Placental Erythroferrone and Erythropoietin mRNA Expression is not Associated with Maternal or Neonatal Iron Status in Adolescents Carrying Singletons and Adult Women Carrying Multiples.

BACKGROUND: The iron regulatory hormones erythroferrone (ERFE), erythropoietin (EPO), and hepcidin, and the cargo receptor nuclear receptor coactivator 4 (NCOA4) are expressed in the placenta. However, determinants of placental expression of these proteins and their associations with maternal or neonatal iron status are unknown. OBJECTIVES: To characterize expression of placental ERFE, EPO, and NCOA4 mRNA in placentae from newborns at increased risk of iron deficiency and to evaluate these in relation to maternal and neonatal iron status and regulatory hormones. METHODS: Placentae were collected from 114 neonates born to adolescents carrying singletons (14-18 y) and 110 neonates born to 54 adults (20-46 y) carrying multiples. Placental EPO, ERFE, and NCOA4 mRNA expression were measured by RT-qPCR and compared with maternal and neonatal iron status indicators (SF, sTfR, total body iron, serum iron) and hormones. RESULTS: Placental ERFE, EPO, and NCOA4 mRNA were detected in all placentae delivered between 25 and 42 wk of gestation. Relationships between placental ERFE and EPO differed by cohort. In the multiples cohort, placental EPO and ERFE were positively correlated (P = 0.004), but only a positive trend (P = 0.08) was evident in the adolescents. Placental EPO and ERFE were not associated with maternal or neonatal iron status markers or hormones in either cohort. Placental NCOA4 was not associated with placental EPO or ERFE in either cohort but was negatively associated with maternal SF (P = 0.03) in the multiples cohort and positively associated with neonatal sTfR (P = 0.009) in the adolescents. CONCLUSIONS: The human placenta expresses ERFE, EPO, and NCOA4 mRNA as early as 25 wk of gestation. Placental expression of ERFE and EPO transcripts was not associated with maternal or neonatal iron status. Greater placental NCOA4 transcript expression was evident in women and newborns with poor iron status (lower SF and higher sTfR, respectively). Further research is needed to characterize the roles of these proteins in the human placenta. TRIAL REGISTRATION NUMBER: These clinical trials were registered at clinicaltrials.gov as NCT01019902 (https://clinicaltrials.gov/ct2/show/NCT01019902) and NCT01582802 (https://clinicaltrials.gov/ct2/show/NCT01582802).

The PPR domain of mitochondrial RNA polymerase is an exoribonuclease required for mtDNA replication in Drosophila melanogaster.

Mitochondrial DNA (mtDNA) replication and transcription are of paramount importance to cellular energy metabolism. Mitochondrial RNA polymerase is thought to be the primase for mtDNA replication. However, it is unclear how this enzyme, which normally transcribes long polycistronic RNAs, can produce short RNA oligonucleotides to initiate mtDNA replication. We show that the PPR domain of Drosophila mitochondrial RNA polymerase (PolrMT) has 3'-to-5' exoribonuclease activity, which is indispensable for PolrMT to synthesize short RNA oligonucleotides and prime DNA replication in vitro. An exoribonuclease-deficient mutant, PolrMTE423P, partially restores mitochondrial transcription but fails to support mtDNA replication when expressed in PolrMT-mutant flies, indicating that the exoribonuclease activity is necessary for mtDNA replication. In addition, overexpression of PolrMTE423P in adult flies leads to severe neuromuscular defects and a marked increase in mtDNA transcript errors, suggesting that exoribonuclease activity may contribute to the proofreading of mtDNA transcription.

Fetal iron uptake from recent maternal diet and the maternal RBC iron pool.

