Al-Gazali Skeletal Dysplasia Constitutes the Lethal End of ADAMTSL2-Related Disorders.

Lethal short-limb skeletal dysplasia Al-Gazali type (OMIM %601356), also called dysplastic cortical hyperostosis, Al-Gazali type, is an ultra-rare disorder previously reported in only three unrelated individuals. The genetic etiology for Al-Gazali skeletal dysplasia has up until now been unknown. Through international collaborative efforts involving seven clinical centers worldwide, a cohort of nine patients with clinical and radiographic features consistent with short-limb skeletal dysplasia Al-Gazali type was collected. The affected individuals presented with moderate intrauterine growth restriction, relative macrocephaly, hypertrichosis, large anterior fontanelle, short neck, short and stiff limbs with small hands and feet, severe brachydactyly, and generalized bone sclerosis with mild platyspondyly. Biallelic disease-causing variants in ADAMTSL2 were detected using massively parallel sequencing (MPS) and Sanger sequencing techniques. Six individuals were compound heterozygous and one individual was homozygous for pathogenic variants in ADAMTSL2. In one of the families, pathogenic variants were detected in parental samples only. Overall, this study sheds light on the genetic cause of Al-Gazali skeletal dysplasia and identifies it as a semi-lethal part of the spectrum of ADAMTSL2-related disorders. Furthermore, we highlight the importance of meticulous analysis of the pseudogene region of ADAMTSL2 where disease-causing variants might be located. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Parent Traumatic Stress After Minor Pediatric Burn Injury.

Parents are at increased risk for psychological sequelae following their child's burn injury which has demonstrated negative impacts on the child. The current study sought to address gaps in the literature on risk factors for parental distress by examining the relationships among demographic variables, burn characteristics, and child functioning after burn injury, with parent post-traumatic stress symptoms (PTSS). Participants included parents of 660 pediatric burn patients from a regional burn clinic. Parents completed measures during their initial visit to the burn clinic. Additional demographic and burn data were retrospectively collected by medical chart review. Fifteen percent of parents reported at-risk levels of parent PTSS. Parent PTSS was independently associated with child burn characteristics of total body surface area (TBSA) affected by the burn, required hospitalization, number of nights hospitalized, and number of ambulatory burn appointments attended. Minority race was associated with higher parent PTSS than non-minority race status, with Asian parents endorsing the highest scores. Furthermore, when considered simultaneously, impaired child quality of life (QOL), a higher number of ambulatory burn appointments attended, and racial minority status were associated with higher parent PTSS. These findings highlight the need for routine parent trauma screening in pediatric burn clinics, while additionally identifying a feasible screening measure.

Anger Outbursts in Youth with ASD and Anxiety: Phenomenology and Relationship with Family Accommodation.

Anger outbursts (AO) are associated with severe symptoms, impairment and poorer treatment outcomes for anxious children, though limited research has examined AO in youth with co-occurring autism and anxiety disorders. This study examined AO in children with autism and anxiety by evaluating clinical characteristics, family accommodation, and changes in AO following anxiety-focused treatment. The sample comprised 167 youth with autism and anxiety enrolled in a multi-site randomized clinical trial comparing standard care CBT for anxiety, CBT adapted for youth with autism, and usual care. Most participants (60%) had AO, which contributed to impairment above and beyond anxiety and autism. AO impacted functional impairment indirectly through a pathway of parental accommodation. AO reduced with anxiety-focused treatment. Findings highlight that AO are common in this population and uniquely contribute to functional impairment, indicating a need for direct targeting in treatment.

Novel molecular mechanisms in Alzheimer's disease: The potential role of DEK in disease pathogenesis.

Alzheimer's disease and age-related dementias (AD/ADRD) are debilitating diseases that exact a significant physical, emotional, cognitive, and financial toll on the individual and their social network. While genetic risk factors for early-onset AD have been identified, the molecular and genetic drivers of late-onset AD, the most common subtype, remain a mystery. Current treatment options are limited for the 35 million people in the United States with AD/ADRD. Thus, it is critically important to identify novel molecular mechanisms of dementia-related pathology that may be targets for the development of new interventions. Here, we summarize the overarching concepts regarding AD/ADRD pathogenesis. Then, we highlight one potential molecular driver of AD/ADRD, the chromatin remodeling protein DEK. We discuss in vitro, in vivo, and ex vivo findings, from our group and others, that link DEK loss with the cellular, molecular, and behavioral signatures of AD/ADRD. These include associations between DEK loss and cellular and molecular hallmarks of AD/ADRD, including apoptosis, Tau expression, and Tau hyperphosphorylation. We also briefly discuss work that suggests sex-specific differences in the role of DEK in AD/ADRD pathogenesis. Finally, we discuss future directions for exploiting the DEK protein as a novel player and potential therapeutic target for the treatment of AD/ADRD.

