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MSc (Med), Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand / Factor X deficiency is a rare bleeding disorder with an incidence of one in a million in the general population. Patients with the severe form of factor X deficiency suffer from serious bleeds occurring mainly into the joints and the muscle. In the two factor X deficient families currently looked after at the Haemophilia Comprehensive Care Centre, there are definite differences in the bleeding tendencies between and within family members. We hypothesize the differences in genetic mutations and the influence of cytokines to be responsible for these bleeding variabilities. These factors were explored in our study. The study population included a total of fourteen members of the two families with factor X deficiency. Blood for factor X measurement, cytokine studies and genetic studies was collected in the Haemophilia Comprehensive Care Centre of the Charlotte Maxeke Johannesburg Academic Hospital. Each blood was processed according to the test to be performed. Factor X activity levels were measured using the factor X assay, and the information on each patient’s bleeding episodes was obtained from the Haemophiliac Clinic database. Cytokines were analyzed in all patients using the ELISA kits from Biosource. Factor X gene was amplified using PCR and sequenced with Spectrumedix SCE 2410. iv For cytokine studies, high levels of IL-1beta and TNF-alpha were observed in frequent bleeding patients compared to infrequent bleeders. These cytokines are known to be involved in acute inflammatory process leading to cellular infiltrate and joint swelling. This results in synovitis and the creation of massive joint bleeding. The low levels of IL-1beta and TNF-alpha detected in infrequent bleeding patients appear to be related to the high levels of IL-1Ra and IL-10. These anti-inflammatory cytokines are known to inhibit the inflammatory synovitis and lessen the severity of joint bleeding. For genetic studies, differences were observed between the amino acid sequence of the three frequent bleeding patients and the consensus. In addition, a novel mutation Cys350Phe was detected in two of these patients. This mutation is characterized by very low factor X levels which sometimes are not detectable in circulation. The substituted cystine is known to cause defect in the substrate binding, leading to the lost of enzyme activity. From these findings we have concluded that the origin of the heterogeneity of bleeding in factor X deficiency is multifactorial, cytokines and genetic mutations seems to have a role in determining the clinical manifestations of the factor X deficient patients.

Social defeat is an ethologically relevant stressor that utilizes the natural establishment of social rank in male rodents and has been shown to be relevant to major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). In the present study, we wished to establish a social defeat stress model in combination with the chronic unpredictable stress model, which is considered a mild stressor to the rodent. In this way, we create a “double hit” model that may more accurately mimic severe stress that is common in both MDD and PTSD. In the present study, residents established dominance over the intruder for 10 consecutive days. In addition, social defeat stress was followed by another stressor given at random times during each day, i.e. chronic unpredictable stress. These unpredictable stressors included 30 min restraint, 1 h shaking/crowding, a cold water swim, a warm water swim or a tipped cage for 24 h. In one cohort of animals, brain tissue was taken 24 h after the last stressor for DNA. In a second cohort, animals were tested on a sucrose preference test in which two bottles containing 0.8% sucrose was placed on their cages for 3 consecutive days (days 8-10 of social defeat stress), and the total amount of sucrose was calculated relative to total volume consumed. Brain tissue analyses revealed significantly elevated DNA oxidation in white matter comparing stressed animals to non-stressed controls, consistent with what has been found in post-mortem white matter from MDD subjects. Further, animals given the social defeat + chronic unpredictable stress demonstrated a deficit in sucrose preference, a natural reward, revealing that these animals were anhedonic as compared to controls. Stressed animals also demonstrated fear of the intruder in a social interaction test performed one day after the social defeat/chronic unpredictable stress was complete. Therefore, it appears that social defeat plus chronic unpredictable stress produces a phenotype relevant to clinical data in humans.

