The relationship between physical activity, structural deformity, and spinal mobility in adolescent idiopathic scoliosis patients.

PURPOSE: Adolescent idiopathic scoliosis (AIS) patients experience structural spinal deformity, but the impact of AIS on physical activity is not widely studied. Reports of physical activity levels between children with AIS and their peers are mixed. This study sought to characterize the relationship between spinal deformity, spinal range of motion, and self-reported physical activity in AIS patients. METHODS: Patients aged 11-21 completed self-reported measures of physical activity using the HSS Pedi-FABS and PROMIS Physical Activity questionnaires. Radiographic measures were obtained from standing biplanar radiographic imaging. Surface topographic (ST) imaging data was obtained using a whole-body ST scanning system. Hierarchical linear regression models analyzed the relationship between physical activity, ST, and radiographic deformity while controlling for age and BMI. RESULTS: 149 patients with AIS (mean age 14.5 ± 2.0 years, mean Cobb angle 39.7° ± 18.9°) were included. In the hierarchical regression predicting physical activity from Cobb angle, no factors were significant predictors of physical activity. When predicting physical activity from ST ROM measurements, age and BMI served as covariates. No covariates or ST ROM measurements were significant predictors of physical activity levels for either activity measure. CONCLUSIONS: Physical activity levels of patients with AIS were not predicted by levels of radiographic deformity or surface topographic range of motion. Although patients may experience severe structural deformity and range of motion limitations, these factors do not appear to be associated with decreased physical activity level utilizing validated patient activity questionnaires. LEVEL OF EVIDENCE: Level II.

TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome.

Velo-cardio-facial syndrome (VCFS)/DiGeorge syndrome (DGS) is a human disorder characterized by a number of phenotypic features including cardiovascular defects. Most VCFS/DGS patients are hemizygous for a 1.5-3.0 Mb region of 22q11. To investigate the etiology of this disorder, we used a cre-loxP strategy to generate mice that are hemizygous for a 1.5 Mb deletion corresponding to that on 22q11. These mice exhibit significant perinatal lethality and have conotruncal and parathyroid defects. The conotruncal defects can be partially rescued by a human BAC containing the TBX1 gene. Mice heterozygous for a null mutation in Tbx1 develop conotruncal defects. These results together with the expression patterns of Tbx1 suggest a major role for this gene in the molecular etiology of VCFS/DGS.

Functional characterization of transforming growth factor beta signaling in Smad2- and Smad3-deficient fibroblasts.

A prominent pathway of transforming growth factor (TGF)-beta signaling involves receptor-dependent phosphorylation of Smad2 and Smad3, which then translocate to the nucleus to activate transcription of target genes. To investigate the relative importance of these two Smad proteins in TGF-beta1 signal transduction, we have utilized a loss of function approach, based on analysis of the effects of TGF-beta1 on fibroblasts derived from mouse embryos deficient in Smad2 (S2KO) or Smad3 (S3KO). TGF-beta1 caused 50% inhibition of cellular proliferation in wild-type fibroblasts as assessed by [(3)H]thymidine incorporation, whereas the growth of S2KO or S3KO cells was only weakly inhibited by TGF-beta1. Lack of Smad2 or Smad3 expression did not affect TGF-beta1-induced fibronectin synthesis but resulted in markedly suppressed induction of plasminogen activator inhibitor-1 by TGF-beta1. Moreover, TGF-beta1-mediated induction of matrix metalloproteinase-2 was selectively dependent on Smad2, whereas induction of c-fos, Smad7, and TGF-beta1 autoinduction relied on expression of Smad3. Investigation of transcriptional activation of TGF-beta-sensitive reporter genes in the different fibroblasts showed that activation of the (Smad binding element)(4)-Lux reporter by TGF-beta1 was dependent on expression of Smad3, but not Smad2, whereas activation of the activin response element-Lux reporter was strongly suppressed in S2KO fibroblasts but, on the contrary, enhanced in S3KO cells. Our findings indicate specific roles for Smad2 and Smad3 in TGF-beta1 signaling.

The DNA mismatch repair genes Msh3 and Msh6 cooperate in intestinal tumor suppression.

Repair of mismatches in DNA in mammalian cells is mediated by a complex of proteins that are members of two highly conserved families of genes referred to as MutS and MutL homologues. Germline mutations in several members of these families, MSH2, MSH6, MLH1, and PMS2, but not MSH3, are responsible for hereditary non-polyposis colorectal cancer. To examine the role of MSH3, we generated a mouse with a null mutation in this gene. Cells from Msh3-/- mice are defective in repair of insertion/ deletion mismatches but can repair base-base mismatches. Msh3-/- mice develop tumors at a late age. When the Msh3-/- and Msh6-/- mutations are combined, the tumor predisposition phenotype is indistinguishable from Msh2-/- or Mlh1-/- mice. These results suggest that MSH3 cooperates with MSH6 in tumor suppression.

