Inherited alterations of TGF beta signaling components in Appalachian cervical cancers.

PURPOSE: This study examined targeted genomic variants of transforming growth factor beta (TGFB) signaling in Appalachian women. Appalachian women with cervical cancer were compared to healthy Appalachian counterparts to determine whether these polymorphic alleles were over-represented within this high-risk cancer population, and whether lifestyle or environmental factors modified the aggregate genetic risk in these Appalachian women. METHODS: Appalachian women's survey data and blood samples from the Community Awareness, Resources, and Education (CARE) CARE I and CARE II studies (n = 163 invasive cervical cancer cases, 842 controls) were used to assess gene-environment interactions and cancer risk. Polymorphic allele frequencies and socio-behavioral demographic measurements were compared using t tests and χ2 tests. Multivariable logistic regression was used to evaluate interaction effects between genomic variance and demographic, behavioral, and environmental characteristics. RESULTS: Several alleles demonstrated significant interaction with smoking (TP53 rs1042522, TGFB1 rs1800469), alcohol consumption (NQO1 rs1800566), and sexual intercourse before the age of 18 (TGFBR1 rs11466445, TGFBR1 rs7034462, TGFBR1 rs11568785). Interestingly, we noted a significant interaction between "Appalachian self-identity" variables and NQO1 rs1800566. Multivariable logistic regression of cancer status in an over-dominant TGFB1 rs1800469/TGFBR1 rs11568785 model demonstrated a 3.03-fold reduction in cervical cancer odds. Similar decreased odds (2.78-fold) were observed in an over-dominant TGFB1 rs1800469/TGFBR1 rs7034462 model in subjects who had no sexual intercourse before age 18. CONCLUSIONS: This study reports novel associations between common low-penetrance alleles in the TGFB signaling cascade and modified risk of cervical cancer in Appalachian women. Furthermore, our unexpected findings associating Appalachian identity and NQO1 rs1800566 suggests that the complex environmental exposures that contribute to Appalachian self-identity in Appalachian cervical cancer patients represent an emerging avenue of scientific exploration.

Effects of intermittent intravenous saline infusions in patients with medication-refractory postural tachycardia syndrome.

BACKGROUND: The postural tachycardia syndrome (POTS) is a heterogeneous group of disorders that results in symptoms of orthostatic intolerance. Excess blood pooling has been observed to cause low effective circulating volume in the central vasculature. Consequently, acute volume loading with IV saline has emerged as a potential strategy for clinical intervention. We evaluated the impact of acute volume loading on both the signs and symptoms of patients suffering from POTS. METHODS: Fifty-seven subjects screened from our population of POTS patients and assenting to participation were administered the two surveys by telephone. Subjects completed each survey twice, before, and after initiating IV hydration therapy. The Orthostatic Hypotension Questionnaire (OHQ) was used to assess change in clinical symptomatology, while the short form 36 health survey (SF-36) was employed to assess the impact of IV saline infusion on quality of life. RESULTS: Fifty-seven patients were included in the analysis. The average number of medications trialed before referral for IV hydration was 3.6 ± 1.7 medications. Saline infusions occurred with mean frequency of 11.3 ± 8.5 days and at a mean volume of 1.5 ± 0.6 l per infusion. The mean change of the OHQ was 3.1 ± 0.3 (95% CI 2.6-3.7; P < 0.001), with significant improvement in all the composite scores. The mean change in the SF-36 form was 19.1 ± 2.7 (95% CI -24.6 to -13.6; P < 0.001). CONCLUSIONS: Intermittent IV infusions of saline dramatically reduce symptoms and improve quality of life in patients suffering from POTS. Further work should explore its efficacy as a bridge study for patients of high symptomatic severity.