BACKGROUND: During pregnancy iron can be obtained from the diet, body iron stores, or iron released from RBC catabolism. Little is known about the relative use of these sources to support fetal iron acquisition. OBJECTIVES: To describe longitudinal change in iron absorption and enrichment across gestation and partitioning of RBC iron to the fetus. METHODS: Fifteen pregnant women ingested an oral stable iron isotope (57Fe) in the second trimester (T2) of pregnancy (weeks 14-16) to label the RBC pool, and a second oral stable isotope (58Fe) in the third trimester (T3) (weeks 32-35). Absorption was measured at T2 and T3. Change in RBC 57Fe enrichment was monitored (18.8-26.6 wk) to quantify net iron loss from this pool. Iron transfer to the fetus was determined based on RBC 57Fe and 58Fe enrichment in umbilical cord blood at delivery. RESULTS: Iron absorption averaged 9% at T2 and increased significantly to 20% (P = 0.01) by T3. The net increase in iron absorption from T2 to T3 was strongly associated with net loss in maternal total body iron (TBI) from T2 to T3 (P = 0.01). Mean time for the labeled RBC 57Fe turnover based on change in RBC enrichment was 94.9 d (95% CI: 43.5, 207.1 d), and a greater decrease in RBC 57Fe enrichment was associated with higher iron absorption in T2 (P = 0.001). Women with a greater decrease in RBC 57Fe enrichment transferred more RBC-derived iron to their fetus (P < 0.05). CONCLUSIONS: Iron absorption doubled from T2 to T3 as maternal TBI declined. Women with low TBI had a greater decrease in RBC iron enrichment and transferred more RBC-derived iron to their neonate. These findings suggest maternal RBC iron serves as a significant source of iron for the fetus, particularly in women with depleted body iron stores.

Umbilical Cord Erythroferrone Is Inversely Associated with Hepcidin, but Does Not Capture the Most Variability in Iron Status of Neonates Born to Teens Carrying Singletons and Women Carrying Multiples.

BACKGROUND: The developing fetus requires adequate iron and produces its own hormones to regulate this process. Erythroferrone (ERFE) is a recently identified iron regulatory hormone, and normative data on ERFE concentrations and relations between iron status and other iron regulatory hormones at birth are needed. OBJECTIVES: The objective of this study was to characterize cord ERFE concentrations at birth and assess interrelations between ERFE, iron regulatory hormones, and iron status biomarkers in 2 cohorts of newborns at higher risk of neonatal anemia. METHODS: Umbilical cord ERFE concentrations were measured in extant serum samples collected from neonates born to women carrying multiples (age: 21-43 y; n = 127) or teens (age: 14-19 y; n = 164). Relations between cord blood ERFE and other markers of iron status or erythropoiesis in cord blood were assessed by linear regression and mediation analysis. RESULTS: Cord ERFE was detectable in all newborns delivered between 30 and 42 weeks of gestation, and mean concentration at birth was 0.73 ng/mL (95% CI: 0.63, 0.85 ng/mL). Cord ERFE was on average 0.25 ng/mL lower in newborns of black as opposed to white ancestry (P = 0.04). Cord ERFE was significantly associated with transferrin receptor (ß: 1.17, P < 0.001), ferritin (ß: -0.27, P < 0.01), and hemoglobin (Hb) (ß: 0.04, P < 0.05). However, cord hepcidin and the hepcidin:erythropoietin (EPO) ratio captured the most variance in newborn iron and hematologic status (>25% of variance explained). CONCLUSIONS: Neonates born to teens and women carrying multiples were able to produce ERFE in response to neonatal cord iron status and erythropoietic demand. ERFE, however, did not capture significant variance in newborn iron or Hb concentrations. In these newborns, cord hepcidin and the hepcidin:EPO ratio explained the most variance in iron status indicators at birth.

Serum Erythroferrone During Pregnancy Is Related to Erythropoietin but Does Not Predict the Risk of Anemia.