Long Non-Coding RNAs: The New Frontier into Understanding the Etiology of Alcohol Use Disorder.

Alcohol use disorder (AUD) is a complex, chronic, debilitating condition impacting millions worldwide. Genetic, environmental, and epigenetic factors are known to contribute to the development of AUD. Long non-coding RNAs (lncRNAs) are a class of regulatory RNAs, commonly referred to as the "dark matter" of the genome, with little to no protein-coding potential. LncRNAs have been implicated in numerous processes critical for cell survival, suggesting that they play important functional roles in regulating different cell processes. LncRNAs were also shown to display higher tissue specificity than protein-coding genes and have a higher abundance in the brain and central nervous system, demonstrating a possible role in the etiology of psychiatric disorders. Indeed, genetic (e.g., genome-wide association studies (GWAS)), molecular (e.g., expression quantitative trait loci (eQTL)) and epigenetic studies from postmortem brain tissues have identified a growing list of lncRNAs associated with neuropsychiatric and substance use disorders. Given that the expression patterns of lncRNAs have been associated with widespread changes in the transcriptome, including methylation, chromatin architecture, and activation or suppression of translational activity, the regulatory nature of lncRNAs may be ubiquitous and an innate component of gene regulation. In this review, we present a synopsis of the functional impact that lncRNAs may play in the etiology of AUD. We also discuss the classifications of lncRNAs, their known functional roles, and therapeutic advancements in the field of lncRNAs to further clarify the functional relationship between lncRNAs and AUD.

In silico gene expression and pathway analysis of DEK in the human brain across the lifespan.

DEK, a chromatin-remodelling phosphoprotein, is associated with various functions and biological pathways in the periphery, including inflammation, oncogenesis, DNA repair, and transcriptional regulation. We recently identified an association between DEK loss and central nervous system diseases, such as Alzheimer's. To understand DEK's potential role in disease, it is critical to characterize DEK in healthy human brain to distinguish between neural DEK expression and function in healthy versus diseased states like dementia. We utilized two public databases, BrainCloud and Human Brain Transcriptome, and analysed DEK mRNA expression across the lifespan in learning and memory relevant brain regions. Since DEK loss induces phenotypes associated with brain ageing (e.g., DNA damage and apoptosis), we hypothesized that neural DEK expression may be highest during foetal development and lower in elderly individuals. In agreement with this hypothesis, DEK was most prominently expressed during foetal development in all queried forebrain areas, relative to other ages. Consistent with its roles in the periphery, pathways related to DEK in the brain were associated with cellular proliferation, DNA replication and repair, apoptosis, and inflammation. We also found novel neural development-relevant pathways (e.g., synaptic transmission, neurite outgrowth, and myelination) to be enriched from genes correlated with DEK expression. These findings suggest that DEK is important for human brain development. Overall, we highlight age-related changes in neural DEK expression across the human lifespan and illuminate novel biological pathways associated with DEK that are distinct from normal brain ageing. These findings may further our understanding of how DEK impacts brain function and disease susceptibility.

Genetic variation within a species of parasitic nematode, Skrjabingylus chitwoodorum, in skunks.

Carnivores in the families Mustelidae and Mephitidae are essential hosts for the cranial roundworm genus Skrjabingylus. A high prevalence of Skrjabingylus chitwoodorum has been observed in the striped skunk, Mephitis mephitis. Genetic barcoding studies of other nematodes have successfully used the cytochrome oxidase I (COI) mitochondrial gene to analyze genetic variation and divergence. We tested the hypothesis that low population structuring occurs within S. chitwoodorum because M. mephitis is widespread across much of North America and has high levels of gene flow. We extracted DNA from 38 samples of Skrjabingylus removed from the sinuses of M. mephitis and one from the plains spotted skunk, Spilogale putorius interrupta, for amplification and sequencing of COI. Analysis of 492 base pairs confirmed all samples were S. chitwoodorum and showed low genetic divergence (1.0%) within Texas, but high haplotype diversity. Supporting our hypothesis, no obvious divergent lineages based on geographic location were recovered within the samples based on Maximum Likelihood analysis and median joining haplotype network analysis. In fact, samples of Skrjabingylus from New York and South Dakota showed little difference compared with samples from Texas.

Loss of DEK Expression Induces Alzheimer's Disease Phenotypes in Differentiated SH-SY5Y Cells.

