statistical significance.
Ten hospitals representing statewide diversity submitted 854 observations (median 98, range 24–106). 83% of cases were elective, 13% urgent, and 4% emergent/trauma. There was significant variation across hospitals in: team introductions, cessation of activity, affirming correct procedure, assessing hypothermia risk, need for beta blocker, or VTE prophylaxis. Uniformly poor compliance was observed with respect to assessment of case duration, blood loss, anesthesiologists’ concerns, or display of essential imaging. Only 71% of observers reported active participation by physicians; 9% reported that “the majority did not pay attention” and 4% reported that the team was “just going through the motions”. There were significant differences among surgical specialty groups in the majority of the elements.
SSCs have been implemented by the vast majority of hospitals in our state; however, compliance with SSC completion in the operating room has wide variation and is generally suboptimal. Although this study was not designed to correlate SSC compliance with outcomes, there are concerns about the risk of a sentinel event or unanticipated complication resulting from poor preparation.
Checklist; Surgery; Safety; Compliance; Observation; Implementation; Surgeons; Operating room; Sentinel events
Black men suffer disproportionately from hypertension (HTN). Antihypertensive medication non-adherence is a major contributor to poor blood pressure control, yet few studies consider how psychosocial functioning may impact Black men’s medication adherence. We examined direct and mediating pathways between depressive symptoms, psychosocial stressors, and substance use on antihypertensive medication non-adherence in 196 Black men enrolled in a clinical trial to improve HTN care and control. We found that greater depressive symptoms was associated with more medication non-adherence (β= 0.05, SE 0.01; p<.001). None of the psychosocial stressor variables were associated with antihypertensive medication non-adherence. Alcohol misuse was associated with more medication non-adherence (β=0.81, SE 0.26; p<.01), but it did not mediate the association between depressive symptoms and medication non-adherence. Clinicians should consider screening for depressive symptoms and alcohol misuse if patients are found to be non-adherent and should treat or refer patients to appropriate resources to address those issues.
Medication Adherence; Hypertension; Black men; Psychosocial factors
Due to the high risk of life-threatening side effects, nonsteroidal anti-inflammatory drugs (NSAIDs) are not favored for treating persistent nonmalignant pain in the elderly. We report national prescription trends with determinants of NSAIDs prescription for persistent nonmalignant pain among older patients (age 65 and over) in the US outpatient setting.
A cross-sectional analysis was performed using National Ambulatory Medical Care Survey data. Prescriptions for NSAIDs, opioids, and adjuvant agents were identified using five-digit National Ambulatory Medical Care Survey drug codes.
About 89% of the 206,879,848 weighted visits in the US from 2000 to 2007 recorded NSAIDs prescriptions in patients (mean age =75.4 years). Most NSAIDs users had Medicare (75%), and about 25% were prescribed with adjuvant medications considered inappropriate for their age. Compared to men, women were 1.79 times more likely to be prescribed NSAIDs.
The high percentage of NSAIDs prescription in older patients is alarming. We recommend investigating the appropriateness of the high prevalence of NSAIDs use among older patients reported in our study.
pain management; NSAIDs; inappropriate adjuvant; AGS guideline; NAMCS
The advent of highly active antiretroviral therapy has prolonged the life expectancy of HIV patients and decreased the number of adults who progress to AIDS and HIV-associated dementia. However, neurocognitive deficits remain a pronounced consequence of HIV/AIDS. HIV-1 infection targets the central nervous system in subcortical brain areas and leads to high rates of delirium, depression, opportunistic central nervous system infections, and dementia. Long-term HIV replication in the brain occurs in astrocytes and microglia, allowing the virus to hide from antiviral medication and later compromise neuronal function. The associated cognitive disturbance is linked to both viral activity and inflammatory and other mediators from these immune cells that lead to the damage associated with HIV-associated neurocognitive disorders, a general term given for these disturbances. We review the severity and prevalence of the neuropsychiatric complications of HIV including delirium, neurobehavioral impairments (depression), minor cognitive-motor dysfunction, and HIV-associated dementia.