BACKGROUND: Maintaining adequate iron status during pregnancy is important for the mother and her developing fetus. Iron homeostasis is influenced by 3 regulatory hormones: erythropoietin (EPO), hepcidin, and erythroferrone (ERFE). To date, normative data on ERFE across pregnancy and its relations to other hormones and iron status indicators are limited. OBJECTIVES: The objective of this study was to characterize maternal ERFE across pregnancy and at delivery and evaluate the utility of hepcidin, ERFE, and EPO in identifying women with increased iron needs. METHODS: ERFE was measured in extant serum samples collected from 2 longitudinal cohorts composed of women carrying multiple fetuses (n = 79) and pregnant adolescents (n = 218) at midgestation (∼26 wk) and delivery (∼39 wk). Receiver operating characteristic curves were generated to characterize the predictive ability of serum ERFE, hepcidin, and EPO and their ratios to identify women at increased risk of iron deficiency and anemia. RESULTS: In these pregnant women, mean ERFE was 0.48 ng/mL at both ∼25 wk of gestation and at delivery. ERFE was positively associated with EPO at midgestation (ß = 0.14, P = 0.002, n = 202) and delivery (ß = 0.12, P < 0.001, n = 225) but was not significantly associated with maternal hepcidin at any time point surveyed. Of all hormones measured at midgestation and delivery, EPO was best able to identify women with anemia (AUC: 0.86 and 0.75, respectively) and depleted iron stores (AUC: 0.77 and 0.84), whereas the hepcidin-to-EPO ratio was best able to identify women with iron deficiency anemia (AUC: 0.85 and 0.84). CONCLUSIONS: Maternal ERFE was significantly associated with EPO but was not able to identify women with gestational iron deficiency. At term, the hepcidin-to-EPO ratio, an index that accounts for both iron status and erythropoietic demand, and EPO were the strongest indicators of maternal iron deficiency and anemia. This trial was registered at clinicaltrials.gov as NCT04517734 (https://clinicaltrials.gov/ct2/show/NCT04517734).

Child Pain Intensity and Parental Attitudes toward Complementary and Alternative Medicine Predict Post-Tonsillectomy Analgesic Use.

Parental attitudes regarding pain interventions and perceptions of their child's pain intensity likely influence the decision to administer postoperative analgesics. Our study examined the impact of daily fluctuations in child pain intensity and parental attitudes regarding complementary and alternative medicine (CAM) on analgesic administration following pediatric tonsillectomy. Parents of children undergoing tonsillectomy (n = 33) completed a survey assessing CAM attitudes and a 7-day postoperative electronic daily diary to record their child's daily pain intensity and analgesic medications (acetaminophen, ibuprofen, or oxycodone). Generalized linear mixed models with Poisson distributions evaluated the effects of within-person (child's daily pain intensity) and between-person (average postoperative pain, parental CAM attitudes) components on the number of medication doses administered. Higher daily pain intensity was associated with more oxycodone doses administered on a given day, but not acetaminophen or ibuprofen. Positive parental CAM attitudes were associated with less oxycodone use, beyond the variations accounted for by the child's daily pain intensity and average postoperative pain. Both parental CAM attitudes and their child's daily pain intensity were independently associated with parental decisions to administer opioids following tonsillectomy. Understanding factors influencing individual variability in analgesic use could help optimize children's postoperative pain management.

Iron absorption during pregnancy is underestimated when iron utilization by the placenta and fetus is ignored.

BACKGROUND: Maternal iron absorption during pregnancy can be evaluated using RBC incorporation of orally administered stable iron isotope. This approach underestimates true maternal absorption of iron as it does not account for absorbed iron that is transferred to the fetus or retained within the placenta. OBJECTIVE: Our objective was to re-evaluate maternal iron absorption after factoring in these losses and identify factors associated with iron partitioning between the maternal, neonatal, and placental compartments. METHODS: This study utilized data from stable iron isotope studies carried out in 68 women during the third trimester of pregnancy. Iron status indicators and stable iron isotopic enrichment were measured in maternal blood, umbilical cord blood, and placental tissue when available. Factors associated with iron isotope partitioning between the maternal, neonatal, and placental compartments were identified. RESULTS: On average, true maternal absorption of iron increased by 10% (from 19% to 21%) after accounting for absorbed iron present in the newborn (P < 0.001), and further increased by 7%, (from 39% to 42%, P < 0.001) after accounting for iron retained within the placenta. On average, 2% of recovered tracer was present in the placenta and 6% was found in the newborn. Net transfer of iron to the neonate was higher in women with lower total body iron (standardized ß = -0.48, P < 0.01) and lower maternal hepcidin (standardized ß = -0.66, P < 0.01). In women carrying multiple fetuses, neonatal hepcidin explained a significant amount of observed variance in net placental transfer of absorbed iron (R = 0.95, P = 0.03). CONCLUSIONS: Maternal RBC iron incorporation of an orally ingested tracer underestimated true maternal iron absorption. The degree of underestimation was greatest in women with low body iron. Maternal hepcidin was inversely associated with maternal RBC iron utilization, whereas neonatal hepcidin explained variance in net transfer of iron to the neonatal compartment.These trials were registered at clinicaltrials.gov as NCT01019096 and NCT01582802.

