Despite a high prevalence of disability, Aboriginal Australians access disability services in Australia less than non-Aboriginal Australians with a disability. The needs of Aboriginal children with disability are particularly poorly understood. They can endure long delays in treatment which can impact adversely on development. This study sought to ascertain the factors involved in accessing services and support for Aboriginal children with a disability.
Using the focus group method, two community forums, one for health and service providers and one for carers of Aboriginal children with a disability, were held at an Aboriginal Community Controlled Health Service (ACCHS) in the Sydney, metropolitan area of New South Wales, Australia. Framework analysis was applied to qualitative data to elucidate key issues relevant to the dimensions of access framework. Independent coding consistency checks were performed and consensus of analysis verified by the entire research team, several of whom represented the local Aboriginal community.
Seventeen health and social service providers representing local area government and non-government-funded health and social service organisations and five carers participated in two separate forums between September and October 2011. Lack of awareness of services and inadequate availability were prominent concerns in both groups despite geographic proximity to a major metropolitan area with significant health infrastructure. Carers noted racism, insufficient or non-existent services, and the need for an enhanced role of ACCHSs and AHWs in disability support services. Providers highlighted logistical barriers and cultural and historical issues that impacted on the effectiveness of mainstream services for Aboriginal people.
Despite dedicated disability services in an urban community, geographic proximity does not mitigate lack of awareness and availability of support. This paper has enumerated a number of considerations to address provision of disability services in an urban Australian Aboriginal community including building expertise and specialist capacity within Aboriginal Health Worker positions and services.
Increasing awareness of services, facilitating linkages and referrals, eliminating complexities to accessing support, and working with families and Aboriginal community organisations within a framework of resilience and empowerment to ensure a relevant and acceptable model are necessary steps to improving support and care for Aboriginal children with a disability.
Childhood disability; Aboriginal and Torres Strait Islander peoples; Early intervention; Focus groups
DNA-damaging agents usually produce a vast collection of lesions within the genome. Analysis of these lesions from the structural and biological viewpoints is often complicated by the reality that some of the lesions are chemically fragile, leading to an even larger set of secondary and tertiary products. In an effort to deconvolute complex DNA-damage spectra, a strategy is presented whereby an oligonucleotide containing a specific target for chemical reaction is allowed to react with a DNA-damaging agent. A large collection of HPLC-resolvable modified oligonucleotides is generated, and chromatographically distinct members of the set are then individually characterized using chemical, spectroscopic, biochemical, and genetic probes. The biological component of this “chemical–biological fingerprinting” tool is the use of polymerase bypass in vivo in cells having defined replication status and quantitative and qualitative patterns of lesion-directed mutagenesis, as key properties that complement physical analysis of modified DNA. This approach was applied to the complex product spectrum generated by peroxynitrite in the presence of CO2; peroxynitrite is a powerful oxidizing and nitrating agent generated as part of immune response. An oligonucleotide containing the primary oxidation product, 7,8-dihydro-8-oxoguanine (8-oxoGua), which is highly susceptible to further oxidation and/or nitration, was treated with peroxynitrite. Using mass spectrometry, coelution with authentic standards, sensitivity to piperidine, recognition and strand cleavage by the DNA repair enzyme MutM, and mutagenicity and genotoxicity in vivo, a matrix was created that defined the properties of the secondary DNA lesions formed when 3-morpholinosydnonimine (SIN-1) delivered a low, constant flux of peroxynitrite to an oligonucleotide containing 8-oxoGua. Two lesions were identified as the diastereomers of spiroiminodihydantoin (Sp), which had been observed previously in nucleoside-based experiments employing SIN-1. A third lesion, triazine, was tentatively identified. However, in addition to these lesions, a number of secondary lesions were generated that had chemical–biological fingerprints inconsistent with that of any known 8-oxoGua-derived lesion described to date. In vitro experiments showed that while some of these newly characterized secondary lesions were removed from DNA by MutM, others were in fact very poor substrates for this repair enzyme. These 8-oxoGua-derived lesions also showed varying degrees of sensitivity to piperidine. Furthermore, all of the secondary lesions observed in this work were potently mutagenic and genotoxic in Escherichia coli. Therefore, while 8-oxoGua itself is nontoxic and only mildly mutagenic in repair-proficient cells, peroxynitrite reveals the promutagenic potential and triggers the covert nature of this DNA lesion.