Alzheimer's disease (AD) is the most common cause of dementia and is characterized by the buildup of ß-amyloid plaques and neurofibrillary Tau tangles. This leads to decreased synaptic efficacy, cell death, and, consequently, brain atrophy in patients. Behaviorally, this manifests as memory loss and confusion. Using a gene ontology analysis, we recently identified AD and other age-related dementias as candidate diseases associated with the loss of DEK expression. DEK is a nuclear phosphoprotein with roles in DNA repair, cellular proliferation, and inhibiting apoptosis. Work from our laboratory determined that DEK is highly expressed in the brain, particularly in regions relevant to learning and memory, including the hippocampus. Moreover, we have also determined that DEK is highly expressed in neurons. Consistent with our gene ontology analysis, we recently reported that cortical DEK protein levels are inversely proportional to dementia severity scores in elderly female patients. However, the functional role of DEK in neurons is unknown. Thus, we knocked down DEK in an in vitro neuronal model, differentiated SH-SY5Y cells, hypothesizing that DEK loss would result in cellular and molecular phenotypes consistent with AD. We found that DEK loss resulted in increased neuronal death by apoptosis (i.e., cleaved caspases 3 and 8), decreased ß-catenin levels, disrupted neurite development, higher levels of total and phosphorylated Tau at Ser262, and protein aggregates. We have demonstrated that DEK loss in vitro recapitulates cellular and molecular phenotypes of AD pathology.

Altered juvenile fish communities associated with invasive Halophila stipulacea seagrass habitats in the U.S. Virgin Islands.

Caribbean seagrass habitats provide food and protection for reef-associated juvenile fish. The invasive seagrass Halophila stipulacea is rapidly altering these seascapes. Since its arrival in the Caribbean in 2002, H. stipulacea has colonized and displaced native seagrasses, but the function of this invasive seagrass as a juvenile fish habitat remains unknown. To compare diversity, community structure, and abundance of juvenile fish between H. stipulacea and native seagrass beds, fish traps were deployed in four nearshore bays around St. Thomas, U.S. Virgin Islands. Traps were deployed in Frenchman, Lindbergh, and Sprat Bays for 24 h intervals in patches of bare sand, patches of H. stipulacea and patches of the native Caribbean seagrasses Thalassia testudinum and Syringodium filiforme. Traps were then deployed in Brewers Bay for 12 h intervals in stands of H. stipulacea and S. filiforme. Relative and total abundances of juvenile fish, identified at least to family, were compared across treatment habitats for each trap deployment period. The catch from H. stipulacea, compared to native seagrasses, comprised a greater abundance of nocturnal carnivores Lutjanus synagris (family Lutjanidae) and Haemulon flavolineatum (family Haemulidae). Additionally, the herbivore species Sparisoma aurofrenatum (family Labridae) and Acanthurus bahianus (family Acanthuridae) and the diurnal carnivore species Pseudopeneus maculatus (family Mullidae) were relatively scarce in H. stipulacea. The catch from sand was much smaller, compared to vegetated habitats, and comprised only L. synagris, H. flavolineatum, and H. aurolineatum. These results provide evidence of reduced family diversity and altered juvenile fish assemblages in H. stipulacea, driven by an abundance of some nocturnal carnivores and scarcity of herbivores and diurnal carnivores. The findings from the present work underpin the need for further investigation and mitigation of this invasion, particularly where H. stipulacea is driving seascape-alterations of key juvenile fish habitats.

Active surveillance of very-low-risk prostate cancer in the setting of active treatment of benign prostatic hyperplasia with 5α-reductase inhibitors.

OBJECTIVE: To review the efficacy of treating benign prostatic hyperplasia and very-low-risk prostate cancer (PCa) in patients receiving active surveillance and 5α-reductase inhibitor (5-ARI; finasteride or dutasteride) treatment. MATERIALS AND METHODS: Eighty-two men with very-low-risk PCa (clinical stage T1c, Gleason score ≤ 6, <3 biopsy cores positive with ≤ 50% involvement, and prostate-specific antigen density ≤ 0.15 ng/mL/g) and benign prostatic hyperplasia (≥ 30 cm(3)) received active surveillance and were treated with a 5-ARI. RESULTS: All 82 men completed 1 year of 5-ARI therapy (n = 79) or underwent early biopsy for cause (n = 3). Restaging biopsies were performed for 76 men (22 underwent a second restaging biopsy and 1 a third restaging biopsy), 4 patients were awaiting biopsy, and 2 were lost to follow-up before the first restaging biopsy. At the first restaging biopsy, of the 76 men, 41 (54%) had no PCa, 16 (21%) continued to have very-low-risk PCa, 15 (20%) had progressed to low-risk PCa (>2 cores positive and Gleason score ≤ 6), and 4 (5%) had progressed to intermediate-risk PCa (Gleason score 7). Of the 76 biopsies, 20 were performed early for cause, with 11 (55%) showing PCa progression. Of the 82 patients, 22 (27%) underwent treatment of PCa. CONCLUSION: Active surveillance of very-low-risk PCa in the setting of 5-ARI therapy for benign prostatic hyperplasia appears to be a safe therapeutic option, because most (57 of 82; 70%) patients maintained very-low-risk PCa or had negative follow-up biopsies during a 3-year follow-up period. Complementary to the Prostate Cancer Prevention Trial, our results indicate that 5-ARI therapy increases prostate-specific antigen sensitivity and can aid the clinician in appropriately targeting biopsies.

