Citations

ABSTRACT Introduction Sexual function through pregnancy and the postpartum period is an important aspect of quality of life. Despite this, prospective studies are limited, and the impact of body image on sexual function has not been explored. Aim To prospectively assess the effects of pregnancy on sexual function, and explore causative factors for sexual function alterations such as body image and pelvic floor symptoms. Materials and Methods Pregnant women completed the questionnaires in the first and third trimester and at 6 months postpartum. These included general information, questions regarding sexual activity and practices, and five validated indices: the Female Sexual Function Index (FSFI), the Body Exposure during Sexual Activities Questionnaire, short forms of Urogenital Distress Inventory and Incontinence Impact Questionnaire, and the Fecal Incontinence Quality of Life Scale. Main Outcome Measures An assessment of the FSFI domains through the 6 months postpartum and relationships between sexual function, body image, and pelvic floor symptoms. Results One hundred seven women were enrolled, 63 completed the final questionnaire. Sexual function declined through pregnancy and was not recovered by postpartum (P = 0.017); sexual frequency was highest prior to becoming pregnant (P < 0.0005). Sexual practices changed during pregnancy but returned to early pregnancy levels in the postpartum period. Although body image during sexual functioning did not significantly change during pregnancy, it worsened in the postpartum period (P = 0.01). In early pregnancy, low sexual function was associated with impaired body image, while in the postpartum period, worse urinary symptoms correlated with poor FSFI. Conclusion Sexual function worsens during pregnancy and is not recovered by the 6 months postpartum; poor scores may be attributable to low body image and urinary complaints.

A hallmark of the pathology of Alzheimer's disease is the accumulation of the microtubule-associated protein tau into fibrillar aggregates. Recent studies suggest that they accumulate because cytosolic chaperones fail to clear abnormally phosphorylated tau, preserving a pool of toxic tau intermediates within the neuron. We describe a mechanism for tau clearance involving a major cellular kinase, Akt. During stress, Akt is ubiquitinated and degraded by the tau ubiquitin ligase CHIP, and this largely depends on the Hsp90 complex. Akt also prevents CHIP-induced tau ubiquitination and its subsequent degradation, either by regulating the Hsp90/CHIP complex directly or by competing as a client protein with tau for binding. Akt levels tightly regulate the expression of CHIP, such that, as Akt levels are suppressed, CHIP levels also decrease, suggesting a potential stress response feedback mechanism between ligase and kinase activity. We also show that Akt and the microtubule affinity-regulating kinase 2 (PAR1/MARK2), a known tau kinase, interact directly. Akt enhances the activity of PAR1 to promote tau hyperphosphorylation at S262/S356, a tau species that is not recognized by the CHIP/Hsp90 complex. Moreover, Akt1 knockout mice have reduced levels of tau phosphorylated at PAR1/MARK2 consensus sites. Hence, Akt serves as a major regulator of tau biology by manipulating both tau kinases and protein quality control, providing a link to several common pathways that have demonstrated dysfunction in Alzheimer's disease.

Background— Little is known about the impact of technological and pharmacological advances on long-term outcome after percutaneous coronary intervention in general clinical practice. Methods and Results— We analyzed in-hospital and long-term outcome of 24 410 percutaneous coronary interventions among 18 575 unique patients who underwent percutaneous coronary intervention at Mayo Clinic over 25 years. The study population was divided into group 1 (n=3708), coronary interventions from 1979 to 1989; group 2 (n=7020), interventions from 1990 to 1996; group 3 (n=10 952), interventions from 1996 to 2003; and group 4 (n=2730), interventions from 2003 to 2004. Despite the fact that patients in groups 3 and 4 were significantly older, sicker, and had greater prevalence of comorbid conditions, heart failure, and previous revascularization than those in groups 1 and 2, procedural success in groups 3 and 4 improved significantly (94%) versus groups 2 (89%) and 1 (78%) ( P <0.001). Significant reduction in in-hospital mortality (groups 4 to 1: 1.8%, 1.7%, 2.6%, 3.0%; P <0.001) and need for emergency bypass surgery (groups 4 to 1: 0.4%, 0.5%, 1.6%, 5%; P <0.001) was noted in groups 3 and 4 compared with groups 1 and 2. Better adherence to currently recommended evidence-based medications for secondary prevention was seen in the recent time periods. After adjustment, significant reduction in follow-up mortality (hazard ratio, 0.81 and 0.74 for groups 3 and 4, respectively); death or myocardial infarction (hazard ratio, 0.80 and 0.75 for groups 3 and 4, respectively); death, myocardial infarction, or revascularization (hazard ratio, 0.76 and 0.58 for groups 3 and 4, respectively) was noted in recent time periods. Conclusions— Despite higher-risk profiles of patients who underwent percutaneous coronary intervention in recent time periods, procedural success as well as in-hospital and long-term outcomes improved significantly over the last 25 years.

