Cross‐sex shifts in two brain imaging phenotypes and their relation to polygenic scores for same‐sex sexual behavior: A study of 18,645 individuals from the UK Biobank

Genetic and hormonal factors have been suggested to influence human sexual orientation. Previous studied proposed brain differences related to sexual orientation and that these follow cross‐sex shifted patterns. However, the neurobiological correlates of sexual orientation and how genetic factors relate to brain structural variation remains largely unexplored. Using the largest neuroimaging‐genetics dataset available on same‐sex sexual behavior (SSB) (n = 18,645), we employed a data‐driven multivariate classification algorithm (PLS) on magnetic resonance imaging data from two imaging modalities to extract brain covariance patterns related to sex. Through analyses of latent variables, we tested for SSB‐related cross‐sex shifts in such patterns. Using genotype data, polygenic scores reflecting the genetic predisposition for SSB were computed and tested for associations with neuroimaging outcomes. Patterns important for classifying between males and females were less pronounced in non‐heterosexuals. Predominantly in non‐heterosexual females, multivariate brain patterns as represented by latent variables were shifted toward the opposite sex. Complementary univariate analyses revealed region specific SSB‐related differences in both males and females. Polygenic scores for SSB were associated with volume of lateral occipital and temporo‐occipital cortices. The present large‐scale study demonstrates multivariate neuroanatomical correlates of SSB, and tentatively suggests that genetic factors related to SSB may contribute to structural variation in certain brain structures. These findings support a neurobiological basis to the differences in human sexuality.     

Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family

This study aimed to identify genetic mechanisms underlying severe retinal degeneration in one large family from northern Sweden, members of which presented with early-onset autosomal recessive retinitis pigmentosa and juvenile macular dystrophy. The clinical records of affected family members were analysed retrospectively and ophthalmological and electrophysiological examinations were performed in selected cases. Mutation screening was initially performed with microarrays, interrogating known mutations in the genes associated with recessive retinitis pigmentosa, Leber congenital amaurosis and Stargardt disease. Searching for homozygous regions with putative causative disease genes was done by high-density SNP-array genotyping, followed by segregation analysis of the family members. Two distinct phenotypes of retinal dystrophy, Leber congenital amaurosis and Stargardt disease were present in the family. In the family, four patients with Leber congenital amaurosis were homozygous for a novel c.2557C>T (p.Q853X) mutation in the CRB1 gene, while of two cases with Stargardt disease, one was homozygous for c.5461-10T>C in the ABCA4 gene and another was carrier of the same mutation and a novel ABCA4 mutation c.4773+3A>G. Sequence analysis of the entire ABCA4 gene in patients with Stargardt disease revealed complex alleles with additional sequence variants, which were evaluated by bioinformatics tools. In conclusion, presence of different genetic mechanisms resulting in variable phenotype within the family is not rare and can challenge molecular geneticists, ophthalmologists and genetic counsellors.     

Experimental Disc Herniation in the Rat Causes Downregulation of Serotonin Receptor 2c in a TNF-dependent Manner

Background

During recent decades, the knowledge of the pathophysiology of disc herniation and sciatica has drastically improved. What previously was considered a strict biomechanical process is now considered a more complex interaction between leaked nucleus pulposus and the tissue in the spinal canal. An inflammatory reaction, with tumor necrosis factor (TNF) playing an essential role, has been demonstrated. However, the exact mechanisms of the pathophysiology of disc herniation remain unknown.

Questions/purposes

In this study we use an animal model to investigate (1) if and/or how experimental disc herniation affects gene expression in the early phase (24 hours postsurgery) in the dorsal root ganglion; and (2) if TNF inhibition can reduce any observed changes.

Methods

A rat model of disc herniation was used. Twenty rats were evenly divided into four groups: naïve, sham, disc herniation, and disc herniation with TNF inhibition. The dorsal root ganglion of the affected nerve root was harvested 24 hours after surgery and analyzed with a TaqMan Low Density Array^® quantitative polymerase chain reaction assay. Gene expression levels in sham were compared with disc herniation to assess question 1 and disc herniation to disc herniation with TNF inhibition to assess question 2.

