The cumulative impact of attention deficit hyperactivity disorder, autism and intellectual disability for young people.

BACKGROUND: Neurodevelopmental conditions frequently co-occur. The aim of this paper was to determine whether there is a cumulative association between (1) the number of neurodevelopmental conditions, specifically hyperkinetic disorder (hereafter referred to as attention deficit hyperactivity disorder), autism spectrum disorder (hereafter referred to as autism) and intellectual disability, and (2) behavioural and socio-emotional problems and the level of clinician-rated functioning for young males and females. METHODS: In this cross-sectional study, diagnostic information, caregiver-rated behavioural and socio-emotional data (as conceptualised by the Strengths and Difficulties Questionnaire) and clinician-rated functioning scores (as conceptualised by the Children's Global Assessment Scale) were extracted from electronic patient records for 2768 young people aged 3-17 years (mean = 11.55, SD = 3.46). All data were extracted at baseline, that is, at the time the young person was diagnosed with attention deficit hyperactivity disorder, autism and/or an intellectual disability. Ordinal regression analyses tested associations between the number of neurodevelopmental conditions met (i.e. 1, 2 or 3) and behavioural and socio-emotional outcomes and functioning. RESULTS: After controlling for age and biological sex, the number of neurodevelopmental conditions was associated with higher levels of inattention/hyperactivity and peer problems, lower levels of prosocial behaviour and poorer clinician-rated functioning. Although these findings were consistent for males, a cumulative association was not identified for females, except for clinician-rated functioning. CONCLUSIONS: For young people, the presence of multiple neurodevelopmental conditions may have a cumulative impact across domains, but this may differ between males and females.

A Scoping Review of HIV Pre-exposure Prophylaxis Stigma and Implications for Stigma-Reduction Interventions for Men and Transwomen Who Have Sex with Men.

HIV remains a public health concern in the United States. Although pre-exposure prophylaxis (PrEP) can be expected to reduce HIV incidence, its uptake, adherence, and persistence remain limited, particularly among highest priority groups such as men who have sex with men and transwomen (MSMTW). Using a socioecological framework, we conducted a scoping review to examine PrEP-related stigma to inform future research, policy, and programmatic planning. Using the PRISMA extension for scoping reviews, we conducted database searches from August 2018 to April 2020 for articles addressing PrEP stigma. Studies were independently screened and coded by three authors, resulting in thematic categorization of several types of PrEP stigma on four socioecological levels. Of 557 references, a final sample of 23 studies was coded, 61% qualitative, and 87% focusing exclusively on MSMTW. Most instances of PrEP-related stigma occurred on the interpersonal level and included associations of PrEP with risk promotion, HIV-related stigma, and promiscuity. Other frequent themes across socioecological levels included provider distrust and discrimination, government and pharmaceutical industry distrust, internalized homonegativity, PrEP efficacy distrust, and anticipated homonegativity. Notably, PrEP was also framed positively as having physical and psychological benefits, and assuming responsibility for protecting one's community via PrEP awareness-raising. PrEP-related stigma persists, demanding interventions to modify its impact. Leveraging PrEP-positive discourses to challenge PrEP stigma is an emerging avenue, alongside efforts to increase provider willingness to promote PrEP routinely by reducing provider bias, aligning with the national strategy to End the HIV Epidemic.

Predicting the diagnosis of autism in adults using the Autism-Spectrum Quotient (AQ) questionnaire.

BACKGROUND: Many adults with autism spectrum disorder (ASD) remain undiagnosed. Specialist assessment clinics enable the detection of these cases, but such services are often overstretched. It has been proposed that unnecessary referrals to these services could be reduced by prioritizing individuals who score highly on the Autism-Spectrum Quotient (AQ), a self-report questionnaire measure of autistic traits. However, the ability of the AQ to predict who will go on to receive a diagnosis of ASD in adults is unclear. METHOD: We studied 476 adults, seen consecutively at a national ASD diagnostic referral service for suspected ASD. We tested AQ scores as predictors of ASD diagnosis made by expert clinicians according to International Classification of Diseases (ICD)-10 criteria, informed by the Autism Diagnostic Observation Schedule-Generic (ADOS-G) and Autism Diagnostic Interview-Revised (ADI-R) assessments. RESULTS: Of the participants, 73% received a clinical diagnosis of ASD. Self-report AQ scores did not significantly predict receipt of a diagnosis. While AQ scores provided high sensitivity of 0.77 [95% confidence interval (CI) 0.72-0.82] and positive predictive value of 0.76 (95% CI 0.70-0.80), the specificity of 0.29 (95% CI 0.20-0.38) and negative predictive value of 0.36 (95% CI 0.22-0.40) were low. Thus, 64% of those who scored below the AQ cut-off were 'false negatives' who did in fact have ASD. Co-morbidity data revealed that generalized anxiety disorder may 'mimic' ASD and inflate AQ scores, leading to false positives. CONCLUSIONS: The AQ's utility for screening referrals was limited in this sample. Recommendations supporting the AQ's role in the assessment of adult ASD, e.g. UK NICE guidelines, may need to be reconsidered.

