Intravesical OnabotulinumtoxinA Injection for Overactive Orthotopic Ileal Neobladder: Feasibility and Efficacy

Nathan Hoag,Vincent Tse,Audrey Wang,Eric Chung,Johan Gani 대한배뇨장애요실금학회 2016 International Neurourology Journal Vol.20 No.1

The efficacy of intravesical onabotulinumtoxinA (BTXA) in the treatment of overactive bladder (OAB) has been well documented. The use of BTXA injection in orthotopic neobladders is yet to be studied. We present 4 cases of patients injected with intravesical BTXA for overactive orthotopic ileal neobladder. We recorded patient demographics, presenting and follow-up symptoms, urodynamic profiles, and Patient Global Impression of Improvement (PGI-I) scores. The 4 patients reported varying degrees of subjective improvements in the symptoms, including urgency, urge incontinence, and pad usage. Mean followup duration was 8.3 months (range, 5–14 months). Average PGI-I score was 3 (“a little better”) (range, 2–4). To our knowledge, the current study is the first case series examining BTXA injection for orthotopic neobladder overactivity. BTXA injection yielded varying degrees of objective and subjective improvements, without significant complications. Intravesical BTXA injection is feasible and may be considered as a potential treatment alternative for OAB in orthotopic neobladders, although further study is warranted.

Association analysis identifies 65 new breast cancer risk loci

Michailidou, Kyriaki,Lindströ,m, Sara,Dennis, Joe,Beesley, Jonathan,Hui, Shirley,Kar, Siddhartha,Lemaç,on, Audrey,Soucy, Penny,Glubb, Dylan,Rostamianfar, Asha,Bolla, Manjeet K.,Wang, Qin,Tyr Macmillan Publishers Limited, part of Springer Nat 2017 Nature Vol.551 No.7678

<P>Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry(1). We identified 65 new loci that are associated with overall breast cancer risk at P < 5 x 10(-8). The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.</P>

Low ambient oxygen prevents atherosclerosis

Kang, Ju-Gyeong,Sung, Ho Joong,Amar, Marcelo J.,Pryor, Milton,Remaley, Alan T.,Allen, Michele D.,Noguchi, Audrey C.,Springer, Danielle A.,Kwon, Jaeyul,Chen, Jichun,Park, Ji-hoon,Wang, Ping-yuan,Hwang, Springer-Verlag 2016 Journal of molecular medicine Vol.94 No.3

<P>Large population studies have shown that living at higher altitudes, which lowers ambient oxygen exposure, is associated with reduced cardiovascular disease mortality. However, hypoxia has also been reported to promote atherosclerosis by worsening lipid metabolism and inflammation. We sought to address these disparate reports by reducing the ambient oxygen exposure of ApoE-/- mice. We observed that long-term adaptation to 10 % O-2 (equivalent to oxygen content at similar to 5000 m), compared to 21 % O-2 (room air at sea level), resulted in a marked decrease in aortic atherosclerosis in ApoE-/- mice. This effect was associated with increased expression of the anti-inflammatory cytokine interleukin-10 (IL-10), known to be anti-atherogenic and regulated by hypoxia-inducible transcription factor-1 alpha (HIF-1 alpha). Supporting these observations, ApoE-/- mice that were deficient in IL-10 (IL10-/- ApoE-/- double knockout) failed to show reduced atherosclerosis in 10 % oxygen. Our study reveals a specific mechanism that can help explain the decreased prevalence of ischemic heart disease in populations living at high altitudes and identifies ambient oxygen exposure as a potential factor that could be modulated to alter pathogenesis. Key messages Chronic low ambient oxygen exposure decreases atherosclerosis in mice. Anti-inflammatory cytokine IL-10 levels are increased by low ambient O-2. This is consistent with the established role of HIF-1 alpha in IL10 transactivation. Absence of IL-10 results in the loss of the antiatherosclerosis effect of low O-2. This mechanism may contribute to decreased atherosclerosis at high altitudes.</P>

Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis

Wheeler, Eleanor,Leong, Aaron,Liu, Ching-Ti,Hivert, Marie-France,Strawbridge, Rona J.,Podmore, Clara,Li, Man,Yao, Jie,Sim, Xueling,Hong, Jaeyoung,Chu, Audrey Y.,Zhang, Weihua,Wang, Xu,Chen, Peng,Marut Public Library of Science 2017 PLoS medicine Vol.14 No.9

<▼1><P><B>Background</B></P><P>Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.</P><P><B>Methods & findings</B></P><P>Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (<I>N</I> = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04–1.06, per HbA1c-raising allele, <I>p</I> = 3 × 10<SUP>−29</SUP>); whereas GS-E was not (OR = 1.00, 95% CI 0.99–1.01, <I>p</I> = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked <I>G6PD</I> G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66–0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38–0.97) in homozygous women. The <I>G6PD</I> variant may cause approximately 2% (<I>N</I> = 0.65 million, 95% CI 0.55–0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.</P><P><B>Conclusions</B></P><P>As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the <I>G6PD</I> genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where <I>G6PD</I> deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.</P></▼1><▼2><P>Ines Barroso and colleagues identify a genetic variant that leads to reduced levels of HbA1c in African American adults; 2% of this population are at risk of missed diagnosis for diabetes.</P></▼2><▼3><P><B>Author summary</B></P><P><B>Why was this study done?</B></P><P>Blood glucose binds in an irreversible manner to circulating hemoglobin in red blood cells (RBCs), generating “glycated hemoglobin,” called HbA1c. HbA1c is used to diagnose and monitor diabetes.</P><P>Previous large-scale human genetic studies have demonstrated that HbA1c is influenced by genetic variants. Some vari