Results

Experimental disc herniation caused a decrease in the expression of the serotonin receptor 2c gene (p = 0.022). TNF inhibition was found to reduce the observed decrease in expression of serotonin receptor 2c (p = 0.037).

Conclusions

Our results suggest that a decrease in the expression of the serotonin receptor 2c gene may contribute to the pathophysiology of disc herniation. Further research on its involvement is warranted.

Clinical Relevance

This pilot study gives a brief insight into cellular changes that may contribute to the pathophysiology of disc herniation. This knowledge may contribute to the development of more and better treatment options for patients with disc herniation and sciatica.     

Cardioangiographic findings in patients with arrhythmogenic right ventricular dysplasia.

The dimension, contractility, and regional wall motion of the right and left ventricles were scored on the angiograms of 13 patients with arrhythmogenic right ventricular dysplasia. In 10 patients the right ventricle was enlarged, in eight the contractility of the right ventricle was reduced, and in all but one patient there were regional wall motion abnormalities of the right ventricle. The most common abnormality of regional wall motion was mild hypokinesia. There were bulging or dyskinetic areas in seven patients. Regional wall motion abnormalities of the left ventricle were found in five patients, two of whom also had bulging or dyskinetic areas. The reproducibility of right ventricular dimension, contractility, and regional wall motion scores was generally fair but varied unexpectedly both within and between two observers (Kendall's Tau 0.38-0.92). The score values of regional wall motion for some of the segments differed considerably within and between observers. One of the observers consistently gave higher scores than the other. These data suggest that a more objective approach is needed for evaluating angiographic changes in arrhythmogenic right ventricular dysplasia.     

Course of radiographic damage over 10 years in a cohort with early rheumatoid arthritis

OBJECTIVE: To investigate development of radiographic damage in hands and feet of patients with early rheumatoid arthritis (RA) monitored prospectively for 10 years, and to search for prognostic factors. PATIENTS AND METHODS: 181 patients with early RA (mean disease duration one year) were assessed annually with radiographs of hands and feet during years 0-5 and at year 10. Radiographs were evaluated according to Larsen (range 0-200). Predictive factors for progressive disease for years 0-5 and 5-10 were evaluated by logistic regression analyses. RESULTS: 82/168 (49%) patients had erosions at inclusion and almost all became erosive with time (90% after two years and 96% after 10 years). Radiographic progression was most rapid during the first two years and 75% of all damage occurred during the first five years. The median Larsen score increased from 6 at inclusion to 41 after five years and 54 after 10 years. Only 5.3% of all evaluated joints became maximally eroded, the second metacarpophalangeal joint being the most commonly affected. Mean ESR during the first three months and rheumatoid factor status were significant predictors for radiographic progressive disease, it was not possible to predict non-progressive disease. CONCLUSIONS: Joint damage in hands and feet developed early and progression was most rapid during the first years of disease. The different rates of progression at different stages should be considered in the design of trials of drugs aimed at retarding joint damage. Disease activity at study start influenced the degree of joint damage during the entire 10 years.     