Umbilical Cord Serum Ferritin Concentration is Inversely Associated with Umbilical Cord Hemoglobin in Neonates Born to Adolescents Carrying Singletons and Women Carrying Multiples.

BACKGROUND: It has been proposed that the fetus prioritizes iron for hemoglobin production over delivery to tissues. However, few studies have evaluated the interrelations between hemoglobin and multiple iron status biomarkers in umbilical cord blood. A full understanding is needed of how these parameters influence each other within cord blood to fully interpret iron and hematologic status at birth. OBJECTIVES: We evaluated the determinants of neonatal hemoglobin and assessed the interrelations between hemoglobin, serum iron status indicators, and serum iron regulatory hormones in healthy neonates. METHODS: This was an observational study that assessed umbilical cord hemoglobin (Hb), serum ferritin (SF), erythropoietin (EPO), soluble transferrin receptor (sTfR), serum iron, hepcidin, vitamin B-12, folate, IL-6, and CRP measured in 234 neonates born to adolescents or to women carrying multiples. Correlations between these indicators were evaluated and mediation models consistent with the observed significant determinants of cord Hb concentrations were developed. RESULTS: A highly significant inverse association was found between cord SF and Hb concentrations that was not attributable to neonatal or maternal inflammation (as measured by IL-6 and CRP). The inverse association was present in the combined cohort, as well as in the adolescent and multiples cohorts independently. Mediation analyses found that EPO and hepcidin had significant indirect effects on cord Hb, associations that are explicable by mediation through SF and sTfR. CONCLUSION: In contrast to observations made in older infants, a highly significant inverse association between Hb and SF, as well positive associations between Hb and both sTfR and EPO, were observed in umbilical cord blood from neonates born to adolescents or women carrying multiples. These findings, combined with review of the published literature, indicate a need for analysis of the relations between multiple parameters to assess iron and hematologic status at birth. These clinical trials were registered at clinicaltrials.gov as NCT01582802 (https://clinicaltrials.gov/ct2/show/NCT01582802) and NCT01019902 (https://clinicaltrials.gov/ct2/show/NCT01019902).

An atypical case of Canavan disease with stroke-like presentation.

BACKGROUND: Canavan disease is an autosomal recessive leukodystrophy caused by a deficiency of aspartoacylase. The disease has a severe course, with death occurring in the first few years of life. Atypical patients with mild courses have been reported, but acute presentations similar to stroke have not been well described. PATIENT DESCRIPTION: We present a boy who presented at 4 months of age with seizures after an episode of cardiopulmonary arrest is discussed. RESULTS: He was initially thought to have an ischemic watershed stroke based on his initial clinical presentation and magnetic resonance imaging. However, biochemical and follow-up radiologic evaluation were consistent with mild Canavan disease. DNA sequencing of the ASPA gene indicated one known mutation (A305E) and a novel mutation, L30V. Follow-up magnetic resonance imaging did not reveal the atrophy which would have been expected with watershed ischemia. Magnetic resonance spectroscopy demonstrated elevated N-acetyl aspartate to creatinine and N-acetyl aspartate to choline ratios. At 4 years of age, he was normocephalic, with mild clumsiness, speech delay, and seizures. CONCLUSIONS: This child's unusual acute presentation, along with his prolonged mild course, raises questions about the relationship between biochemical signs of abnormal aspartoacylase function and clinical findings. This patient highlights the need for long-term clinical follow-up of children with mild Canavan disease to clarify the significance of these biochemical abnormalities.

