Prevalence of CADASIL and Fabry Disease in a Cohort of MRI Defined Younger Onset Lacunar Stroke

Background and Purpose

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by mutations in the NOTCH3 gene, is the most common monogenic disorder causing lacunar stroke and cerebral small vessel disease (SVD). Fabry disease (FD) due to mutations in the GLA gene has been suggested as an underdiagnosed cause of stroke, and one feature is SVD. Previous studies reported varying prevalence of CADASIL and FD in stroke, likely due to varying subtypes studied; no studies have looked at a large cohort of younger onset SVD. We determined the prevalence in a well-defined, MRI-verified cohort of apparently sporadic patients with lacunar infarct.

Methods

Caucasian patients with lacunar infarction, aged ≤70 years (mean age 56.7 (SD8.6)), were recruited from 72 specialist stroke centres throughout the UK as part of the Young Lacunar Stroke DNA Resource. Patients with a previously confirmed monogenic cause of stroke were excluded. All MRI’s and clinical histories were reviewed centrally. Screening was performed for NOTCH3 and GLA mutations.

Results

Of 994 subjects five had pathogenic NOTCH3 mutations (R169C, R207C, R587C, C1222G and C323S) all resulting in loss or gain of a cysteine in the NOTCH3 protein. All five patients had confluent leukoaraiosis (Fazekas grade ≥2). CADASIL prevalence overall was 0.5% (95% CI 0.2%-1.1%) and among cases with confluent leukoaraiosis 1.5% (95% CI 0.6%-3.3%). No classic pathogenic FD mutations were found; one patient had a missense mutation (R118C), associated with late-onset FD.

Conclusion

CADASIL cases are rare and only detected in SVD patients with confluent leukoaraiosis. No definite FD cases were detected.     

Finished sequence and assembly of the DUF1220-rich 1q21 region using a haploid human genome

Background

Although the reference human genome sequence was declared finished in 2003, some regions of the genome remain incomplete due to their complex architecture. One such region, 1q21.1-q21.2, is of increasing interest due to its relevance to human disease and evolution. Elucidation of the exact variants behind these associations has been hampered by the repetitive nature of the region and its incomplete assembly. This region also contains 238 of the 270 human DUF1220 protein domains, which are implicated in human brain evolution and neurodevelopment. Additionally, examinations of this protein domain have been challenging due to the incomplete 1q21 build. To address these problems, a single-haplotype hydatidiform mole BAC library (CHORI-17) was used to produce the first complete sequence of the 1q21.1-q21.2 region.

Results

We found and addressed several inaccuracies in the GRCh37sequence of the 1q21 region on large and small scales, including genomic rearrangements and inversions, and incorrect gene copy number estimates and assemblies. The DUF1220-encoding NBPF genes required the most corrections, with 3 genes removed, 2 genes reassigned to the 1p11.2 region, 8 genes requiring assembly corrections for DUF1220 domains (~91 DUF1220 domains were misassigned), and multiple instances of nucleotide changes that reassigned the domain to a different DUF1220 subtype. These corrections resulted in an overall increase in DUF1220 copy number, yielding a haploid total of 289 copies. Approximately 20 of these new DUF1220 copies were the result of a segmental duplication from 1q21.2 to 1p11.2 that included two NBPF genes. Interestingly, this duplication may have been the catalyst for the evolutionarily important human lineage-specific chromosome 1 pericentric inversion.

Conclusions

Through the hydatidiform mole genome sequencing effort, the 1q21.1-q21.2 region is complete and misassemblies involving inter- and intra-region duplications have been resolved. The availability of this single haploid sequence path will aid in the investigation of many genetic diseases linked to 1q21, including several associated with DUF1220 copy number variations. Finally, the corrected sequence identified a recent segmental duplication that added 20 additional DUF1220 copies to the human genome, and may have facilitated the chromosome 1 pericentric inversion that is among the most notable human-specific genomic landmarks.     