Signal pathways which promote invasion and metastasis: critical and distinct contributions of extracellular signal-regulated kinase and Ral-specific guanine exchange factor pathways.

Approximately 50% of metastatic tumors contain Ras mutations. Ras proteins can activate at least three downstream signaling cascades mediated by the Raf-MEK-extracellular signal-regulated kinase family, phosphatidylinositol-3 (PI3) kinase, and Ral-specific guanine nucleotide exchange factors (RalGEFs). Here we investigated the contribution of RalGEF and ERK activation to the development of experimental metastasis in vivo and associated invasive properties in vitro. Each pathway contributes distinct properties to the metastatic phenotype. Following lateral tail vein injection, 3T3 cells transformed by constitutively active Raf or MEK produced lung metastasis that displayed circumscribed, noninfiltrating borders. In contrast, 3T3 cells transformed by Ras(12V,37G), a Ras effector mutant that activates RalGEF but not Raf or P13 kinase, formed aggressive, infiltrative metastasis. Dominant negative RalB inhibited Ras(12V,37G)-activated invasion and metastasis, demonstrating the necessity of the RalGEF pathway for a fully transformed phenotype. Moreover, 3T3 cells constitutively expressing a membrane-associated form of RalGEF (RalGDS-CAAX) formed invasive tumors as well, demonstrating that activation of a RalGEF pathway is sufficient to initiate the invasive phenotype. Despite the fact that Ras(12V,37G) expression does not elevate ERK activity, inhibition of this kinase by a conditionally expressed ERK phosphatase demonstrated that ERK activity was necessary for Ras(12V,37G)-transformed cells to express matrix-degrading activity in vitro and tissue invasiveness in vivo. Therefore, these experiments have revealed a hitherto-unknown but essential interaction of the RalGEF and ERK pathways to produce a malignant phenotype. The generality of the role of the RalGEF pathway in metastasis is supported by the finding that Ras(12V,37G) increased the invasiveness of epithelial cells as well as fibroblasts.

Mg(++)-induced endothelial cell migration: substratum selectivity and receptor-involvement.

The activation of endothelial cells during angiogenesis requires cell spreading and migration. These processes are influenced by extracellular signals such as chemoattractants from the local microenvironment. We have shown previously that transmembrane Ca++ influx is necessary for motility and cell spreading, thus we hypothesized that the extracellular divalent cations Mg++ and Ca++ may regulate human umbilical vein endothelial cell (HUVEC) spreading and act as chemoattractants. Studies demonstrated that extracellular Mg++ induced a statistically better spread phenotype when cells were plated on multiple extracellular matrix substrata; Ca++ promoted cell spreading only on vitronectin. Mg++ but not Ca++ acted as a potent chemoattractant when HUVEC migrated on gelatin- and type IV collagen- but not on vitronectin-coated filters. A checkerboard analysis of migration showed that Mg++ induces both chemokinetic and chemotactic migration peaking at 0.1 and 10 mM, respectively. An equivalent effect of oligomycin was seen on motility to Mg++ or to vascular endothelial growth factor (VEGF) in extracellular Mg(++)-free conditions, ruling out an exclusive role for Mg++ as a migration energy producer. The Mg(++)-stimulated chemotaxis was inhibited > 60% by pertussis toxin, d-erythrosphingosine, and tyrphostin B48, but unaffected by cholera toxin exposure. These data suggest that Mg(++)-induced chemotaxis may be promoted through a Gi protein-coupled receptor pathway with a requirement for protein kinase C activity and protein tyrosine phosphorylation. Thus, Mg++ may be a newly recognized receptor-mediated chemoattractant for endothelial cells.

Cyclocreatine inhibits stimulated motility in tumor cells possessing creatine kinase.