Postgastrulation Smad2-deficient embryos show defects in embryo turning and anterior morphogenesis.

SMAD2 is a member of the transforming growth factor beta and activin-signaling pathway. To examine the role of Smad2 in postgastrulation development, we independently generated mice with a null mutation in this gene. Smad2-deficient embryos die around day 7.5 of gestation because of failure of gastrulation and failure to establish an anterior-posterior (A-P) axis. Expression of the homeobox gene Hex (the earliest known marker of the A-P polarity and the prospective head organizer) was found to be missing in Smad2-deficient embryos. Homozygous mutant embryos and embryonic stem cells formed mesoderm derivatives revealing that mesoderm induction is SMAD2 independent. In the presence of wild-type extraembryonic tissues, Smad2-deficient embryos developed beyond 7.5 and up to 10.5 days postcoitum, demonstrating a requirement for SMAD2 in extraembryonic tissues for the generation of an A-P axis and gastrulation. The rescued postgastrulation embryos showed malformation of head structures, abnormal embryo turning, and cyclopia. Our results show that Smad2 expression is required at several stages during embryogenesis.

Mouse models for colorectal cancer.

Colorectal cancer (CRC) is one of the most common cancers in the Western world. Much has been learned about colorectal cancer from human inherited syndromes, such as familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC). Mouse models for CRC were generated by introducing mutations into the mouse genes, whose human counterparts were implicated in the onset and progression of CRC. Central among these are mice carrying mutations in the Adenomatous polyposis coli (Apc) gene. Although most of these Apc mutations share some common phenotypes as homozygous embryonic lethality and tumor predisposition, the severity of the tumor predisposition is variable. Mice with mutations in the mismatch repair genes, Msh2 and Mlh1, exhibit a mismatch repair defect and are predisposed to developing gastrointestinal cancer, lymphomas and tumors of other organ systems. Mice carrying a mutation in the Pms2 gene are predisposed to lymphomas and other tumors. Mice with a mutation in the Msh6 gene have a defect in base mismatch repair and show a tumor predisposition phenotype. Mice with mutations in Mlh1, Pms2 and Msh5 have defects in meiosis suggesting unique roles for these genes in gametogenesis.

Tumorigenesis in Mlh1 and Mlh1/Apc1638N mutant mice.

An3 1 KAL I MutL homologue 1 (MLH1) is a member of the family of proteins required for DNA mismatch repair. Germ-line mutations in MLH1 lead to the cancer susceptibility syndrome hereditary nonpolyposis colorectal cancer (HNPCC). We generated mice carrying a null mutation in the Mlh1 gene. We showed that mice heterozygous and homozygous for the Mlh1 gene are predisposed to developing tumors of the gastrointestinal (GI) tract, lymphomas, and a number of other tumor types. We also examined the role of adenomatous polyposis coli gene (Apc) gene mutations in the GI tumors of Mlh1 mutant mice by different methods and showed that the GI tumors in Mlh1 mice express little or no adenomatous polyposis coli protein. When an Apc gene mutation was bred into the Mlh1 mutant mice, the GI tumor incidence increased 40-100-fold. The wild-type Apc allele in these tumors was found to contain mutations. Together, these results show that we have developed two mouse models for human HNPCC and that the mechanisms of tumor development in the GI tract of these mice involve loss of Apc gene function in a manner very similar to that seen in the GI tumors of HNPCC.

Mammalian MutS homologue 5 is required for chromosome pairing in meiosis.

MSH5 (MutS homologue 5) is a member of a family of proteins known to be involved in DNA mismatch repair. Germline mutations in MSH2, MLH1 and GTBP (also known as MSH6) cause hereditary non-polyposis colon cancer (HNPCC) or Lynch syndrome. Inactivation of Msh2, Mlh1, Gtmbp (also known as Msh6) or Pms2 in mice leads to hereditary predisposition to intestinal and other cancers. Early studies in yeast revealed a role for some of these proteins, including Msh5, in meiosis. Gene targeting studies in mice confirmed roles for Mlh1 and Pms2 in mammalian meiosis. To assess the role of Msh5 in mammals, we generated and characterized mice with a null mutation in Msh5. Msh5-/- mice are viable but sterile. Meiosis in these mice is affected due to the disruption of chromosome pairing in prophase I. We found that this meiotic failure leads to a diminution in testicular size and a complete loss of ovarian structures. Our results show that normal Msh5 function is essential for meiotic progression and, in females, gonadal maintenance.

Goosecoid-like (Gscl), a candidate gene for velocardiofacial syndrome, is not essential for normal mouse development.