Two-step transurethral surgery of the prostate and permanent implant brachytherapy for patients with lower urinary tract symptoms and low- to intermediate-risk prostate cancer.

PURPOSE: Prostate brachytherapy is an increasingly used treatment option for low- to intermediate-risk prostate cancer (PCa). However, patients with preexisting lower urinary tract symptoms (LUTS) and PCa, who would otherwise be good brachytherapy candidates, are often contraindicated because of the risk of postoperative urinary morbidity. We report our clinical experience with limited transurethral resection of the prostate (LTURP) and/or transurethral incision of the prostate (TUIP) months before brachytherapy to treat patients with LUTS and low- to intermediate-risk PCa. METHODS AND MATERIALS: Of 258 men undergoing prostate brachytherapy at our institution between 1998 and 2011, 42 were treated with planned LTURP and/or TUIP well before (mean, 5.7 months) seed implantation. Transurethral surgery was considered before brachytherapy for patients who at presentation required α-blocker therapy for LUTS, had an International Prostate Symptom Score greater than 14 off α-blockers, or had an elevated postvoid residual (>100 mL). Patients only proceeded to brachytherapy once LUTS resolved. RESULTS: All 42 patients in our series underwent TUIP (25), LTURP (7), or TUIP/LTURP (10) with mean 5.7 months before prostate brachytherapy for low- or intermediate-risk PCa. Mean International Prostate Symptom Score, peak flow rate, and postvoid residual significantly improved after transurethral surgery, and improvement persisted at the latest followup. No patient developed retention, urethral necrosis, or urinary incontinence after transurethral surgery or brachytherapy (median followup, 39 months and range, 1-121). CONCLUSIONS: Planned LTURP and/or TUIP more than 4 months before brachytherapy is a safe and effective treatment strategy for men with LUTS and low- to intermediate-risk PCa.

Anaplastic nephroblastomas express transketolase-like enzyme 1.

AIM: Transketolase-like enzyme 1 (TKTL1) is a glycolytic enzyme that has been found to be upregulated in several tumours, and it is associated with tumour progression. Nephroblastoma is the commonest paediatric renal malignancy and has a good prognosis except for those with anaplasia. To the best of the authors' knowledge, the expression of TKTL1 in nephroblastomas has not been studied before and the aim of this study was to compare the immunoexpression of TKTL1 in anaplastic and non-anaplastic nephroblastomas. METHODS: Twenty-eight patients who had nephrectomies for nephroblastomas were studied. Archival formalin-fixed paraffin-wax-embedded tissue sections were stained with monoclonal TKTL1 antibody. RESULTS: Six of the 15 anaplastic nephroblastomas showed staining in 80-100% of the tumour (p = 0.36). None of the 13 non-anaplastic nephroblastomas showed TKTL1 staining in >80% of the tumour. CONCLUSION: TKTL1 expression is associated with the presence of anaplasia and may be a mechanism via which anaplastic tumour cells thrive under different conditions. Glycolytic inhibitors may play a role in anaplastic nephroblastomas.

Efficacy of membrane TNF mediated host resistance is dependent on mycobacterial virulence.

TNF is required for protection against virulent and non-virulent mycobacterial infections. Here we compared the effect of Tm-TNF and sTNF, two different molecular forms of TNF, in virulent and non-virulent murine challenge models. Using non-virulent Mycobacterium bovis BCG intranasal infection we established that immunity is durably compromised in Tm-TNF mice, with augmented bacilli burden, leading to chronic but non-lethal infection. Acute infection by a virulent Mycobacterium tuberculosis low-dose aerosol challenge was controlled in Tm-TNF mice with bacilli burdens equivalent to that in WT mice and pulmonary pathology characterised by the formation of well-defined, bactericidal granulomas. Protective immunity was however compromised in Tm-TNF mice during the chronic phase of M. tuberculosis infection, with increased lung bacterial growth and inflammatory cell activation, dissolution of granulomas associated with dispersed iNOS expression, increased pulmonary IFNgamma and IL-10 expression but decreased IL-12 production, followed by death. In conclusion, membrane TNF is sufficient to control non-virulent, M. bovis BCG infection, and acute but not chronic infection with virulent M. tuberculosis.