Antiphospholipid Antibody and Risk of Retinal Vein Occlusion: A Systematic Review and Meta-Analysis

Background

Retinal vein occlusion (RVO) is a common retinal vascular disease and it is one of the most frequently reported causes of visual damage and blindness in the elderly. The current study investigated the potential association between antiphospholipid antibodies (APLA) and RVO risk by conducting a meta-analysis of case–control studies.

Methods

A systematic literature search of Pubmed and Embase databases was conducted in August 1^st, 2014. Odds ratios (ORs) were used to evaluate the associations between APLA and the incidence of RVO. A random-effects model was obtained for the quantitative synthesis.

Results

A total of 11 studies were included in this meta-analysis. A meta-analysis of all studies assessing the risk of RVO revealed that APLA was associated with a statistically increased risk of RVO incidence (OR = 5.18, 95% CI = [3.37, 7.95]). The association between anticardiolipin antibodies (ACA) and the risk of RVO was significant (n =8, OR = 4.59, 95% CI = [2.75, 7.66]). However, the association between lupus anticoagulants (LA) and risk of RVO was non-significant (n = 5, OR = 3.90, 95% CI = [0.99, 15.37]). No significant publication bias was found in the 11 selected studies.

Conclusion

APLA was significantly associated with the risk of RVO. Advanced analyses showed that ACA rather than LA affected the risk of RVO. Additional well-designed and well-conducted epidemiological studies are required to further our understanding of the relationship between APLA and RVO risk.     

Examining the Genetic and Environmental Associations between Autistic Social and Communication Deficits and Psychopathic Callous-Unemotional Traits

Background

Difficulties in appropriate social interaction are characteristic of both children with autism spectrum disorders and children with callous-unemotional traits (who are at risk of developing psychopathy). Extant experimental studies suggest that the nature of atypical social cognition that characterises these two profiles is not identical. However, ‘empathizing’ difficulties have been hypothesised for both groups, raising questions about the degree of aetiological separation between social impairments that characterize each disorder. This study explored the relative contribution of independent vs. shared aetiological influences to social and communication impairments associated with autistic traits and callous-unemotional traits, indexed by parent-report in a population-based cohort of twins.

Methods

Participants were over 5,000 twin pairs from a UK cohort (the Twins Early Development Study; TEDS), assessed for callous-unemotional traits at 7 years and autistic social and communication impairments at 8 years. Multivariate model-fitting was used to explore the relative contribution of independent vs. overlapping genetic/environmental influences on these traits.

Results

Both social and communication impairments and callous-unemotional traits were highly heritable, although the genetic and environmental influences accounting for individual differences on each domain were predominantly independent.

Conclusions

Extant evidence from experimental and neuro-imaging studies has suggested that, despite some superficially overlapping behaviours, the social difficulties seen in children with autism spectrum disorders and callous-unemotional traits are largely distinct. The current study is the first to demonstrate considerable aetiological independence of the social interaction difficulties seen in children with autism spectrum disorders and those with callous-unemotional traits.     

The Leber Congenital Amaurosis Protein AIPL1 and EB Proteins Co-Localize at the Photoreceptor Cilium

Purpose

The aim of this study was to investigate the interaction and co-localization of novel interacting proteins with the Leber congenital amaurosis (LCA) associated protein aryl hydrocarbon receptor interacting protein-like 1 (AIPL1).

Methods

The CytoTrapXR yeast two-hybrid system was used to screen a bovine retinal cDNA library. A novel interaction between AIPL1 and members of the family of EB proteins was confirmed by directed yeast two-hybrid analysis and co-immunoprecipitation assays. The localization of AIPL1 and the EB proteins in cultured cells and in retinal cryosections was examined by immunofluorescence microscopy and cryo-immunogold electron microscopy.