Abstract Germ line inactivating mutations in BRCA1 confer susceptibility for breast and ovarian cancer. However, the relevance of the many missense changes in the gene for which the effect on protein function is unknown remains unclear. Determination of which variants are causally associated with cancer is important for assessment of individual risk. We used a functional assay that measures the transactivation activity of BRCA1 in combination with analysis of protein modeling based on the structure of BRCA1 BRCT domains. In addition, the information generated was interpreted in light of genetic data. We determined the predicted cancer association of 22 BRCA1 variants and verified that the common polymorphism S1613G has no effect on BRCA1 function, even when combined with other rare variants. We estimated the specificity and sensitivity of the assay, and by meta-analysis of 47 variants, we show that variants with &lt;45% of wild-type activity can be classified as deleterious whereas variants with &gt;50% can be classified as neutral. In conclusion, we did functional and structure-based analyses on a large series of BRCA1 missense variants and defined a tentative threshold activity for the classification missense variants. By interpreting the validated functional data in light of additional clinical and structural evidence, we conclude that it is possible to classify all missense variants in the BRCA1 COOH-terminal region. These results bring functional assays for BRCA1 closer to clinical applicability. [Cancer Res 2007;67(4):1494–501]

A subset of proteins that transit the endosomal system are directed into the intralumenal vesicles of multivesicular bodies (MVBs). MVB formation is critical for a variety of cellular functions including receptor down-regulation, viral budding, antigen presentation, and the generation of lysosome-related organelles. Entry of transmembrane proteins into the intralumenal vesicles of a MVB is a highly regulated process that is positively modulated by covalent modification of cargoes with ubiquitin. To identify additional MVB sorting signals, we examined the previously described ubiquitination-independent MVB cargo Sna3. Although Sna3 ubiquitination is not essential, Sna3 MVB sorting is positively modulated by its ubiquitination. Examination of MVB sorting determinants within a form of Sna3 lacking all lysine residues identified two critical regions: an amino-terminal tyrosine-containing region and a carboxyl-terminal PPAY motif. This PPAY motif interacts with the WW domains of the ubiquitin ligase Rsp5, and mutations in either the WW or, surprisingly, the HECT domains of Rsp5 negatively impacted MVB targeting of lysine-minus Sna3. These data indicate that Rsp5 function is required for MVB targeting of Sna3 in a capacity beyond cargo ubiquitination. These results uncover a series of determinants impacting Sna3 MVB sorting, including unexpected roles for Rsp5.

A number of hypotheses regarding how anti‐Aβ antibodies alter amyloid deposition have been postulated, yet there is no consensus as to how Aβ immunotherapy works. We have examined the in vivo binding properties, pharmacokinetics, brain penetrance, and alterations in Aβ levels after a single peripheral dose of anti‐Aβ antibodies to both wild‐type (WT) and young non‐Aβ depositing APP and BRI‐Aβ42 mice. The rapid rise in plasma Aβ observed after antibody (Ab) administration is attributable to prolongation of the half‐life of Aβ bound to the Ab. Only a miniscule fraction of Ab enters the brain, and despite dramatic increases in plasma Aβ, we find no evidence that total brain Aβ levels are significantly altered. Surprisingly, cerebral spinal fluid Aβ levels transiently rise, and when Ab:Aβ complex is directly injected into the lateral ventricles of mice, it is rapidly cleared from the brain into the plasma where it remains stable. When viewed in context of daily turnover of Aβ, these data provide a framework to evaluate proposed mechanisms of Aβ attenuation mediated by peripheral administration of an anti‐Aβ monoclonal antibody (mAb) effective in passive immunization paradigm. Such quantitative data suggest that the mAbs are either indirectly enhancing clearance of Aβ or targeting a low abundance aggregation intermediate.—Levites, Y., Smithson, L. A., Price, R. W., Dakin. R. S., Yuan, B., Sierks, M. R., Kim, J., McGowan, E., Reed, D. K., Rosenberry, T. L., Das, P., Golde, T. E. Insights into the mechanisms of action of anti‐Aβ antibodies in Alzheimer's disease mouse models. FASEB J. 20, E2002–E2014 (2006)

