UNITY: A low-field magnetic resonance neuroimaging initiative to characterize neurodevelopment in low and middle-income settings.

Measures of physical growth, such as weight and height have long been the predominant outcomes for monitoring child health and evaluating interventional outcomes in public health studies, including those that may impact neurodevelopment. While physical growth generally reflects overall health and nutritional status, it lacks sensitivity and specificity to brain growth and developing cognitive skills and abilities. Psychometric tools, e.g., the Bayley Scales of Infant and Toddler Development, may afford more direct assessment of cognitive development but they require language translation, cultural adaptation, and population norming. Further, they are not always reliable predictors of future outcomes when assessed within the first 12-18 months of a child's life. Neuroimaging may provide more objective, sensitive, and predictive measures of neurodevelopment but tools such as magnetic resonance (MR) imaging are not readily available in many low and middle-income countries (LMICs). MRI systems that operate at lower magnetic fields (< 100mT) may offer increased accessibility, but their use for global health studies remains nascent. The UNITY project is envisaged as a global partnership to advance neuroimaging in global health studies. Here we describe the UNITY project, its goals, methods, operating procedures, and expected outcomes in characterizing neurodevelopment in sub-Saharan Africa and South Asia.

Co-occurrence of Aicardi-Goutières syndrome type 6 and dyschromatosis symmetrica hereditaria due to compound heterozygous pathogenic variants in ADAR1: a case series from India.

Aicardi-Goutières syndrome type 6 (AGS6) and dyschromatosis symmetrica hereditaria (DSH) are allelic disorders caused respectively by biallelic and heterozygous pathogenic variants in ADAR1. We report three unrelated children presenting with features of both AGS6 and DSH, two of whom had compound heterozygous pathogenic variants in ADAR1. We also describe the novel genetic variants in our cases and review the literature on association of ADAR1-related AGS6 and DSH with these phenotypes.

Effect of cryptosporidial and giardial diarrhoea on social maturity, intelligence and physical growth in children in a semi-urban slum in south India.

BACKGROUND: Early childhood diarrhoea is a major cause of infant morbidity and mortality in developing countries. Recurrent and persistent diarrhoea affect growth and cognition in children as young as 6 years. OBJECTIVES: To evaluate the effect of early childhood cryptosporidial and giardial diarrhoea on growth and development in children in a semi-urban slum in India. This is the first report of such assessment at 3 years of age. METHODS: This study was undertaken on 116 children who were part of an ongoing birth cohort study (n=452) of rotaviral and cryptosporidial diarrhoea between June and December 2005. Social quotients (SQ) assessed by the Vineland Social Maturity Scale, intelligence quotients (IQ) assessed by the Seguin Form Board Test, physical growth parameters and sociodemographic data in 84 children with a history of cryptosporidial or giardial diarrhoea were compared with those of 32 without diarrhoea. RESULTS: Children with a past history of giardial diarrhoea showed a trend towards lower SQ (p=0.09) and had significantly lower IQ (p=0.04) and increased wasting (p=0.04). Cryptosporidial diarrhoea was not associated with poor IQ, SQ or physical growth. CONCLUSION: This study demonstrates the long-term effect of protozoan diarrhoea, especially that caused by giardia, on both intelligence and physical growth in Indian children as early as 3 years of age and re-inforces the need for early detection and prevention of early childhood protozoan diarrhoea.

A pilot study of the use and perceived utility of a scale to assess clinical dental teaching within a UK dental school restorative department.