Results

Yeast two-hybrid (Y2H) analysis identified the interaction between AIPL1 and the EB proteins, EB1 and EB3. EB1 and EB3 were specifically co-immunoprecipitated with AIPL1 from SK-N-SH neuroblastoma cells. In directed 1:1 Y2H analysis, the interaction of EB1 with AIPL1 harbouring the LCA-causing mutations A197P, C239R and W278X was severely compromised. Immunofluorescent confocal microscopy revealed that AIPL1 did not co-localize with endogenous EB1 at the tips of microtubules, endogenous EB1 at the microtubule organising centre following disruption of the microtubule network, or with endogenous β-tubulin. Moreover, AIPL1 did not localize to primary cilia in ARPE-19 cells, whereas EB1 co-localized with the centrosomal marker pericentrin at the base of primary cilia. However, both AIPL1 and the EB proteins, EB1 and EB3, co-localized with centrin-3 in the connecting cilium of photoreceptor cells. Cryo-immunogold electron microscopy confirmed the co-localization of AIPL1 and EB1 in the connecting cilia in human retinal photoreceptors.

Conclusions

AIPL1 and the EB proteins, EB1 and EB3, localize at the connecting cilia of retinal photoreceptor cells, but do not co-localize in the cellular microtubule network or in primary cilia in non-retinal cells. These findings suggest that AIPL1 function in these cells is not related to the role of EB proteins in microtubule dynamics or primary ciliogenesis, but that their association may be related to a specific role in the specialized cilia apparatus of retinal photoreceptors.     

A Novel Method for Measuring Anterior Segment Area of the Eye on Ultrasound Biomicroscopic Images Using Photoshop

Purpose

To describe a novel method for quantitative measurement of area parameters in ocular anterior segment ultrasound biomicroscopy (UBM) images using Photoshop software and to assess its intraobserver and interobserver reproducibility.

Methods

Twenty healthy volunteers with wide angles and twenty patients with narrow or closed angles were consecutively recruited. UBM images were obtained and analyzed using Photoshop software by two physicians with different-level training on two occasions. Borders of anterior segment structures including cornea, iris, lens, and zonules in the UBM image were semi-automatically defined by the Magnetic Lasso Tool in the Photoshop software according to the pixel contrast and modified by the observers. Anterior chamber area (ACA), posterior chamber area (PCA), iris cross-section area (ICA) and angle recess area (ARA) were drawn and measured. The intraobserver and interobserver reproducibilities of the anterior segment area parameters and scleral spur location were assessed by limits of agreement, coefficient of variation (CV), and intraclass correlation coefficient (ICC).

Results

All of the parameters were successfully measured by Photoshop. The intraobserver and interobserver reproducibilities of ACA, PCA, and ICA were good, with no more than 5% CV and more than 0.95 ICC, while the CVs of ARA were within 20%. The intraobserver and interobserver reproducibilities for defining the spur location were more than 0.97 ICCs. Although the operating times for both observers were less than 3 minutes per image, there was significant difference in the measuring time between two observers with different levels of training (p<0.001).

Conclusion

Measurements of ocular anterior segment areas on UBM images by Photoshop showed good intraobserver and interobserver reproducibilties. The methodology was easy to adopt and effective in measuring.     

Small Peptide Inhibitor of JNK3 Protects Dopaminergic Neurons from MPTP Induced Injury via Inhibiting the ASK1-JNK3 Signaling Pathway

Introduction and Aims

The ASK1-JNK3 signaling pathway plays a pivotal role in the pathogenesis of Parkinson''s disease (PD). The specific binding of β-arrestin2 to JNK3 is essential for activation of the ASK1-JNK3 cascade, representing a potential therapeutic target for preventing dopaminergic neuronal death in PD. The aim of this study was to identify a novel strategy for the prevention of dopaminergic neuronal death in PD.

Methods

Based on the specific binding of β-arrestin2 to JNK3, a 21-amino-acid fusion peptide, termed JNK3-N-Tat, was synthesized. We evaluated the ability of this peptide to inhibit the binding of β-arrestin2 to its target domain in JNK3 in vitro and in vivo.