Abstract Marrow stromal cells can differentiate into osteoblasts, adipocytes, myoblasts, and chondrocytes. Bone morphogenetic protein 2 (BMP-2) is a potent stimulator of osteoblastic differentiation, and identification of the genes regulated by BMP-2 in these cells should provide insight into the mechanism(s) of osteoblastic differentiation. Thus, we used a conditionally immortalized human marrow stromal cell line (hMS) and a gene expression microarray containing probes for a total of 6800 genes to compare gene expression in control and BMP-2-treated cultures. A total of 51 genes showed a consistent change in messenger RNA (mRNA) frequency between two repeat experiments. Seventeen of these genes showed a change in expression of at least 3-fold in BMP-2-treated cultures over control cultures. These included nuclear binding factors (10 genes), signal transduction pathway genes (2 genes), molecular transport (1 gene), cell surface proteins (2 genes) and growth factors (2 genes). Of particular interest were four of the nuclear binding factor genes ID−1, ID−2, ID−3, and ID−4. These encode dominant negative helix-loop-helix (dnHLH) proteins that lack the nuclear binding domain of the basic HLH proteins and thus have no transcriptional activity. They have been implicated in blocking both myogenesis and adipogenesis. Other transcription factors up-regulated at least 3-fold by BMP-2 included Dlx-2, HES-1, STAT1, and JunB. The changes in these nuclear binding factor mRNA levels were confirmed by real-time reverse-transcriptase-polymerase chain reaction (RT-PCR). A further three transcription factors, core binding factor β (CBFβ), AREB6, and SOX4, showed changes in expression of between 2- and 3-fold with BMP-2 treatment. In summary, we have used a gene chip microarray to identify a number of BMP-2 responsive genes in hMS cells. Thus, these studies provide potential candidate genes that may induce osteoblastic differentiation or, in the case of the ID proteins, block differentiation along alternate pathways.

A polymorphism in the gene encoding the β2-adrenergic receptor (arginine or glycine at amino acid position 16) is associated with altered vasodilator responses to β2-agonists, which may modulate the pressor response to endogenous catecholamines during stress. To test the hypothesis that the Arg16/Gly polymorphism is associated with differences in acute pressor responses to sympathoexcitation, we measured mean arterial pressure (MAP, Finapres) and heart rate (HR, ECG) during mental stress (MS), cold pressor test (CPT), and handgrip (HG) to fatigue in 31 healthy, nonobese, normotensive adults (mean age ± SE: 31 ± 1; 16 females). Subjects were homozygous for Gly16 ( n = 16) or Arg16 ( n = 15). Both groups had similar baseline MAP (Arg16, 86 ± 3 mmHg; Gly16, 89 ± 2 mmHg; P = 0.4) and HR (Arg16, 68 ± 2 beats/min; Gly16, 65 ± 3 beats/min; P = 0.3). For MS and CPT, MAP and HR did not differ between genotype groups. Handgrip also produced similar increases in MAP; however, the change in HR was greater in the Gly16 homozygotes ( PANOVA= 0.001, genotype-by-time interaction). During HG, peak HR at fatigue was 100 ± 4 beats/min for Gly16 (54% increase from rest) vs. 93 ± 3 beats/min for Arg16 (37% increase). We conclude that the cardiovascular responses to MS and CPT do not differ between Gly16 and Arg16 homozygotes. However, the greater HR response to exercise in the Gly16 homozygotes may serve to maintain the pressor response (increased cardiac output) in the face of augmented peripheral vasodilation (decreased total peripheral resistance) in this group.