INTRODUCTION: Feedback on individual teaching performance gives an important contribution and support to the reflective practices of educators. Unfortunately, feedback is an infrequent exercise provided to dental teachers about their teaching practices. The Effective Clinical Dental Teaching (ECDT) scale has been used previously to assess clinical teachers, but has not been used within the UK. METHODS: This study looks at the use of the ECDT scale in the setting of a UK dental school, as a method of feedback collection and delivery in seven domains of clinical teaching. The ECDT was used to evaluate the teaching of 16 clinical teachers by dental undergraduates, and to investigate the opinions of these clinical teachers and clinical dental students about the utility of this scale. RESULTS: The study identified that there was a disparity between self and student perception of teaching. The total ECDT scores ranged from a minimum of 55% 66.6/125 to a maximum of 90% 113.8/125, with a mean group score of 73% 91.6/125. Most clinicians evaluated by students scored above 3/5 for all teaching domains, although there appeared to be significant differences between the four teacher groups. The majority of staff and students were in favour of the use of such a scale to support the progression and development of teaching styles. CONCLUSION: The ECDT scale is a useful tool for highlighting the areas of strength and deficiency within clinical dental teaching. Its use may complement peer review for individual teachers and identify future topics for staff development sessions. Further research is recommended to identify the individual strengths and weaknesses that different types of teacher may bring to curriculum teaching.

Coherence between cortical and muscular activities after subcortical stroke.

BACKGROUND AND PURPOSE: Functional connection between the motor cortex and muscle can be measured by electroencephalogram-electromyogram (EEG-EMG) coherence. To evaluate the functional connection to muscle between contralateral and ipsilateral motor cortices after pyramidal tract lesions, we investigated 6 patients with chronic subcortical stroke. METHODS: High-resolution EEG and EMG of the hand, forearm, and biceps muscles were recorded during 3 tonic contraction tasks: (1) elbow flexion, (2) wrist extension, and (3) power grip. To evaluate the cortical control of EMG, EEG-EMG coherence was computed. RESULTS: EEG-EMG coherence was localized over the contralateral sensorimotor area in all circumstances, and there was no significant coherence at the ipsilateral side. EEG-EMG coherence was significantly smaller on the affected side for the hand and forearm muscles but not for the biceps muscle. CONCLUSIONS: All direct functional connections to muscle after recovered subcortical stroke come from the contralateral motor cortex. The different effects of the lesion on the proximal and distal muscles appear to be associated with the strength of the corticospinal pathway.

Haplotype variation and linkage disequilibrium in 313 human genes.

Variation within genes has important implications for all biological traits. We identified 3899 single nucleotide polymorphisms (SNPs) that were present within 313 genes from 82 unrelated individuals of diverse ancestry, and we organized the SNPs into 4304 different haplotypes. Each gene had several variable SNPs and haplotypes that were present in all populations, as well as a number that were population-specific. Pairs of SNPs exhibited variability in the degree of linkage disequilibrium that was a function of their location within a gene, distance from each other, population distribution, and population frequency. Haplotypes generally had more information content (heterozygosity) than did individual SNPs. Our analysis of the pattern of variation strongly supports the recent expansion of the human population.

Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures.

Spinocerebellar ataxia type 1 (SCA1) is one of several neurodegenerative disorders caused by an expansion of a polyglutamine tract. It is characterized by ataxia, progressive motor deterioration, and loss of cerebellar Purkinje cells. To understand the pathogenesis of SCA1, we examined the subcellular localization of wild-type human ataxin-1 (the protein encoded by the SCA1 gene) and mutant ataxin-1 in the Purkinje cells of transgenic mice. We found that ataxin-1 localizes to the nuclei of cerebellar Purkinje cells. Normal ataxin-1 localizes to several nuclear structures approximately 0.5 microm across, whereas the expanded ataxin-1 localizes to a single approximately 2-microm structure, before the onset of ataxia. Mutant ataxin-1 localizes to a single nuclear structure in affected neurons of SCA1 patients. Similarly, COS-1 cells transfected with wild-type or mutant ataxin-1 show a similar pattern of nuclear localization; with expanded ataxin-1 occurring in larger structures that are fewer in number than those of normal ataxin-1. Colocalization studies show that mutant ataxin-1 causes a specific redistribution of the nuclear matrix-associated domain containing promyelocytic leukaemia protein. Nuclear matrix preparations demonstrate that ataxin-1 associates with the nuclear matrix in Purkinje and COS cells. We therefore propose that a critical aspect of SCA1 pathogenesis involves the disruption of a nuclear matrix-associated domain.