<p>Attachment and personality disorders (PDs) both describe patterns of interpersonal dysfunction. Indeed, there are many similarities and few differences between these constructs, suggesting that they may represent two iterations of a common dimension. However, the paucity of empirical tests on this topic has precluded integration of clinical efforts. Also limiting clinical efforts is the inability to target individuals and relationships most prone to dysfunction. The current study used a large sample (N=812) of unselected undergraduates (N=355) and adults currently in psychological treatment (N=457) to test whether a joint hierarchical factor structure of attachment and PDs is tenable and whether it varies reliably by gender, treatment status, or attachment figure. Results suggested that attachment and PDs can be quantified jointly in specific instances of emotional lability and detachment, but attachment was not isomorphic with antagonistic, impulsigenic, or psychosis-spectrum traits. This joint structure was relatively consistent across attachment figures and treatment status but varied somewhat across gender. Clinical applications of these findings on commonalities of interpersonal dysfunction are discussed. </p>

Studies have shown that aberrant activity in some brain regions involved in the pathology of OCD overlaps similarly with individuals with addiction disorders. The reduced anxiety following a compulsion together with findings of diminished activation in the striatum during reward anticipation proposes a view of OCD being a behavior addiction. To investigate if there are consistent results across studies that support this view a systematic search of the literature was conducted. The keywords in the final search string used were: Obsessive-compulsive disorder, OCD, reward, risk, functional MRI, MRI, fMRI. Databases used for the search were Web of Science and PubMed. The inclusion criteria were studies that compared the neural activity during the anticipation phase of reward between OCD patients and healthy controls. The intervention and brain imaging used in the included studies were the monetary incentive delay task and fMRI. The main data extracted were the alterations in the striatum. Four studies were included in this review with inconsistent results. Three studies did not find any significant difference between OCD and healthy controls and therefore the findings in principle did not support the view of OCD being a behavior addiction. However, differences in study design between studies could be an explanation for the conflicting findings.

<p>  </p> <p>Recent advancements in genetics have revealed that <em>SCN2A</em> is one of the leading genes associated with neurodevelopmental disorders including autism spectrum disorder and epilepsy. In particular, loss-of-function and truncation variants account for a majority of cases. As there are no current treatments specific for <em>SCN2A</em>, the neuropharmacogenomics field has strived to further elucidate the role of <em>SCN2A</em> in neurodevelopment to identify intervention targets. Rodent models offer <em>in vivo</em>, pre-clinical insight into the effects of genetic variation on behavior, biochemistry, and electrophysiology as well as the mechanisms on molecular, cellular, and circuitry levels. Due to <em>SCN2A</em>’s critical involvement in the initiation and propagation of action potential neuronal firing early in neurological development, full null homozygous knockout of <em>Scn2a</em> in mice is perinatal lethal. Furthermore, canonical heterozygous knockout of <em>Scn2a </em>in mice does not render phenotypes that recapitulate <em>SCN2A</em> deficiency in humans. Therefore my dissertation aims at developing a mouse model that better parallels the human condition, then using that pre-clinical platform to explore precision medicine.</p> <p>  </p> <p>Using the unconventional strategy of gene trapping, we generated mice with a severe reduction in <em>Scn2a</em> expression, resulting in significant behavioral and electrophysiological differences from neurotypical wild-type mice with full <em>Scn2a</em> expression, but enough residual expression that the <em>Scn2a</em>-deficient mice survived into adulthood. The severely decreased sociability accompanied by increased high and low order repetitive behaviors observed with the <em>Scn2a</em>-deficient mice suggest autism-like phenotypes. In addition, <em>Scn2a</em>-deficient mice also displayed other co-morbidities of neurodevelopmental disorders including atypical innate behavior, increased anxiety, increased sensitivity to stimuli, motor discoordination, and impaired learning and memory. On the electrophysiological level, these mice displayed enhanced intrinsic excitabilities of principal neurons in the prefrontal cortex and striatum, brain regions known to be involved in seizures and social behavior. This increased excitability was autonomous and reversible by the genetic restoration of <em>Scn2a</em> expression in adult mice. Further, RNA-sequencing revealed a downregulation of multiple potassium channels as well as differential expression of glutamate excitatory and GABA inhibitory signaling, which led to the pursuit of targeting these pathways. Indeed, the use of potassium channel openers alleviated the hyperexcitability of <em>Scn2a</em>-deficient neurons, thus supporting the pursuit of these targets.  </p> <p>Since characterization of the <em>Scn2a</em>-deficient mouse model revealed disruption in excitatory and inhibitory pathways, excitatory/inhibitory balance was examined further as a precision medicine target. Increasing <em>Scn2a</em> expression throughout the whole brain by excising the gene trap, as well as specific targeting of the striatum and the neurons that project to it using a retrograde viral vector, rescued social deficits. However the striatum-specific injection did not lead to a social rescue. This shifted the focus to the neurons that project to the striatum such as the medial prefrontal cortex. Using chemogenetics to reduce excitatory signaling in the prelimbic region of the medial prefrontal cortex, we were able to increase the social behavior in <em>Scn2a</em>-deficient mice. Synthesizing the results from the retrograde striatum and prelimbic-specific rescue, the next hypothesis tested was a circuity-level manipulation of the medial prefrontal cortex projections to the striatum. Retrograde control (striatum) of chemogenetics (medial prefrontal cortex) decreased the excitatory signaling in the medial prefrontal cortex neurons that project to the striatum, which also led to improved sociability. On the other side of the excitatory/inhibitory balance, increasing inhibitory signaling through acute exposure to small-molecule GABA receptor positive allosteric modulators, clonazepam and AZD7325, rescued sociability.</p> <p>This dissertation opens up new avenues of research by supporting the use of a pre-clinical mouse model of <em>Scn2a</em> deficiency to advance the study of underlying mechanisms behind <em>SCN2A</em>-related neurodevelopmental disorders. Although the results of this dissertation need additional validation such as cellular support, the data and results in this dissertation can serve as a guide to further explore excitatory/inhibitory balance as a neuropharmacogenomics precision medicine target to treat <em>SCN2A</em>-related neurodevelopmental disorders. </p> <p><br></p> <p><br></p>