Cyclocreatine (1-carboxymethyl-2-iminoimidazolidine), an analog of creatine and a substrate for creatine kinase (EC 2.7.3.2), inhibits the stimulated motility of tumor cells which possess creatine kinase. A2058-055 human melanoma cells, transfected with a creatine kinase gene, showed an 80-90% reduction in chemotactic response to type IV collagen when incubated overnight in the presence of 10 mM cyclocreatine (p < 0.0001 for n = 8 experiments). This inhibitory effect of cyclocreatine can be partially reversed by addition of creatine to the overnight cell treatment. Non-transfected cells, with very low levels of creatine kinase, were not significantly inhibited. Further experiments utilizing type IV collagen as attractant demonstrated that cyclocreatine inhibited the chemokinetic (91%) and the haptotactic (73%) responses and the in vitro invasion of A2058-055 cells through Matrigel-coated membranes (88%). In addition, motility stimulation of A2058-055 cells by either autotaxin or fibronectin was markedly inhibited by cyclocreatine. DU-145 prostatic tumor cells, which express endogenous creatine kinase, also have a reduced motility response to either autotaxin or epidermal growth factor induced motility in the presence of cyclocreatine.

Adenosine receptor mediates motility in human melanoma cells.

Cell motility is an essential component of tumor progression and metastasis. A number of factors, both autocrine and paracrine, have been found to influence cell motility. In the present study, adenosine and adenine nucleotides directly stimulated chemotaxis of A2058 melanoma cells in the absence of exogenous factors. Three adenosine receptor agonists stimulated motility in the melanoma cells and two adenosine receptor antagonists strongly inhibited the chemotactic response to both adenosine and AMP. The chemotactic stimulation by adenosine and AMP was pertussis toxin sensitive. Otherwise unresponsive Chinese hamster ovary cells which were transfected with the adenosine A1 receptor cDNA acquired the direct, pertussis toxin sensitive, chemotactic response to adenosine, and this response was inhibited by adenosine receptor antagonists. These findings demonstrate that adenosine and adenine nucleotides are capable of stimulating chemotaxis of tumor cells mediated through an adenosine receptor, probably of the A1 subtype. The possibility of antimetastatic therapies based on inhibition of adenosine receptor activity is raised.

Growth, metastasis, and invasiveness of Drosophila tumors caused by mutations in specific tumor suppressor genes.

More than 50 genes have been identified in Drosophila by loss-of-function mutations that lead to overgrowth of specific tissues. Loss-of-function mutations in the lethal giant larvae, discs large, or brain tumor genes cause neoplastic overgrowth of larval brains and imaginal discs. In the present study, the growth and metastatic potential of tumors resulting from mutations in these genes were quantified. Overgrown brains and imaginal discs were transplanted into adults and beta-galactosidase accumulation was used as a marker to identify donor cells. Mutations in these three genes generated tumors with similar metastatic patterns. For brain tumors, the metastatic index (a measure we defined as the fraction of hosts that acquired secondary tumors normalized for the amount of primary tumor growth) of each of the three mutants was similar. Analysis of cell proliferation in mutant brains suggests that the tumors arise from a population of several hundred cells which represent only 1-2% of the cells in third instar larval brains. For imaginal disc tumors from lethal giant larvae and brain tumor mutants, it is shown for the first time that they can be metastatic and invasive. Primary imaginal disc tumors from lethal giant larvae and brain tumor mutants formed secondary tumors in 43 and 53% of the hosts, respectively, although the secondary tumors were, in general, smaller than the secondary tumors derived from primary brain tumors.

General mechanisms of metastasis.

In the present article, the steps involved in the process of tumor metastasis are discussed. Several events are required for malignant cells to leave the primary tumor and proliferate at a distant site: vessel formation (angiogenesis), cell attachment, invasion (matrix degradation, cell motility), and cell proliferation. Molecular mechanisms underlying each of these steps are described. Based on blocking these processes, new anti-metastasis therapies are being developed.

Stimulation of tumor cell motility linked to phosphodiesterase catalytic site of autotaxin.