Preparation of dibenzo[e,g]isoindol-1-ones via Scholl-type oxidative cyclization reactions.

A flexible synthesis of dibenzo[e,g]isoindol-1-ones has been developed. Dibenzo[e,g]isoindol-1-ones represent simplified benzenoid analogues of biological indolo[2,3-a]pyrrolo[3,4-c]carbazol-5-ones (indolocarbazoles), compounds that have demonstrated a wide range of biological activity. The synthesis of the title compounds involved tetramic acid sulfonates. Different aryl groups were introduced at C4 of the heterocyclic ring via Suzuki-Miyaura cross-coupling reactions. Finally, mild Scholl-type oxidative cyclizations mediated by phenyliodine(III) bis(trifluoroacetate) (PIFA) converted some of the latter compounds into the corresponding dibenzo[e,g]isoindol-1-ones. A systematic study of the oxidative cyclization revealed the following reactivity trend: 3,4-dimethoxyphenyl ≫ 3-methoxyphenyl > 3,4,5-trimethoxyphenyl > 4-methoxyphenyl ≈ phenyl. Overall, the oxidative cyclization required at least two methoxy groups distributed in the aromatic rings, at least one of which had to be located para to the site of the cyclization.

Heterogeneous rate constants for indium mediated allylations: cinnamyl chloride in ethanol/water mixtures.

Indium mediated allylation (IMA) offers a powerful tool to synthetic chemists for creating carbon-carbon bonds. However, its rate limiting step, the heterogeneous reaction of allyl halides at solid indium surfaces, is still poorly understood. For example, solvent effects, especially the presence of water, on IMA are dramatic. We report for the first time rate constants for the heterogeneous rate limiting step of IMA. The rate constant for reaction of cinnamyl chloride on indium decreases from 5.5 × 10(-4) cm/s in 80% ethanol/20% water to 1 × 10(-4) cm/s in 99.8% ethanol/0.2% water. In addition, the percent water has a dramatic effect on induction time. This study further establishes photomicroscopy as a powerful tool for the determination of heterogeneous rate constants.

Tissue remodeling gene expression in a murine model of chronic rhinosinusitis.

OBJECTIVE/HYPOTHESIS: The matrix metalloproteinase (MMP), fibroblast growth factor (FGF), and bone morphogenetic protein (BMP) families regulate tissue remodeling in many normal and pathophysiologic processes. We hypothesize that induction of chronic sinonasal inflammation will be associated with changes in regulation of these tissue remodeling cytokines. METHODS: Balb/c mice aged 8 to 12 weeks were sensitized and treated with intranasal Aspergillus fumigatis (AF) three times per week for 1 week, 3 weeks, 2 months, and 3 months (n = 8 each time point). Sinonasal tissues were evaluated for changes in MMP, FGF, and BMP regulation using standard RT-PCR techniques. Additional snouts were processed for histology and immunohistochemistry. Untreated mouse snouts of identical age were used as controls. RESULTS: Significant upregulation of MMP8 was observed at 2 months, and MMP1a, MMP7, MMP8, and MMP12 were all significantly upregulated at 3 months. FGF3 was significantly upregulated at 3 weeks and 3 months, and FGF5, FGF6, and FGF8 were all significantly upregulated at 3 months. BMP8b and BMP9 were significantly upregulated at 3 months. Histologic analysis revealed mucosal, stromal, and mucin gland hypertrophy, increased mucin production, and metaplasia with loss of cilia. Antibody staining was strongly positive in the AF-treated group. CONCLUSIONS: Induction of CRS is associated with time-dependent changes in tissue remodeling cytokine expression occurring in conjuction with inflammatory tissue changes. Antibody staining for upregulated cytokines suggests local production within the sinonasal mucosa. Further study is required to better understand the association between BMP, FGF, and MMP regulation and tissue remodeling changes resulting from chronic inflammation.

Measurement of heterogeneous reaction rates: three strategies for controlling mass transport and their application to indium-mediated allylations.