Results

The JNK3-N-Tat peptide inhibited activation of the ASK1-JNK3 cascade by disrupting the interaction between β-arrestin2 and JNK3. JNK3-N-Tat exerted beneficial effects through pathways downstream of JNK3 and improved mitochondrial function, resulting in attenuated MPP+/MPTP-induced damage. JNK3-N-Tat protected mesencephalic dopaminergic neurons against MPTP-induced toxicity.

Conclusions

JNK3-N-Tat, a JNK3-inhibitory peptide, protects dopaminergic neurons against MPP+/MPTP-induced injury by inhibiting the ASK1-JNK3 signaling pathway.     

Gender Difference in the Interaction Effects of Diabetes and Hypertension on Stroke among the Elderly in the Shih-Pai Study,Taiwan

Aims

To investigate the interaction effects of diabetes and hypertension on stroke, and also investigate the independent and interaction effects of parental history and environmental factors on diabetes and hypertension in a cross-sectional elderly population.

Methods

The Shih-Pai Community Medical Service Program was a community-based, fixed cohort study conducted between June 1999 and November 2002. Socio-demographic and clinical data of subjects aged 65 years and older were collected by well-trained interviewers during home visits. Interaction effects were analyzed using Rothman’s synergy index (SI).

Results

In total, 4,124 subjects were included in the study, with 2,284 males and 1,840 females. The synergistic interaction of diabetes and hypertension on stroke was statistically significant in women (SI = 3.16, 95% CI: 1.35–7.39). The synergistic interaction of parental diabetes and being overweight on diabetes was only statistically significant in men, and not in women (SI = 3.30, 95% CI: 1.00–10.83 in men, and SI = 1.15, 95% CI: 0.30–4.39 in women).

Conclusions

A synergistic interaction was found for diabetes and hypertension in both sexes when parental history and being overweight were combined. Furthermore, combining diabetes and hypertension in elderly women was significant in terms of the risk of stroke. Strategies to control risk factors in individuals at additional high risk are urgently needed.     

Structure and sequence analyses of Bacteroides proteins BVU_4064 and BF1687 reveal presence of two novel predominantly-beta domains,predicted to be involved in lipid and cell surface interactions

Background

N-terminal domains of BVU_4064 and BF1687 proteins from Bacteroides vulgatus and Bacteroides fragilis respectively are members of the Pfam family PF12985 (DUF3869). Proteins containing a domain from this family can be found in most Bacteroides species and, in large numbers, in all human gut microbiome samples. Both BVU_4064 and BF1687 proteins have a consensus lipobox motif implying they are anchored to the membrane, but their functions are otherwise unknown. The C-terminal half of BVU_4064 is assigned to protein family PF12986 (DUF3870); the equivalent part of BF1687 was unclassified.

Results

Crystal structures of both BVU_4064 and BF1687 proteins, solved at the JCSG center, show strikingly similar three-dimensional structures. The main difference between the two is that the two domains in the BVU_4064 protein are connected by a short linker, as opposed to a longer insertion made of 4 helices placed linearly along with a strand that is added to the C-terminal domain in the BF1687 protein. The N-terminal domain in both proteins, corresponding to the PF12985 (DUF3869) domain is a β–sandwich with pre-albumin-like fold, found in many proteins belonging to the Transthyretin clan of Pfam. The structures of C-terminal domains of both proteins, corresponding to the PF12986 (DUF3870) domain in BVU_4064 protein and an unclassified domain in the BF1687 protein, show significant structural similarity to bacterial pore-forming toxins. A helix in this domain is in an analogous position to a loop connecting the second and third strands in the toxin structures, where this loop is implicated to play a role in the toxin insertion into the host cell membrane. The same helix also points to the groove between the N- and C-terminal domains that are loosely held together by hydrophobic and hydrogen bond interactions. The presence of several conserved residues in this region together with these structural determinants could make it a functionally important region in these proteins.

Conclusions

Structural analysis of BVU_4064 and BF1687 points to possible roles in mediating multiple interactions on the cell-surface/extracellular matrix. In particular the N-terminal domain could be involved in adhesive interactions, the C-terminal domain and the inter-domain groove in lipid or carbohydrate interactions.