The cerebellar leucine-rich acidic nuclear protein interacts with ataxin-1.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder characterized by ataxia, progressive motor deterioration, and loss of cerebellar Purkinje cells. SCA1 belongs to a growing group of neurodegenerative disorders caused by expansion of CAG repeats, which encode glutamine. Although the proteins containing these repeats are widely expressed, the neurodegeneration in SCA1 and other polyglutamine diseases selectively involves a few neuronal subtypes. The mechanism(s) underlying this neuronal specificity is unknown. Here we show that the cerebellar leucine-rich acidic nuclear protein (LANP) interacts with ataxin-1, the SCA1 gene product. LANP is expressed predominantly in Purkinje cells, the primary site of pathology in SCA1. The interaction between LANP and ataxin-1 is significantly stronger when the number of glutamines is increased. Immunofluorescence studies demonstrate that both LANP and ataxin-1 colocalize in nuclear matrix-associated subnuclear structures. The features of the interaction between ataxin-1 and LANP, their spatial and temporal patterns of expression, and the colocalization studies indicate that cerebellar LANP is involved in the pathogenesis of SCA1.

The CAG/polyglutamine tract diseases: gene products and molecular pathogenesis.

In the past few years, a new type of genetic mutation, expansion of trinucleotide repeats, has been shown to cause neurologic disease. This new class of mutations was first identified in 1991 as the underlying genetic defect in spinal and bulbar muscular atrophy and the fragile X syndrome, and in recent years, trinucleotide repeat expansions have been found to be the causative mechanism in 10 other neurologic diseases. These mutations are produced by heritable unstable DNA and are termed "dynamic mutations" because of changes in the number of repeat units inherited from generation to generation. In the normal population, these repeat units, although polymorphic, are stably inherited. To date four types of trinucleotide repeat expansions have been identified: (1) long cytosine-guanine-guanine (CGG) repeats in the two fragile X syndromes (FRAXA and FRAXE), (2) long cytosine-thymine-guanine (CTG) repeat expansions in myotonic dystrophy, (3) long guanine-adenine-adenine repeat expansions in Friedreich's ataxia and (4) short cytosine-adenine-guanine repeat expansions (CAG) which are implicated in eight neurodegenerative disorders and are the focus of this review. Diseases that are caused by trinucleotide repeat expansions exhibit a phenomenon called anticipation that can not be explained by conventional Mendelian genetics. Anticipation is defined as increase in the severity of disease with an earlier age of onset of symptoms in successive generations. Anticipation is often influenced by the sex of the transmitting parent, and for most CAG repeat disorders, the disease is more severe when paternally transmitted. The severity and the age of onset of the disease have been correlated with the size of the repeats on mutant alleles, with the age of onset being inversely correlated with the size of the expansion. In all eight disorders caused by CAG repeat expansion, the repeat is located within the coding region of the gene involved and in all cases it is translated into a stretch of polyglutamines in the respective proteins. All the proteins are unrelated outside of the polyglutamine stretch and most are novel with exception of the androgen receptor and the voltage gated alpha 1A calcium channel, which are mutated in spinal and bulbar muscular atrophy and spinocerebellar ataxia type 6. It is intriguing that the proteins are ubiquitously expressed in both peripheral and nervous tissue but in each disorder only a select population of nerve cells are targeted for degeneration as a consequence of the expanded CAG repeat. Current thinking among scientists working on the molecular mechanisms of neurodegeneration in these diseases is that the presence of an expanded polyglutamine confers a gain of function onto the involved protein. To understand the mechanisms underlying the pathogenesis of these diseases, investigators have turned to generating transgenic mice which recapitulate some of the features of the human disease and hence are excellent model systems to study the progression of the disease in vivo.