Evidence of Hantavirus Infection among Bats in Brazil

Hantaviruses are zoonotic viruses harbored by rodents, bats, and shrews. At present, only rodent-borne hantaviruses are associated with severe illness in humans. New species of hantaviruses have been recently identified in bats and shrews greatly expanding the potential reservoirs and ranges of these viruses. Brazil has one of the highest incidences of hantavirus cardiopulmonary syndrome in South America, hence it is critical to know what is the prevalence of hantaviruses in Brazil. Although much is known about rodent reservoirs, little is known regarding bats. We captured 270 bats from February 2012 to April 2014. Serum was screened for the presence of antibodies against a recombinant nucleoprotein (rN) of Araraquara virus (ARAQV). The prevalence of antibody to hantavirus was 9/53 with an overall seroprevalence of 17%. Previous studies have shown only insectivorous bats to harbor hantavirus; however, in our study, of the nine seropositive bats, five were frugivorous, one was carnivorous, and three were sanguivorous phyllostomid bats.Hantaviruses (family Bunyaviridae) are present throughout the globe in rodents, bats, and shrews.¹ Humans exposed to rodent excreta from hantaviral reservoirs may develop life-threatening diseases. However, none of the other reservoirs are associated with human illness presently.^1,2 Bats (order Chiroptera) are known to harbor a broad diversity of emerging zoonotic pathogens.² Their ability to fly and social behavior favors maintenance, evolution, and spread of pathogens.^1,2 The prevailing hypothesis has been that hantaviruses have coevolved with their rodent reservoirs over millions of years.^1,3 With the recognition of new species of hantavirus in bats in Africa and Asia,⁴ Guo and others⁵ hypothesized that hantaviruses originated primarily in bats and then spilled over into rodents and shrews, but it seems that shrews are the original hosts from which the viruses jumped into both rodents and bats.³ To determine if New World bats in Brazil may harbor hantaviruses, we screened bat sera for antibodies that react against the recombinant nucleoprotein (rN) of Araraquara hantavirus (ARAQV).Bats were collected at five ecologically distinct sites in the northeast region of São Paulo state (sites 1–3) and north region of Minas Gerais state (sites 4 and 5), southeastern Brazil (Figure 1 and 9 and one specimen per species by trap-night was anesthetized to collect blood by cardiac puncture; blood samples were stored in cryovials and flash-frozen in liquid nitrogen. At sites 4 and 5, five specimens per trap-night were randomly selected for blood collection. All bats were handled and sampled according to Sikes and others¹⁰ guidelines. This research project, along with its procedures and protocols, is in accordance with Brazilian environment and wildlife protection laws and regulations, and have been approved by the Chico Mendes Institute of Biodiversity Conservation (Ministry of Environment, Brasília, Distrito Federal, Brazil.), protocols nos. 19838-1 and 41709-3. It has also been approved by the Ethics Committee for Animal Research of University of São Paulo and Federal University of Minas Gerais (nos. 020/2011 and 333/2013, respectively). From 270 captured bats, 53 were bled for detection of immunoglobulin G (IgG) antibodies to rN-ARAQV by indirect enzyme-linked immunosorbent assay (ELISA) using anti-bat (Bethyl Laboratories, Inc., Montgomery, TX) secondary antibody. This ELISA, as previously described, showed 97.2% sensitivity, 100% specificity, 100% positive predictive value, and 98.1% negative predictive value when compared with an IgG-ELISA using rN antigen of Andes virus, which is the serological test for hantavirus most used in South America.^11,12Open in a separate windowFigure 1.Study areas, highlighting the states of São Paulo and Minas Gerais in southeastern Brazil. The map shows cities where bats have been captured.

Table 1

Trap sites general features⁶

Semiquantitative determination of Cc and C3 receptors on human lymphocytes by isotope-labelled marker cells.

The number of Fc and C3 receptors on normal B lymphocytes, isolated from blood, was assessed semiquantitatively by a new method in which the marker cells (pretreated sheep erythrocytes) for Fc and C3 receptors are labelled by 99Tc and 51Cr respectively. The mean number of bound marker cells per rosette was assessed simultaneously by measurements of radioactivity. Control studies showed that a measuring system using 1/4 agglutinating titre of antibody on the marker cells is particularly advantageous: (1) Fc and C3 receptors are not demonstrable on T lymphocytes; thus, B lymphocyte fractions with Fc and/or C3 receptors are well-defined. (2) The binding affinity of the marker cells for normal lymphocytes is so weak that the number of bound marker cells per rosette rarely reaches the maximum which was calculated and measured as about 30 marker cells per rosette; thus, the measuring system is sensitive to changes in the number of receptors. (3) By binding of marker cells to lymphocytes bearing Fc as well as C3 receptors it has been demonstrated that interference phenomena between the two marker cells are not operative. Studies of blood lymphocytes from normal human subjects showed B lymphocytes carrying either Fc and C3 receptors as well as a fraction of B lymphocytes having both Fc and C3 receptors. The latter maker up about 6% of the lymphocyte mass. Comparative assessment of the quantitative distribution of these receptors indicates a developmental sequence, B lymphocyte with Fc receptors evidently developing, via B lymphocytes with Fc as well as C3 receptors, into B lymphocytes having C3 receptors only.