HIV; delirium; depression; HAND; dementia; HIV-associated neurocognitive disorder
Despite the importance of disseminating the results of community-based participatory research (CBPR), community health partnerships face many challenges in getting their work published. The purpose of this article is to present practical guides for writing about CBPR for those who have little experience in writing for publication or those who want to help their partners write strong manuscripts for peer-reviewed journals. The article includes tips on how to organize each part of a manuscript, suggestions on how partners can collaborate on preparing manuscripts, recommendations on how to convey unique aspects of a partnership’s work throughout a manuscript, and an annotated bibliography of well-written CBPR articles. By understanding how to prepare a manuscript about CBPR for a peer-reviewed journal, authors should be more effective in disseminating information that will help other communities to benefit from their partnership’s work.
Community-based participatory research; professional development; manuscripts
Apolipoprotein E (ApoE), a protein component of blood lipid particles, plays an important role in lipid transport. Different mutations in the ApoE gene have been associated with various clinical phenotypes. In an initiated study of Qataris, we observed that 17% of the African-derived genetic subgroup were heterozygotes for a rare Arg145Cys (R145C) variant that functions as a dominant trait with incomplete penetrance associated with type III hyperlipoproteinemia. Based on this observation, we hypothesized that the R145C polymorphism may be common in African-derived populations. The prevalence of the R145C variant was assessed worldwide in the 1000 Genomes Project (1000G) and in 1012 Caucasians and 1226 African-Americans in New York City. The 1000G data demonstrated that the R145C polymorphism is rare in non-African derived populations, but present in 5–12% of sub-Saharan African-derived populations. The R145C polymorphism was also rare in New York City Caucasians (1/1012, 0.1%), but strikingly, 53 (4.3%) of 1226 New York City African-Americans were R145C heterozygotes. Lipid profiles of the Qatari and New York R145C were compared to controls. Qatari R145C had higher triglyceride levels compared to Qatari controls (p<0.007) and NY African-Americans R145C had an average of 52% higher fasting triglyceride levels compared to NY African-American controls (p<0.002). Based on these observations, there are likely millions of people worldwide derived from Sub-Saharan Africans that are ApoE R145C. In conclusion, while larger epidemiologic studies are necessary to determine the long-term consequences of this polymorphism, the available evidence suggests it is a common cause of a mild triglyceride dyslipidemia.
Apolipoprotein E; polymorphism; lipids; dyslipidemia; ethnicity
Macrophages are important drivers in the development of inflammation-associated colon cancers, but the mechanistic underpinnings for their contributions are not fully understood. Further, Toll-like receptors (TLR) have been implicated in colon cancer, but their relevant cellular sites of action are obscure. In this study, we show that the endoplasmic reticulum chaperone gp96 is essential in tumor-associated macrophages (TAM) to license their contributions to inflammatory colon tumorigenesis. Mice where gp96 was genetically deleted in a macrophage-specific manner exhibited reduced colitis and inflammation-associated colon tumorigenesis. Attenuation of colon cancer in these mice correlated strikingly with reduced mutation rates of β-catenin, increased efficiency of the DNA repair machinery and reduced expression of pro-inflammatory cytokines, including IL-17 and IL-23 in the tumor microenvironment. The genotoxic nature of TAM-associated inflammation was evident by increased expression of genes in the DNA repair pathway. Our work deepens understanding of how TAM promote oncogenesis by altering the molecular oncogenic program within epithelial cells, and it identifies gp96 as a lynchpin chaperone needed in TAM to license their function and impact on expression of critical inflammatory cytokines in colon tumorigenesis.