Identification of a self-association region within the SCA1 gene product, ataxin-1.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by the expansion of a polyglutamine tract within the SCA1 gene product, ataxin-1. Expansion of this tract is believed to result in a gain of function by the mutant protein, perhaps through altered self-associations or interactions with other cellular proteins. We have used the yeast two hybrid system to determine if ataxin-1 is capable of multimerization. This analysis revealed that ataxin-1 does have the ability to self-associate, however, this association does not appear to be influenced by expansion of the polyglutamine tract. Consistent with this finding, deletion analysis excluded the involvement of the polyglutamine tract in ataxin-1 self-association, and instead localized the multimerization region to amino acids 495-605 of the wild type protein. These results, while identifying an ataxin-1 self-interaction region, fail to support a proposed model of polar-zipper mediated multimerization involving the ataxin-1 polyglutamine tract.

Spinocerebellar ataxia type-1 and spinobulbar muscular atrophy gene products interact with glyceraldehyde-3-phosphate dehydrogenase.

Spinocerebellar ataxia type1 (SCA1) is one of several neurodegenerative disorders caused by expansions of translated CAG trinucleotide repeats which code for polyglutamine in the respective proteins. Most hypotheses about the molecular defect in these disorders suggest a gain of function, which may involve interactions with other proteins via the expanded polyglutamine tract. In this study we used ataxin-1, the SCA1 gene product, as a bait in the yeast two-hybrid system and identified the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase as an ataxin-1 interacting protein. In addition, the yeast two hybrid data demonstrate that wild type and mutant ataxin-1 form homo and heterodimers. Physical interaction between GAPDH and ataxin-1 was also demonstrated in vitro. To investigate if GAPDH might interact with other glutamine repeat-containing proteins involved in neurodegenerative disorders, we tested its binding to the androgen receptor which is mutated in spinobulbar muscular atrophy. The androgen receptor interacts with GAPDH both in the yeast two-hybrid system and in vitro. The binding of both ataxin-1 and the androgen receptor to GAPDH does not vary with the length of the polyglutamine tract. While provocative, these findings do not address the selective neuronal loss in each of these disorders in light of the wide expression patterns of GAPDH and the respective polyglutamine containing proteins. Nonetheless, such interactions may increase the susceptibility of specific neurons to a variety of insults and initiate degeneration.

Antigenic determinants at the carboxy terminus of chicken egg white riboflavin carrier protein (RCP): epitope mapping and antibody-mediated pregnancy curtailment in rodents.

The epitopic core sequences recognized by three monoclonal antibodies raised to chicken riboflavin carrier protein (RCP) were mapped to the C-terminal tail-end of the protein using the pepscan method. A 21-residue synthetic peptide corresponding to residues 200-219 of the protein and comprising the regions corresponding to the antibodies was synthesized. Administration of polyclonal antibodies specific to this peptide led to termination of early pregnancy in mice. Also, active immunization of rats with the peptide-purified protein derivative conjugate inhibited establishment of pregnancy. These results demonstrate the functional importance of the C-terminal 200-219 region of chicken RCP.

Expression analysis of the ataxin-1 protein in tissues from normal and spinocerebellar ataxia type 1 individuals.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by expansion of a CAG trinucleotide repeat which codes for glutamine in the protein ataxin-1. We have investigated the effect of this expansion on ataxin-1 by immunoblot analysis. The wild-type protein is detected in both normal and affected individuals; however, a mutant protein which varies in its migration properties according to the size of the CAG repeat is detected in cultured cells and tissues from SCA1 individuals. The protein has a nuclear localization in all normal and SCA1 brain regions examined but a cytoplasmic localization of ataxin-1 was also observed in cerebellar Purkinje cells. Our data show that in SCA1, the expanded alleles are faithfully translated into proteins of apparently normal stability and distribution.