Velocardiofacial syndrome (VCFS) and DiGeorge syndrome (DGS) are characterized by a wide spectrum of abnormalities, including conotruncal heart defects, velopharyngeal insufficiency, craniofacial anomalies and learning disabilities. In addition, numerous other clinical features have been described, including frequent psychiatric illness. Hemizygosity for a 1.5-3 Mb region of chromosome 22q11 has been detected in >80% of VCFS/DGS patients. It is thought that a developmental field defect is responsible for many of the abnormalities seen in these patients and that the defect occurs due to reduced levels of a gene product active in early embryonic development. Goosecoid-like ( GSCL ) is a homeobox gene which is present in the VCFS/DGS commonly deleted region. The mouse homolog, Gscl, is expressed in mouse embryos as early as E8.5. Gscl is related to Goosecoid ( Gsc ), a gene required for proper craniofacial development in mice. GSCL has been considered an excellent candidate for contributing to the developmental defects in VCFS/DGS patients. To investigate the role of Goosecoid-like in VCFS/DGS etiology, we disrupted the Gscl gene in mouse embryonic stem cells and produced mice that transmit the disrupted allele. Mice that are homozygous for the disrupted allele appear to be normal and they do not exhibit any of the anatomical abnormalities seen in VCFS/DGS patients. RNA in situ hybridization to mouse embryo sections revealed that Gscl is expressed at E8.5 in the rostral region of the foregut and at E11.5 and E12.5 in the developing brain, in the pons region and in the choroid plexus of the fourth ventricle. Although the gene inactivation experiments indicate that haploinsufficiency for GSCL is unlikely to be the sole cause of the developmental field defect thought to be responsible for many of the abnormalities in VCFS/DGS patients, its localized expression during development could suggest that hemizygosity for GSCL, in combination with hemizygosity for other genes in 22q11, contributes to some of the developmental defects as well as the behavioral anomalies seen in these patients. The mice generated in this study should help in evaluating these possibilities.

The interleukin 2 receptor alpha chain/CD25 promoter is a target for nuclear factor of activated T cells.

The expression of the murine interleukin (IL)-2 receptor alpha chain/CD25 is strongly induced at the transcriptional level after T cell activation. We show here that nuclear factor of activated T cell (NF-AT) factors are involved in the control of CD25 promoter induction in T cells. NF-ATp and NF-ATc bind to two sites around positions -585 and -650 located upstream of the proximal CD25 promoter. Immediately 3' from these NF-AT motifs, nonconsensus sites are located for the binding of AP-1-like factors. Mutations of sites that suppress NF-AT binding impair the induction and strong NF-ATp-mediated transactivation of the CD25 promoter in T cells. In T lymphocytes from NF-ATp-deficient mice, the expression of CD25 is severely impaired, leading to a delayed IL-2 receptor expression after T cell receptor (TCR)/CD3 stimulation. Our data indicate an important role for NF-AT in the faithful expression of high affinity IL-2 receptors and a close link between the TCR-mediated induction of IL-2 and IL-2 receptor alpha chain promoters, both of which are regulated by NF-AT factors.

Retarded thymic involution and massive germinal center formation in NF-ATp-deficient mice.

NF-ATp and NF-ATc are the most prominent nuclear NF-AT transcription factors in peripheral T lymphocytes. After T cell activation both factors bind to and control the promoters and enhancers of numerous lymphokine and receptor ligand genes. In order to define a specific role for NF-ATp in vivo we have inactivated the NF-ATp gene by gene targeting in mice. We show that NF-ATp deficiency leads to the accumulation of peripheral T cells with a "preactivated" phenotype, enhanced immune responses of T cells after secondary stimulation in vitro and severe defects in the proper termination of antigen responses, as shown by a reduced deletion of superantigen-reactive CD4+ T cells. These alterations in the function of the immune system are correlated with drastic changes in the morphology of lymphoid organs. Approximately 25 % of NF-ATp-deficient mice older than 6 months develop large germinal centers in the spleen and peripheral lymph nodes. In addition, they exhibit a pronounced retardation in the involution of the thymus. The thymus of these NF-ATp-deficient mice exhibits large cortical areas typical for newborn mice and a massive infiltration of IgM+/ IgD+ B lymphocytes. Contrary to the T lymphocytes from IL-2-deficient mice which develop a phenotype similar to the NF-ATp-/- mice, NF-ATp-/- T cells do not show obvious defects in Fas-mediated apoptosis. This might indicate defects in other types of programmed cell death which are controlled by the activity of NF-ATp.

Mutation in the mismatch repair gene Msh6 causes cancer susceptibility.