A family of extracellular type I phosphodiesterases has recently been isolated by cDNA cloning, but a physiological function linked to the phosphodiesterase active site has remained unknown. We now present evidence that the phosphodiesterase catalytic site, 201YMRPVYPTKTFPN213, is essential for the motility stimulating activity of autotaxin (ATX), one member of the exophosphodiesterase family. Native ATX possesses phosphodiesterase activity at neutral and alkaline pH, binds ATP noncovalently, and undergoes threonine phosphorylation. Homogeneously purified recombinant ATX, based on the teratocarcinoma sequence, retains these same activities. A single amino acid in the phosphodiesterase catalytic site, Thr210, is found to be necessary for motility stimulation, phosphodiesterase activity, and phosphorylation. Two mutant recombinant proteins, Ala210- and Asp210-ATX, lack motility stimulation and lack both enzymatic activities; Ser210-ATX possesses intermediate activities. Another mutation, with the adjacent lysine (Lys209) changed to Leu209-ATX, possesses normal motility stimulation with sustained phosphodiesterase activity but exhibits no detectable phosphorylation. This mutation eliminates the phosphorylation reaction and indicates that the dephosphorylated state is an active motility-stimulating form of the ATX molecule. By demonstrating that the phosphodiesterase enzymatic site is linked to motility stimulation, these data reveal a novel role for this family of exo/ecto-enzymes and open up the possibility of extracellular enzymatic cascades as a regulatory mechanism for cellular motility.

Genomic structure of a Y-specific ribonucleic acid binding motif-containing gene: a putative candidate for a subset of male infertility.

The genetic basis of infertility remains unclear in a majority of infertile men. Deletion mapping studies suggest that genes on the long arm of the Y-chromosome (Yq) may be important in the spermatogenic process and may play a pathogenetic role in a subset of infertile men. Complementary DNA sequences of two Y-specific genes that contain ribonucleic acid binding motifs and, therefore, referred to as RBM genes (previously named YRRM) were published recently. To develop a PCR-single strand conformation polymorphism strategy for detection of point mutations in the RBM gene(s) in infertile men, we determined the genomic structure and flanking sequences at the intron-exon junctions. Two separate strategies were used in parallel to isolate the genomic fragment bearing the RBM gene. The first strategy employed screening of a P1 genomic library using PCR primers corresponding to the sequences in the 5'- and 3'-ends of the published RBM-1 complementary DNA sequence. The second strategy used subcloning of the YAC clone 925D10 (that contained the RBM gene described here) into cosmids. The P1 and cosmid clones were further restriction mapped and subcloned for DNA sequencing. Because the sequences contained in the P1 and cosmid clones were identical, the sequence information was pooled. A 15-kilobase genomic segment includes the entire RBM gene. The genomic structure of this RBM gene is characterized by 12 exons and 11 introns. There is considerable homology among exons VII, VIII, IX, and X; each encodes one of the SRGY boxes. Several introns also have a high degree of homology among them (introns VI, VII, VIII, and IX). Eleven of the 12 exons have complete sequence homology with the RBM-1 sequence. There is 1 base difference in exon IV at position 495 (a T in the previously published DNA sequence vs. an A in the sequence reported here). The exonic sequences of this gene are distinct from that of the RBM-2 gene. The flanking sequences at the exon-intron junctions were also determined and are reported. Reverse transcription-PCR analysis, using human testis ribonucleic acid suggests that this gene is either not expressed in the testis or, more likely, the single base difference from RBM1 represents a polymorphism in the YAC clone. A high degree of homology between intronic and exonic sequences within the same gene and between different members of the RBM gene family (data not reported in this paper) suggests origin from common ancestral sequences; this also indicates that development of a single strand conformation polymorphism approach for detection of point mutations is likely to prove difficult for some of the exons of this gene.

Increased type IV collagenase in lgl-induced invasive tumors of Drosophila.

Loss of function mutations in the lethal giant larvae (lgl) gene causes neoplastic brain tumors in Drosophila. We have introduced a lacZ reporter gene into lgl mutant cells and used beta-galactosidase expression as a marker to monitor the growth of such tumors following transplantation into wild-type adult hosts. Whereas normal larval brains do not grow when transplanted, mutant brains can develop into enormous tumors that fill the entire abdominal cavity. To investigate whether these tumors are similar to mammalian tumors at the biochemical level, we examined the accumulation of a specific protein which is differentially expressed in mammalian metastatic tumors and is likely to be involved in the invasive and/or metastatic mechanism. Increased accumulation of a 72 kilodalton (kDa) type IV collagenase has been observed in several metastatic human tumors. Using antibodies directed against this human 72 kDa type IV collagenase, we show for the first time that Drosophila has a cross-reacting 49 kDa protein with gelatinase activity. In brains dissected from lgl mutant larvae, the accumulation of this 49 kDa gelatinase of Drosophila is increased compared to the level in brains dissected from wild-type larvae. In tumors derived from mutant brains, all of the cells express this protein. Moreover, the tumor cells that invade host organs express this protein. These data suggest that the metastasis of Drosophila tumor cells is similar to the metastasis of some human tumors at the biochemical level as well as at the cellular level.