We describe three new strategies for determining heterogeneous reaction rates using photomicroscopy to measure the rate of retreat of metal surfaces: (i) spheres in a stirred solution, (ii) microscopic powder in an unstirred solution, and (iii) spheres on a rotating shaft. The strategies are applied to indium-mediated allylation (IMA), which is a powerful tool for synthetic chemists because of its stereoselectivity, broad applicability, and high yields. The rate-limiting step of IMA, reaction of allyl halides at indium metal surfaces, is shown to be fast, with a minimum value of the heterogeneous rate constant of 1 × 10(-2) cm/s, an order of magnitude faster than the previously determined minimum value. The strategies described here can be applied to any reaction in which the surface is retreating or advancing, thereby broadening the applicability of photomicroscopy to measuring heterogeneous reaction kinetics.

Tissue remodeling in the acute otitis media mouse model.

OBJECTIVES: Otitis media is an infectious, inflammatory process involving the middle ear space. Chronic inflammation is associated with fibrosis, scarring and osteogenesis within the middle ear, which may contribute to subsequent hearing loss and increase the difficulty of treatment. METHODS: Heat-killed Streptococcus pneumoniae was injected into the middle ears of 8-12 week old Balb/c mice. Control mice were treated with PBS middle ear injections. Middle ears were harvested at 1, 3, 5 and 7 days following injection (n=8 for each time point). The middle ears were processed using standard RT-PCR techniques. Up- and down-regulation of mRNA expression of various members of the Bone Morphogenetic Protein (BMP), Fibroblast Growth Factor (FGF) and Matrix Metalloproteinase (MMP) families was quantified and compared to PBS treated controls (n=8 for each time point). RESULTS: Significant upregulation of MMP2, MMP3 and MMP9 was observed at varying time points (p<0.05). Significant downregulation of BMP3, BMP4, BMP5 BMP6 and BMP8a was seen at varying time points (p<0.05). Significant downregulation of FGF3, FGF6, FGF10 and FGFr1 was observed at varying time points (p<0.05). No significant expression of BMP8b, BMP9, BMP10, FGF5, FGF8, MMP1a, MMP7 and MMP14 was detected within the middle ear. CONCLUSIONS: Inflammation within the middle ear following injection of bacterial products results in changes in the regulation of several tissue remodeling cytokines and proteinases in the mouse model. Further understanding of these molecular processes may allow for the development of treatment modalities aimed at preventing middle ear tissue remodeling.

Altered expression of tissue remodeling genes in a mouse model of acute allergic rhinitis.

BACKGROUND: Osteogenesis, fibrosis, and scarring are prominent pathologic changes resulting from chronic sinonasal inflammation, and these tissue changes may increase the degree of disease symptomatology and the level of surgical difficulty. Members of the bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) families of cytokines and the matrix metalloproteinase (MMP) family of endopeptidases are known to regulate tissue remodeling in other disease processes, but their role in acute and chronic sinonasal inflammation remains undefined. METHODS: A previously described mouse model of acute allergic rhinitis secondary to Aspergillus fumigatis exposure in BALB/C mice was used. Intranasal challenge was performed 1 week following intraperitoneal sensitization with A. fumigatis extract and mice were sacrificed 6 hours (n = 8) and 24 hours (n = 8) later. Additional mice were intranasally challenged 3 times per week and sacrificed at the end of 7 days (n = 8) and 21 days (n = 8). The snouts were processed for quantitative reverse-transcription polymerase chain reaction (RT-PCR) and compared to untreated controls for messenger ribonucleic acid (mRNA) expression of BMP1, 2, 3, 4, 5, 6, 7, 8a, 8b, 9, 10, FGF1, 2, 3, 4, 5, 6, 7, 8, 10, and MMP1a, 2, 3, 7, 8, 9, 12, and 14. Additional 21-day-old mice were prepared for sinonasal histopathology. Control mice were treated with the same protocol, with intraperitoneal phosphate-buffered saline (PBS) and intranasal PBS substituted for A. fumigatis extract. Untreated mice were used for additional comparison. RESULTS: Compared to both the PBS-treated and untreated control groups, statistically significant (p < 0.05) upregulation of MMP8 was observed in the 6-hour time point. Significant downregulation of MMP8 was observed at 1 week. Significant upregulation of FGF3 was observed at 1 week (p < 0.05). BMP3 and BMP5 were significantly downregulated in the 1-week group (p < 0.05). The mice exhibited histologic sinonasal changes consistent with allergic inflammation. CONCLUSION: Intranasal exposure to A. fumigatis results in altered expression of several tissue remodeling cytokines at varying time points in the acute allergic rhinitis mouse model. These changes in cytokine regulation may subsequently contribute to sinonasal osteogenesis, scarring, and fibrosis as seen in chronic rhinosinusitis.