Electronic supplementary material

The online version of this article (doi:10.1186/s12859-014-0434-7) contains supplementary material, which is available to authorized users.     

Local interleukin-10 production during respiratory syncytial virus bronchiolitis is associated with post-bronchiolitis wheeze

Background

Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in infants. Following RSV bronchiolitis, 50% of children develop post-bronchiolitis wheeze (PBW). Animal studies have suggested that interleukin (IL)-10 plays a critical role in the pathogenesis of RSV bronchiolitis and subsequent airway hyperresponsiveness. Previously, we showed that ex vivo monocyte IL-10 production is a predictor of PBW. Additionally, heterozygosity of the single-nucleotide polymorphism (SNP) rs1800872 in the IL10 promoter region was associated with protection against RSV bronchiolitis.

Methods

This study aimed to determine the in vivo role of IL-10 in RSV pathogenesis and recurrent wheeze in a new cohort of 235 infants hospitalized for RSV bronchiolitis. IL-10 levels in nasopharyngeal aspirates (NPAs) were measured at the time of hospitalization and the IL10 SNP rs1800872 genotype was determined. Follow-up data were available for 185 children (79%).

Results

Local IL-10 levels during RSV infection turned out to be higher in infants that later developed physician diagnosed PBW as compared to infants without PBW in the first year after RSV infection (958 vs 692 pg/ml, p = 0.02). The IL10 promoter SNP rs1800872 was not associated with IL-10 concentration in NPAs.

Conclusion

The relationship between high local IL-10 levels during the initial RSV infection and physician diagnosed PBW provides further evidence of the importance of the IL-10 response during RSV bronchiolitis.     

Construct Validity of the Chinese Version of the Activities of Daily Living Rating Scale III in Patients with Schizophrenia

Background

The Chinese version of the Activities of Daily Living Rating Scale III (ADLRS-III), which has 10 domains, is commonly used for assessing activities of daily living (ADL) in patients with schizophrenia. However, construct validity (i.e., unidimensionality) for each domain of the ADLRS-III is unknown, limiting the explanations of the test results.

Purpose

This main purpose of this study was to examine unidimensionality of each domain in the ADLRS-III. We also examined internal consistency and ceiling/floor effects in patients with schizophrenia.

Methods

From occupational therapy records, we obtained 304 self-report data of the ADLRS-III. Confirmatory factor analysis (CFA) was conducted to examine the 10 one-factor structures. If a domain showed an insufficient model fit, exploratory factor analysis (EFA) was performed to investigate the factor structure and choose one factor representing the original construct. Internal consistency was examined using Cronbach’s alpha (α). Ceiling and floor effects were determined by the percentage of patients with the maximum and minimum scores in each domain, respectively.

Results

CFA analyses showed that 4 domains (i.e., leisure, picture recognition, literacy ability, communication tools use) had sufficient model fits. These 4 domains had acceptable internal consistency (α = 0.79-0.87) and no ceiling/floor effects, except the leisure domain which had a ceiling effect. The other 6 domains showed insufficient model fits. The EFA results showed that these 6 domains were two-factor structures.

Conclusion

The results supported unidimensional constructs of the leisure, picture recognition, literacy ability, and communication tool uses domains. The sum scores of these 4 domains can be used to represent their respective domain-specific functions. Regarding the 6 domains with insufficient model fits, we have explained the two factors of each domain and chosen one factor to represent its original construct. Future users may use the items from the chosen factors to assess domain-specific functions in patients with schizophrenia.     

Impaired H-Reflex Gain during Postural Loaded Locomotion in Individuals Post-Stroke

Objective

Successful execution of upright locomotion requires coordinated interaction between controllers for locomotion and posture. Our earlier research supported this model in the non-impaired and found impaired interaction in the post-stroke nervous system during locomotion. In this study, we sought to examine the role of the Ia afferent spinal loop, via the H-reflex response, under postural influence during a locomotor task. We tested the hypothesis that the ability to increase stretch reflex gain in response to postural loads during locomotion would be reduced post-stroke.

