Analysis of Variation in Clubfoot Candidate Genes

Isolated clubfoot, a common birth defect occurring in more than 135,000 livebirths worldwide each year, is associated with significant health care and financial burdens. Clubfoot is defined by forefoot adduction, hindfoot varus, midfoot cavus and hindfoot equinus. Isolated clubfoot, which is the focus of these studies, is distinct from syndromic clubfoot because there are no other associated malformations. Population, family, twin and segregation analysis studies provide evidence that genetic and environmental factors play an etiologic role in isolated clubfoot. The studies described in this thesis were performed to define the role of genetic variation in isolated clubfoot. Interrogation of a deletion region associated with syndromic clubfoot, suggested that CASP8 and CASP10, two apoptotic genes, play a role in isolated clubfoot. To explore the role of apoptotic genes in clubfoot, SNPs spanning genes involved in the apoptotic pathway in the six chromosomal deletion regions, and limb patterning genes, HOXD and HOXA, were interrogated. SNPs in mitochondrial mediated apoptotic genes and several SNPs in HOXA and HOXD genes were modestly associated with clubfoot with the most significant SNP, rs3801776, located in the basal promoter of HOXA9. Several significant associations were found with SNPs in NFAT2 and TNIP2. Significant gene interactions were detected between SNPs in HOX and apoptotic genes. These findings suggest a model for clubfoot in which variation in one gene is not sufficient to cause the malformation but requires variation several genes to perturb protein expression sufficiently to alter muscle and foot development. These results significantly impact our knowledge base by delineating underlying mechanisms causing clubfoot.

CD8+ Pagetoid Reticulosis Presenting as a Solitary Foot Plaque in a Young Woman.

Background: Pagetoid reticulosis is a rare variant of mycosis fungoides. This rare condition typically presents as a solitary plaque located on the extremities with an indolent clinical course (Woringer-Kolopp disease) or as a more generalized presentation with diffuse cutaneous involvement and a more aggressive clinical course (Ketron-Goodman disease). Purpose: To review the cutaneous manifestations, pathology, and treatment of localized pagetoid reticulosis. Methods: The authors describe a 24-year-old woman with a slowly enlarging, localized plaque of seven months duration, representing the localized form of pagetoid reticulosis with CD8+ immunophenotype. Results: The histological, immunohistochemical, and clinical features of the patient's skin lesion were characteristic for a diagnosis of Woringer-Kolopp disease. Systemic work-up for lymphoma was negative. Conclusion: Woringer-Kolopp disease is most commonly seen in middle-aged men as a solitary lesion of the extremities, and it should always be considered in the differential diagnosis when a patient presents with such a lesion. A histological analysis demonstrated atypical lymphocytes preferentially localized to the epidermis with a CD4+, CD8+, or CD4-/CD8- phenotype. The treatment of choice for a solitary lesion may be localized radiation therapy, but newer therapies, such as bexarotene, may warrant further investigation.

Polysensory interneuronal projections to foot contractile pedal neurons in Hermissenda.

A Pavlovian-conditioning procedure may produce modifications in multiple behavioral responses. As an example, conditioning may result in the elicitation of a specific somatomotor conditioned response (CR) and, in addition, other motor and visceral CRs. In the mollusk Hermissenda conditioning produces two conditioned responses: foot-shortening and decreased locomotion. The neural circuitry supporting ciliary locomotion is well characterized, although the neural circuit underlying foot-shortening is poorly understood. Here we describe efferent neurons in the pedal ganglion that produce contraction or extension of specific regions of the foot in semi-intact preparations. Synaptic connections between polysensory type Ib and type Is interneurons and identified foot contractile efferent neurons were examined. Type Ib and type Is interneurons receive synaptic input from the visual, graviceptive, and somatosensory systems. Depolarization of type Ib interneurons evoked spikes in identified tail and lateral foot contractile efferent neurons. Mechanical displacement of the statocyst evoked complex excitatory postsynaptic potentials (EPSPs) and spikes recorded from type Ib and type Is interneurons and complex EPSPs and spikes in identified foot contractile efferent neurons. Depolarization of type Ib interneurons in semi-intact preparations produced contraction and shortening along the rostrocaudal axis of the foot. Depolarization of Is interneurons in semi-intact preparations produced contraction of the anterior region of the foot. Taken collectively, the results suggest that type Ib and type Is polysensory interneurons may contribute to the neural circuit underlying the foot-shortening CR in Hermissenda.

The impact of a brief foot care intervention for persons with diabetes

Purpose of the study. The purpose of this randomized controlled clinical trial was to determine if a brief intervention would improve foot self-care behaviors in adult patients with Type 2 diabetes who presented to the emergency department for non-emergent care in a predominantly Hispanic southwestern border community. ^ Methods. A pre-post-test, three-group design was used to compare the foot self-care behaviors of patients who received usual care to those who received lower extremity amputation (LEA) risk assessment and to those who received LEA risk assessment plus a brief foot self-care intervention. After being randomized into 3 groups (N = 167), baseline assessments of demographics, diabetes history, acculturation, and the Summary of Diabetes Self Care Activities (SDSCA) questionnaire and Modified Insulin Management Diabetes Self Efficacy Scale (MIMDSES) were completed in English or Spanish. At one-month, 144 (84%) participants were available for follow-up by the research assistant masked to group assignment. ^ Results. At baseline, significant differences in foot self-care behaviors and self monitoring blood glucose were noted based on ethnicity and gender. Men had significantly lower confidence in their ability to manage their diabetes overall. There was a significant difference between baseline and follow up self reported foot self-care behaviors within the intervention group (t (47) = −4.32, p < .01) and the control group (t (46) = −2.06, p < .05). There were no significant differences between groups for self-reported foot self-care behaviors. There was a significant difference in observed foot self-care behaviors between groups (F(2,135) = 2.99, p < .05). Self-efficacy scores were positively correlated with self-reported self-care behaviors. ^ Conclusions. This predominantly Hispanic population with type 2 diabetes reported performing diabetes self-care behaviors less than five days a week. There were within group changes, but no significant between group changes in reported self-care behaviors. However, at the one month follow up, there were significant differences between groups in observed foot self-care behaviors with the intervention group demonstrating the most accurate behaviors. Differences based on gender and ethnicity emphasize the need to individualize diabetes education. Priorities for culturally competent diabetes education, approaches to increasing self-efficacy and future research directions are suggested. ^