Autism prevalence studies have often relied on administrative prevalence or clinical diagnosis as case-identification strategies. We report the incidence of clinical diagnoses of autism spectrum disorders (ASD), versus research-identified autism among residents of Olmsted County, Minnesota, age =21 years, from 1976-1997. The incidence of clinically diagnosed ASD (with 95% CI) was 1.5 per 100,000 (0.0-3.7) in 1980-1983 and 33.1 (22.8-43.3) in 1995-1997, a 22.1-fold increase. In contrast, the incidence of research-identified autism increased from 5.5 (1.4-9.5) per 100,000 to 44.9 (32.9-56.9), an 8.2-fold increase. Only 46.8% of research-identified cases received a clinical diagnosis of ASD. These findings demonstrate the potential for misleading interpretation of results from epidemiologic studies that rely on clinical diagnosis of autism to identify cases.

The introduction of comments regarding the care of persons with gender identity disorder (GID) residing in prison settings began in 1998 with Version 5 of the Standards of Care (SOC), the first major revision of the SOC since 1985. Minor revisions to this brief section were made for Version 6 in 2001. Since 2001, there have been many legal and regulatory actions in countries where the SOC are widely used as the minimum standards to evaluate and treat persons with GID that have referenced this section in the SOC. The original paragraph addressing care for incarcerated persons has proven to be helpful by its existence, but limiting in its brevity and lack of scope. Version 7, likely to be a significant revision compared with the minor changes in Version 6, can be informed by the information that has come to light in the last 6 years, most notably through court actions that have used, or misused, the SOC. This invited article reviews the background of this section, rationale for revisions, suggested conceptual changes, and specific content for consideration for inclusion in Version 7 of the SOC.

Objective: Phenomenological and treatment differences between children and adolescents with bipolar I disorder in a public mental health system were examined. Method: A systematic medical record review was performed on a sample of 83 patients, focusing on documented DSM IV symptoms of mania or depression, attention deficit hyperactivity disorder, conduct disorder, schizophrenia, and post-traumatic stress disorder. Cross-tabulation and logistic regression analyses were performed comparing the presence/absence of symptoms for each disorder and treatments provided for children and adolescents. Results: Prepubertal patients were significantly more likely to be male, easily distracted, inattentive, detached from others, hyper-vigilant, prescribed stimulant medication, and to meet the diagnostic criteria for attention-deficit/hyperactivity disorder or Conduct Disorder than adolescents. Conclusions: Consistent with the published literature, phenomenological differences between children and adolescents are present and being recognized for differential diagnosis and treatment by community practitioners. More attention to documenting some cardinal symptoms of mania, the persistence of bipolar symptoms, and the nature of cycling for those with mixed states is needed.