The expression of the Drosophila awd gene during normal development and in neoplastic brain tumors caused by lgl mutations.

The abnormal wing discs (awd) gene of Drosophila is homologous to the nm23 gene of mammals, a gene whose expression is altered in metastatic tumors. Both awd and nm23 encode nucleoside diphosphate kinases (NDP kinases). We have examined the accumulation of AWD/NDP kinase during normal development by assaying enzyme activity in extracts. There is a nearly constant level of activity throughout larval and pupal development. We have examined the tissue-specific transcription of the awd gene by RNA in situ hybridization and by reporter gene expression. In imaginal discs and brains there is no detectable awd gene expression until the beginning of the third larval instar, despite the constant level of enzyme activity measured in extracts of larvae and pupae. The most intense awd gene expression in imaginal discs and brains occurs after the end of larval development. We have also examined awd gene expression in neoplastic brain tumors caused by mutations in the lethal giant larvae (lgl) gene. In lgl mutant brains, as in normal brains, awd gene expression begins during the third larval instar. No tumors form in brains from lgl-; awd- double mutant larva, so awd gene expression is required for tumor formation and/or proliferation. There is more accumulation of AWD/NDP kinase in lgl- mutant brains than there is in normal brains. Using an awd reporter gene, we show that this is a consequence of an increased proportion of awd gene-expressing cells in mutant brains. Using the same awd reporter gene as a marker of donor cells, we have confirmed the invasiveness of lgl-induced neuroblastomas.

Human cysticercosis: antigens, antibodies and non-responders.

Immunoelectrophoresis of sera from patients with brain cysticercosis against a crude antigenic extract from Cysticercus cellulosae indicates that nearly 50% of the patients do not make sufficient antibodies to ostensively precipitate. The other 50% of the patients who do make precipitating antibodies show a very heterogeneous response in the number of antigens they recognize as well as in the type of antigen--as classified by their electrophoretic mobilities. The most favoured, called antigen B, is recognized by 84% of positive sera and corresponds to one or a limited number of antigens isoelectric at pH 8.6. Indirect immunofluorescence with monospecific anti-human immunoglobulins, performed upon the immunoelectrophoretic preparations, reveal that all cysticercus antigens induced the synthesis of antibodies in the immunoglobulin classes in the order G greater than M greater than E greater than A greater than D. Finally, antigen H (an anodic component) seems to favour IgE relative to its ability to induce IgG. Thus, although in natural infection a good proportion of cysticercotic patients do not seem to mount an energetic antibody response against the parasite, giving rise to some speculations about immunosuppression, the fact that 50% do synthesize antibodies allows for some optimistic expectations from vaccination of humans--in view of the good results of vaccination in experimental animals mediated by IgG antibodies. A likely prospect for a human vaccine would be antigen B because it is the most frequently detected by humans, although its immunizing and toxic properties remain to be properly studied.

Fibrous contracture of bladder neck: cause, prevention, and treatment.

Through a retrospective study of bladder neck contracture it was found that bladder neck resection and incision were equally effective for treatment of postoperative bladder neck contractures. It was also found that incising the bladder neck at the end of transurethral resection of the prostate (TURP) did not cause vesicoureteral reflux and did not improve the incidence of postoperative bladder neck contracture.

[Seroepidemiologic study of human cysticerosis in the predominantly indigenous rural Indian population of the State of Chiapas]. / Estudio seroepidemiológico de la cisticercósis humana en problaciones predominantemente indígenas y rurales del estado de Chiapas

The overall proportion of sera with antibodies against cyticercus antigens in 3226 serum samples collected among the Indian rural population in the proximity of San Cristóbal de Las Casas, Chiapas, México is 0.49. The proportion of positive sera varied from 0.4 to 7.6% inversely with the number of inhabitants in the community. The global proportion of positive sera in Chiapas being considerably lower than that expected from the autopsy frequency of brain cysticercosis in México City (1.4-3.6%), it is perhaps indicative of different epidemiologic dynamics in rural and urban areas.