study seeks to delineate the ligand interactions that drive
biomarker induction in fish exposed to estrogenic pollutants and provide
a case study on the capacity of human (h) estrogen receptor (ER)-based in vitro screening assays to predict estrogenic effects
in aquatic species. Adult male Japanese medaka (Oryzias latipes) were exposed to solutions of singular steroidal estrogens or to
the estrogenic extract of an anaerobic swine waste lagoon. All exposure
concentrations were calibrated to be equipotent based on the yeast
estrogen screen (YES), which reports activation of hERα. These
exposures elicited significantly different magnitudes of hepatic vitellogenin
and choriogenin gene induction in the male medaka. Effects of the
same YES-calibrated solutions in the T47D-KBluc assay, which reports
activation of hERα and hERβ, generally recapitulated observations
in medaka. Using competitive ligand binding assays, it was found that
the magnitude of vitellogenin/choriogenin induction by different estrogenic
ligands correlated positively with preferential binding affinity for
medaka ERβ subtypes, which are highly expressed in male medaka
liver prior to estrogen exposure. Results support emerging evidence
that ERβ subtypes are critically involved in the teleost estrogenic
response, with the ERα:ERβ ratio being of particular importance.
Accordingly, incorporation of multiple ER subtypes into estrogen screening
protocols may increase predictive value for the risk assessment of
aquatic systems, including complex estrogenic mixtures.
Colorectal cancer (CRC) progression is mediated by cancer stem cells (CSCs). We sought to determine if expression of the CSC marker aldehyde dehydrogenase 1 (ALDH1) in CRC tumors varies by AJCC stage or correlates to clinical outcomes.
Primary and metastatic CRC samples from 96 patients were immunostained with antibodies to ALDH1 and imaged to evaluate marker expression. The percentage of ALDH1+ cells was correlated to clinical outcomes.
ALDH1 was overexpressed in CRC tumors compared to non-neoplastic tissue. Marker expression was highest in non-metastatic tumors; loss of expression was associated with advanced stage and metastatic disease. No significant correlation was found between ALDH1 expression and metastasis, recurrence or survival.
ALDH1 was highly expressed in non-metastatic CRC, but expression was lost with advancing stage. ALDH1 could be an effective therapeutic target in early CRC but not late stage disease. No correlation was found between ALDH1 and disease prognosis.
Colorectal cancer; cancer stem cells; aldehyde dehydrogenase 1 (ALDH1)
Embryonic stem cells (ESCs) self-renew in a state of naïve pluripotency in which they are competent to generate all somatic cells1. It has been hypothesized that, before irreversibly committing, ESCs pass through at least one metastable transition state2-4. This transition would represent a gateway for differentiation and reprogramming of somatic cells5,6. We sought a mechanical phenotype of transition by probing the nuclear response to compressive and tensile forces and found that, during transition, nuclei of ESCs are auxetic: they displayed a cross-sectional expansion when stretched and a cross-sectional contraction when compressed, and their stiffness increased under compression. We show that the auxetic phenotype of transition ESC nuclei is driven at least in part by global chromatin decondensation. Through the regulation of molecular turnover in the differentiating nucleus by external forces, auxeticity could be a key element in mechanotransduction. Our findings highlight the importance of nuclear structure in the regulation of differentiation and reprogramming.
Nonhomologous end joining (NHEJ) can effectively resolve chromosome breaks despite diverse end structures, but it is unclear how the steps employed for resolution are determined. We sought to address this question by analyzing cellular NHEJ of ends with systematically mispaired and damaged termini. We show NHEJ is uniquely proficient at bypassing subtle terminal mispairs and radiomimetic damage by direct ligation. Nevertheless, bypass ability varies widely, with increases in mispair severity gradually reducing bypass products from 85% to 6%. End-processing by nucleases and polymerases is increased to compensate, though paths with the fewest number of steps to generate a substrate suitable for ligation are favored. Thus, both the frequency and nature of end processing are tailored to meet the needs of the ligation step. We propose a model where the ligase organizes all steps during NHEJ within the stable paired-end complex to limit end processing and associated errors.
To evaluate the accuracy of the Edinburgh Postnatal Depression Scale (EPDS) and 3 subscales for identifying postpartum depression among primiparous adolescent mothers.