Methods

Fifteen individuals with chronic post-stroke hemiparesis and 13 non-impaired controls pedaled on a motorized cycle ergometer with specialized backboard support system under (1) seated supported, and (2) non-seated postural-loaded conditions, generating matched pedal force outputs of two levels. H-reflexes were elicited at 90°crank angle.

Results

We observed increased H-reflex gain with postural influence in non-impaired individuals, but a lack of increase in individuals post-stroke. Furthermore, we observed decreased H-reflex gain at higher postural loads in the stroke-impaired group.

Conclusion

These findings suggest an impaired Ia afferent pathway potentially underlies the defects in the interaction between postural and locomotor control post-stroke and may explain reduced ability of paretic limb support during locomotor weight-bearing in individuals post-stroke.

Significance

These results support the judicious use of bodyweight support training when first helping individuals post-stroke to regain locomotor pattern generation and weight-bearing capability.     

Evolution of BCR/ABL Gene Mutation in CML Is Time Dependent and Dependent on the Pressure Exerted by Tyrosine Kinase Inhibitor

Background

Mutations in the ABL kinase domain and SH3-SH2 domain of the BCR/ABL gene and amplification of the Philadelphia chromosome are the two important BCR/ABL dependent mechanisms of imatinib resistance. Here, we intended to study the role played by TKI, imatinib, in selection of gene mutations and development of chromosomal abnormalities in Indian CML patients.

Methods

Direct sequencing methodology was employed to detect mutations and conventional cytogenetics was done to identify Philadelphia duplication.

Results

Among the different mechanisms of imatinib resistance, kinase domain mutations (39%) of the BCR/ABL gene were seen to be more prevalent, followed by mutations in the SH3-SH2 domain (4%) and then BCR/ABL amplification with the least frequency (1%). The median duration of occurrence of mutation was significantly shorter for patients with front line imatinib than those pre-treated with hydroxyurea. Patients with high Sokal score (p = 0.003) showed significantly higher incidence of mutations, as compared to patients with low/intermediate score. Impact of mutations on the clinical outcome in AP and BC was observed to be insignificant. Of the 94 imatinib resistant patients, only 1 patient exhibited duplication of Philadelphia chromosome, suggesting a less frequent occurrence of this abnormality in Indian CML patients.

Conclusion

Close monitoring at regular intervals and proper analysis of the disease resistance would facilitate early detection of resistance and thus aid in the selection of the most appropriate therapy.     

Assessment of Brainstem Function with Auricular Branch of Vagus Nerve Stimulation in Parkinson’s Disease

Background

The efferent dorsal motor nucleus of the vagal nuclei complex may degenerate early in the course of Parkinson’s disease (PD), while efferent nucleus ambiguous, the principal source of parasympathetic vagal neurons innervating the heart, and afferent somatosensory nuclei remain intact.

Objective

To obtain neurophysiological evidence related to this pattern, we tested processing of afferent sensory information transmitted via the auricular branch of the vagus nerve (ABVN) which is known to be connected to autonomic regulation of cardiac rhythm.

Methods

In this cross-sectional observational study, we recorded (i) somatosensory evoked potentials (ABVN-SEP) and (ii) cutaneo-cardioautonomic response elicited by stimulation of the ABVN (modulation of heart-rate variability (HRV index; low frequency power, ln(LF), high frequency power, ln(HF); ln(LF/HF) ratio)) in 50 PD patients and 50 age and sex matched healthy controls. Additionally, auditory evoked potentials and trigeminal nerve SEP were assessed.

Results

Neither ABVN-SEP nor any of the other functional brainstem parameters differed between patients and controls. Although HRV index was decreased in PD patients, modulation of ln(LF/HF) by ABVN-stimulation, likely indicating cardiac parasympathetic activation, did not differ between both groups.

Conclusions

Findings do not point to prominent dysfunction of processing afferent information from ABVN and its connected parasympathetic cardiac pathway in PD. They are consistent with the known pattern of degeneration of the vagal nuclei complex of the brainstem.     