Participation in an Older Adult Heart Health Program affects lifestyle behavior.

The Older Adult Heart Health Program (HHP) was a university-based outreach health screen and education program. The purpose of this study was to determine whether the HHP was associated with lifestyle behavior change among participants. HHP volunteers (n=136) were mostly white (98.5%) women (79.4%) with a mean (+/- SEM) age of 75.1+/-0.6 years. A follow-up survey was sent to the participants' homes 4 months after the HHP inquiring about physician office visitation and adoption of healthy lifestyle behaviors since the HHP. A majority (n=60, 64.5%) of those who completed the survey (n=93, 68.4% response rate) indicated they visited their physician after the HHP. A greater percentage of survey respondents who visited their physician made lifestyle behavior changes than those who did not, 71.1% vs. 45.4%, respectively (p=0.032). These findings suggest participating in programs such as the HHP prompt physician visitation and behavior change among older adults residing in the community.

Obsessive-compulsive behaviors in parents of multiplex autism families.

Parents of autistic probands with high and low rates of repetitive behaviors were compared for rates of obsessive-compulsive traits and disorder. The rate of repetitive behaviors was assessed using the Autism Diagnostic Interview-Revised (ADI-R) in 176 autistic probands from 57 multiplex families. Obsessive-compulsive disorder (OCD) in parents was determined by direct interview using a parental history questionnaire, with screening for obsessive-compulsive traits using the Yale-Brown Obsessive-Compulsive Scale checklist. Children who had high total scores on the repetitive behavior domain of the ADI-R were significantly more likely to have one or both parents with obsessive-compulsive traits or disorder compared with children who had low total scores on this domain. Children with high scores on D1/D2 of the ADI-R (narrow restricted interests and rituals) were significantly more likely to have one or both parents with OCD, especially fathers, than those with low D1/D2. The occurrence of obsessive-compulsive traits or disorder in parents of autistic children in multiplex families is significantly more likely if autistic children have a high occurrence of repetitive behaviors. Dichotomizing autistic probands by severity and type of repetitive behaviors (circumscribed interests and compulsive rituals) may yield more homogenous groups, which could be helpful in genetic linkage studies.

Symptom domains in autism and related conditions: evidence for familiality.

Heterogeneity in autism impairs efforts to localize and identify the genes underlying this disorder. As autism comprises severe but variable deficits and traits in three symptom domains (social interaction, communication, and repetitive behaviors) and shows variability in the presence and emergence of useful phrase speech, different genetic factors may be associated with each. The affected cases (n=457) in multiply affected siblingships (n=212), including a proband with autism and one or more siblings with either autism or marked deficits in autism symptom domains, were assessed using the Autism Diagnostic Interview, Revised. Symptom domain scores and language features were examined to determine their similarity within siblingships. The variance within siblingships was reduced for the repetitive behavior domain and for delays in and the presence of useful phrase speech. These features and the nonverbal communication subdomain provided evidence of familiality when we considered only the diagnosis of autism to define multiply affected siblingships (cases: n=289; siblingships: n=136). In addition, the same familial features identified also appeared familial for those with autism-related conditions. Finally, the level of severity of almost all of the familial features varied within multiplex siblingships independently. The features identified as familial replicate the combined set suggested in earlier, smaller studies. Furthermore, the familiality of these features extend to related conditions of milder severity than autism and appear to be independent. Making distinctions among families by the severity of these features may be useful for identifying more genetically homogeneous subgroups in studies targeted at genes for specific autism-related symptom domains.