Increased resistance to mycobacterial infection in the absence of interleukin-10.

Interleukin-10 (IL-10) down-regulates T helper type 1 cell and macrophage functions. As IL-10 is induced along with tumour necrosis factor (TNF) and IL-12 in mycobacterial infection, we asked whether endogenous IL-10 plays a role in the antimycobacterial response. We demonstrate here that IL-10-deficient mice eliminate Mycobacterium bovis Calmette-Guérin bacillus faster than wild-type mice. Granulomas are significantly larger, containing more CD-11b- and CD11c-positive antigen-presenting cells and T cells, and the expression of major histocompatibility complex class II and intracellular adhesion molecule-1 is increased. Macrophages in granulomas of IL-10-deficient mice express high levels of TNF, acid phosphatase and inducible nitric oxide synthase (iNOS). Finally, an increased cutaneous delayed-type hypersensitivity reaction to mycobacterial proteins is further evidence of an augmented cell-mediated immune response. In conclusion, the cell-mediated immunity is enhanced in the absence of IL-10, resulting in a robust granuloma response, which accelerates the clearance of mycobacteria. Therefore, endogenous IL-10 attenuates mycobacterial immunity.

Tumor necrosis factor receptor 2 plays a minor role for mycobacterial immunity.

Tumor necrosis factor (TNF) signalling via the TNF receptor 1 (TNF-R1) is required for host resistance to mycobacterial infection. The role of TNF-R2 in anti-mycobacterial immunity is not known. Therefore, we compared TNF-R1 and TNF-R2 knockout (KO) mice infected with Mycobacterium bovis BCG (10(7) CFU, i.v.). While the bacterial burden of TNF-R1-deficient mice was significantly increased and the mice succumbed to infection between 4 and 5 weeks, TNF-R2 KO mice were less sensitive, and only 3 of 10 mice died within 12 weeks. Wild-type (WT) mice were resistant to BCG infection. The inability to clear the infection of TNF-R1 KO mice was associated with a reduced delayed-type hypersensitivity (DTH) response to purified protein derivative and severe impairment in forming granulomas with reduced macrophage recruitment and activation, and diminished expression of adhesion molecules. By contrast, TNF-R2 KO mice developed normal DTH response and mature mycobactericidal granulomas as the WT mice. Therefore, anti-mycobacterial immunity is largely dependent on TNF signalling via the TNF-R1, while activation of TNF-R2 plays a minor role.

Fatal Mycobacterium bovis BCG infection in TNF-LT-alpha-deficient mice.

Neutralization of TNF or disruption of TNF-R1 leads to fatal Mycobacterium bovis BCG infection. Here we used TNF-LT-alpha-deficient mice to test whether a complete disruption of TNF and LT-alpha reduces further host resistance to BCG infection. The bacterial burden especially in the lungs of TNF-LT-alpha-deficient mice was significantly increased and the mice succumbed to infection between 8 and 10 weeks. In the absence of TNF-LT-alpha the granulomatous response was severely impaired and delayed. The cells in the granulomas of TNF-LT-alpha-deficient mice expressed low levels of MHC class II and ICAM-1. They contained a few T cells and F4/80-positive macrophages expressing little iNOS and acid phosphatase activity. By contrast, the lethal action of endotoxin was dramatically reduced in BCG-infected TNF-LT-alpha-deficient mice. In summary, in the absence of TNF-LT-alpha the recruitment and activation of mononuclear cells in response to BCG infection were significantly delayed and reduced resulting in immature granulomas allowing uncontrolled fatal infection.

Hearing conservation programs in Massachusetts' vocational/technical schools.

A survey of vocational/technical schools in Massachusetts was performed to evaluate the prevalence of and need for hearing conservation programs. The surveys were sent to the superintendents or principals of all 27 regional schools in Massachusetts. Surveys consisted of questions in the areas of shop noise exposure, use of safety equipment, and hearing conservation education. Results indicate that (1) many teachers and students may be exposed to hazardous noise levels (2) hearing protection is not required in one-third of the schools and is used less frequently than other safety equipment, and (3) teachers desire additional training in hearing conservation and would welcome the assistance of an audiologist. These results point out the need for obtaining measurements of noise levels in the school shops, designing hearing conservation programs for school settings, implementing mandatory use of hearing protection, and providing education in hearing conservation for students and teachers.