Mice carrying a null mutation in the mismatch repair gene Msh6 were generated by gene targeting. Cells that were homozygous for the mutation did not produce any detectable MSH6 protein, and extracts prepared from these cells were defective for repair of single nucleotide mismatches. Repair of 1, 2, and 4 nucleotide insertion/deletion mismatches was unaffected. Mice that were homozygous for the mutation had a reduced life span. The mice developed a spectrum of tumors, the most predominant of which were gastrointestinal tumors and B- as well as T-cell lymphomas. The tumors did not show any microsatellite instability. We conclude that MSH6 mutations, like those in some other members of the family of mismatch repair genes, lead to cancer susceptibility, and germline mutations in this gene may be associated with a cancer predisposition syndrome that does not show microsatellite instability.

Inefficient termination of antigen responses in NF-ATp-deficient mice.

In order to elucidate the role of NF-ATp, one of the most prominent members of family of NF-AT transcription factors in peripheral T lymphocytes, in T cell activation and differentiation we created NF-ATp-deficient mice by gene targeting. Such NF-ATp-/- mice are born and appear to develop a normal immune system. Apart from clear-cut defects in the synthesis of mRNAs for Th2-type lymphokines, such as IL-4, IL-5, IL-10 and IL-13, in primary and secondary stimulations of spleen cells in vitro, of a distinct impaired deletion of V beta 11+/CD4+ T lymphocytes from these mice was detected after superantigen injection. Moreover, NF-ATp-/- mice older than 6 weeks show an 2-5 fold increase in number of lymphocytes. This is correlated with an increased expression of activation markers CD44 and CD69 and decreased expression of CD62.

The responsibilities of speech-language pathologists toward children with ADHD.

The speech-language pathologist has the skills needed to be an active participant in both the diagnostic and intervention phases of the treatment of children with ADHD. Many of the behaviors that define ADHD are directly linked to communication. Westby and Cutler (1994) assert that "the strong association between language disorders and ADHD suggests the possibility of a common antecedent to both disorders, perhaps a temperamental or neurological characteristic linked to deficits in behavioral regulation" (p. 61). Although the speech-language pathologist may not have the security of standardized test scores to support his or her diagnosis, behaviors that cannot be tested (e.g., pragmatics and social interactions) may be keys to a child's classroom difficulties. As discussed, many of the criteria found in the DSM-IV diagnostic criteria for ADHD are characteristics of pragmatic skills. Supported by Barkley's (1993) new theory of ADHD which is based on poor response inhibition or inability to delay responses, the speech-language pathologist can be an important resource to both the teacher and parents by helping them understand the behaviors exhibited by an ADHD child. The impulsivity that is so disruptive in the classroom is directly linked to the inability to delay responses. It is agreed that continued research into the behavioral characteristics associated with ADHD as well as their long-term implications for learning is needed. ADHD is a multifaceted developmental disorder. There is no known cure for ADHD, and we are dependent on early diagnosis and ongoing intervention to reduce its lifelong effects. Effective treatment must be multi-modal and involve the coordination of a professional team as well as the child's family. It is vital that we help children with ADHD develop positive self-esteem, effective social skills, and good pragmatic language skills that will eventually have a positive impact on their functioning in all aspects of their interactions with their environment. If this is accomplished, the effects of ADHD will be minimized. The speech-language pathologist needs to take a leadership role in this process.

Eye movements in myotonic dystrophy.

Smooth pursuit eye movements were studied with infrared reflection equipment in 10 patients with myotonic dystrophy and in 10 age- and sex-matched controls. Smooth pursuit gain, measured after correction for catch-up saccades, was decreased in the patient group. Normal latencies of saccadic eye movements made a lack of attention an unlikely explanation for this low gain. Likewise, presence of catch-up saccades and normal fixation made it unlikely that extra-ocular myopathy explained the low smooth pursuit gain. We suggest that periventricular white matter abnormalities represent a more likely explanation.

Horizontal and vertical saccadic eye movement abnormalities in Huntington's chorea.

With a newly developed infrared reflection technique, voluntary saccadic eye movements (VOLS), visually evoked saccades (VES) and unsuppressed visually evoked reflex saccades (USVERS) were measured in 11 patients with Huntington's chorea. Abnormalities, including latency increase, peak velocity decrease and undershoot dysmetria with multiple step saccades were found in all types of saccadic eye movements. Peak velocity decrease and undershoot dysmetria can be explained by dysfunction of the brainstem reticular formation in Huntington's chorea. USVERS and square wave jerks occurred abnormally frequently and showed direction-dependent differences. Both were more frequent in horizontal than in vertical direction. Frequency of USVERS and square-wave jerks tended to be correlated. These findings point to disinhibited superior colliculi as a possible common supranuclear origin of USVERS and square-wave jerks in Huntington's chorea.