Susceptibility-Weighted Imaging Manifestations in the Brain of Wilson’s Disease Patients

Purpose

It is well known that patients with Wilson’s disease (WD) suffer copper metabolism disorder. However, recent studies point to an additional iron metabolism disorder in WD patients. The purpose of our study was to examine susceptibility-weighted imaging (SWI) manifestations of WD in the brains of WD patients.

Methods

A total of 33 patients with WD and 18 normal controls underwent conventional MRI (Magnetic resonance imaging) and SWI. The phase values were measured on SWI-filtered phase images of the bilateral head of the caudate nuclei, globus pallidus, putamen, thalamus, substantia nigra, and red nucleus. Student’s t-tests were used to compare the phase values between WD groups and normal controls.

Results

The mean phase values for the bilateral head of the caudate nuclei, globus pallidus, putamen, thalamus, substantia nigra, and red nucleus were significantly lower than those in the control group (P < 0.001), and bilateral putamen was most strongly affected.

Conclusions

There is paramagnetic mineralization deposition in brain gray nuclei of WD patients and SWI is an effective method to evaluate these structures.     

Prenatal Docosahexaenoic Acid Supplementation and Offspring Development at 18 Months: Randomized Controlled Trial

Objective

We evaluated the effects of prenatal docosahexaenoic acid (DHA) supplementation on offspring development at 18 months of age.

Design

Randomized placebo double-blind controlled trial.

Settings

Cuernavaca, Mexico.

Participants and Methods

We followed up offspring (n = 730; 75% of the birth cohort) of women in Mexico who participated in a trial of DHA supplementation during the latter half of pregnancy. We assessed the effect of the intervention on child development and the potential modifying effects of gravidity, gender, SES, and quality of the home environment.

Interventions or Main Exposures

400 mg/day of algal DHA.

Outcome Measures

Child development at 18 months of age measured using the Spanish version of the Bayley Scales of Infant Development-II. We calculated standardized psychomotor and mental development indices, and behavior rating scale scores.

Results

Intent-to-treat differences (DHA-control) were: Psychomotor Developmental Index -0.90 (95% CI: -2.35, 0.56), Mental Developmental Index -0.26 (95% CI: -1.63, 1.10) and Behavior Rating Scale -0.01 (95% CI: -0.95, 0.94). Prenatal DHA intake attenuated the positive association between home environment and psychomotor development index observed in the control group (p for interaction = 0.03) suggesting potential benefits for children living in home environments characterized by reduced caregiver interactions and opportunities for early childhood stimulation.

Conclusions

Prenatal DHA supplementation in a population with low intakes of DHA had no effects on offspring development at 18 months of age although there may be some benefit for infants from poor quality home environments.

Trial Registration

Clinicaltrials.gov NCT00646360     

A Second Look at the Association between Gender and Mortality on Antiretroviral Therapy

Objective

We assessed the association between gender and mortality on antiretroviral therapy (ART) using identical models with and without sex-specific categories for weight and hemoglobin.

Design

Cohort study of adult patients on ART.

Setting

GHESKIO Clinic in Port-au-Prince, Haiti.

Participants

4,717 ART-naïve adult patients consecutively enrolled on ART at GHESKIO from 2003 to 2008.

Main Outcome Measure

Mortality on ART; multivariable analyses were conducted with and without sex-specific categories for weight and hemoglobin.

Results

In Haiti, male gender was associated with mortality (OR 1.61; 95% CI: 1.30–2.00) in multivariable analyses with hemoglobin and weight included as control variables, but not when sex-specific interactions with hemoglobin and weight were used.

Conclusions

If sex-specific categories are omitted, multivariable analyses indicate a higher risk of mortality for males vs. females of the same weight and hemoglobin. However, because males have higher normal values for weight and hemoglobin, the males in this comparison would generally have poorer health status than the females. This may explain why gender differences in mortality are sometimes observed after controlling for differences in baseline variables when gender-specific interactions with weight and hemoglobin are omitted.