Mothers enrolled in a randomized controlled trial to prevent postpartum depression completed a psychiatric diagnostic interview and the 10-item EPDS at 6 weeks, 3 months, and 6 months postpartum. Three subscales of the EPDS were assessed as brief screening tools: 3-item anxiety subscale (EPDS-3), 7-item depressive symptoms subscale (EPDS-7), and 2-item subscale (EPDS-2) that resemble the Patient Health Questionnaire-2. Receiver operating characteristic curves and the areas under the curves for each tool were compared to assess accuracy. The sensitivities and specificities of each screening tool were calculated in comparison with diagnostic criteria for a major depressive disorder. Repeated-measures longitudinal analytical techniques were used.
A total of 106 women contributed 289 postpartum visits; 18% of the women met criteria for incident postpartum depression by psychiatric diagnostic interview. When used as continuous measures, the full EPDS, EPDS-7, and EPDS-2 performed equally well (area under the curve >0.9). Optimal cutoff scores for a positive depression screen for the EPDS and EPDS-7 were lower (≥9 and ≥7, respectively) than currently recommended cutoff scores (≥10). At optimal cutoff scores, the EPDS and EPDS-7 both had sensitivities of 90% and specificities of >85%.
The EPDS, EPDS-7, and EPDS-2 are highly accurate at identifying postpartum depression among adolescent mothers. In primary care pediatric settings, the EPDS and its shorter subscales have potential for use as effective depression screening tools.
teenage; pregnancy; screening; postpartum depression; validity
Exome sequencing of families of related individuals has been highly successful in identifying genetic polymorphisms responsible for Mendelian disorders. Here, we demonstrate the value of the reverse approach, where we use exome sequencing of a sample of unrelated individuals to analyze allele frequencies of known causal mutations for Mendelian diseases. We sequenced the exomes of 100 individuals representing the three major genetic subgroups of the Qatari population (Q1 Bedouin, Q2 Persian-South Asian, Q3 African) and identified 37 variants in 33 genes with effects on 36 clinically significant Mendelian diseases. These include variants not present in 1000 Genomes and variants at high frequency when compared to 1000 Genomes populations. Several of these Mendelian variants were only segregating in one Qatari subpopulation, where the observed subpopulation specificity trends were confirmed in an independent population of 386 Qataris. Pre-marital genetic screening in Qatar tests for only 4 out of the 37, such that this study provides a set of Mendelian disease variants with potential impact on the epidemiological profile of the population that could be incorporated into the testing program if further experimental and clinical characterization confirms high penetrance.
Mendelian; consanguinity; exome sequencing; OMIM; diagnostic biomarkers
To assess if sertraline treatment (vs. placebo) or remission of depression at 12 weeks (vs. non-remission) in Alzheimer’s patients is associated with improved caregiver wellbeing.
A randomized, double-blind, placebo-controlled clinical trial of the efficacy and safety of sertraline for the treatment of depression in individuals with Alzheimer’s disease.
Five clinical research sites across the United States.
Caregivers of patients enrolled in the Depression in Alzheimer’s Disease Study 2 (N=131).
All caregivers received standardized psychosocial support throughout the study.
Caregiver outcome measures included depression (Beck Depression Inventory), distress (Neuropsychiatric Inventory), burden (Zarit Burden Interview), and quality of life (Medical Outcomes Study Short Form Health Survey).
Fifty-nine percent of caregivers were spouses, 63.4% were female, and 64.1% were white. Caregivers of patients in both treatment groups had significant reductions in distress scores over the 24 week study period, but there was not a greater benefit for caregivers of patients taking sertraline. However, caregivers of patients whose depression was in remission at week 12 had greater declines in distress scores over the 24 weeks than caregivers of patients whose depression did not remit by week 12.
Patient treatment with sertraline was not associated with significantly greater reductions in caregiver distress than placebo treatment. Distress but not level of depression or burden lessened for all caregivers regardless of remission status and even more so for those who cared for patients whose depression remitted. Results imply an interrelationship between caregiver distress and patient psychiatric outcomes.
sertraline; depression; Alzheimer’s; caregivers; DIADS-2