Leg ulcers are a debilitating complication of patients with sickle cell disease, and their frequency in North America was reported to be 2.5% by the Cooperative Study of Sickle Cell Disease more than 20 years ago. We sought to determine if the frequency of leg ulcers in sickle cell patients in the United States had declined and to assess which treatments providers use most commonly. We sent an e-mail survey to health professionals belonging to the national Sickle Cell Adult Provider Network. Responses were obtained from 31 of them (26.0%). Most of them (96.0%) reported having some patients with leg ulcers. Providers reported a total of 185 patients with active leg ulcers and 224 in the previous 5 years, for a total of 409 patients. Hb SS (homozygous sickle cell anemia) was the most common genotype of affected individuals, followed by Hb SC (double heterozygote for Hb S [β6(A3)Glu→Val, GAG>GTG; HBB: c.20A>T] and Hb C [β6(A3)Glu→Lys, GAG>AAG; HBB: c.19G>A]). Males showed a 2:1 predominance. Two-thirds of patients were treated with either hydroxyurea (HU) or transfusion therapy and most used compression stockings and topical therapies as directed by wound care services. We conclude that leg ulcers continue to be a debilitating complication of young adults with sickle cell disease, despite improved supportive care and the widespread use of disease modifying agents such HU and transfusion. While some providers offer office-based ulcer care, the majority prefer specialty consultation including podiatry, plastic surgery and dermatology. Despite their frequency, there is no clear consensus among providers as to the best treatment.
Leg Ulcers; Sickle cell disease; Hydroxyurea (HU); Survey
Trinucleotide repeats (TNRs) occur throughout the genome and their expansion has been linked to several neurodegenerative disorders, including Huntington’s Disease. TNRs have been studied using both oligonucleotides and plasmids; however, less is know about how repetitive DNA responds to genomic packaging. Here, we investigate the behavior of CAG/CTG repeats incorporated into nucleosome core particles, the most basic unit of chromatin packaging. To assess the general interaction between CAG/CTG repeats and the histone core, we determined the efficiency with which various TNR-containing DNA substrates form nucleosomes, revealing that even short CAG/CTG tracts are robust incorporators. However, presence of the Huntingtin gene flanking sequence (htt) decreases incorporation. Enzymatic and chemical probing revealed repositioning of the DNA in the nucleosome as the number of CAG/CTG repeats increased, regardless of the flanking sequence. Notably, the periodicity of the repeat tract remained unchanged as a function of length and is consistently 10.7 base pairs per helical turn. In contrast, the periodicity of the non-repetitive flanking sequence varies, and is smaller than the repeat tract at ~10.0–10.5 base pairs per turn. Furthermore, while the CAG/CTG repeats remain as canonical duplex in the nucleosome, nucleosome formation causes kinking in a secondary repeat tract in the htt gene, comprised of CCG/CGG repeats. This work highlights the innate ability of CAG/CTG repeats to incorporate and to position in nucleosomes and how that behavior is modulated by the htt flanking sequence. In addition, it illuminates the differences in packaging of healthy and diseased length repeat tracts within the genome.
Transplantation of one or two umbilical cord blood products is a useful alternative stem cell source. However, the limited number of stem cells in the infusion results in slow engraftment. In mouse models, administration of parathyroid hormone is an effective way to enhance the ability of limited numbers of hematopoietic stem cells to support hematopoiesis. In this study, patients received either a myeloablative or a reduced intensity double umbilical cord blood transplantation followed by parathyroid hormone at 100 μg daily for 28 days. Thirteen patients (median age 42 years) were enrolled. All patients engrafted; the median time to neutrophil and platelet engraftment >20x109 cells/L were 30 and 61 days respectively. The incidence of Grades II–IV acute GVHD was 38.5% at day 100. There were four deaths prior to Day 100, prompting early study closure. No patients receiving a myeloablative regimen relapsed. Overall survival at 6 months after transplantation was 62% and disease-free survival at 2 years was 39%. At the dose and schedule studied, there was no evidence that PTH influenced blood count recovery.
Transplantation; Umbilical Cord Blood; Parathyroid Hormone
Examine effects of HMO penetration, hospital competition, and patient severity on the uptake of laparoscopic colectomy and its price relative to open surgery for colon cancer.
We used 2002-2007 the MarketScan Database to identify admissions for privately insured colorectal cancer patients undergoing laparoscopic or open partial colectomy (n=1,035 and n=6,389, respectively). Patient and health plan characteristics were retrieved from these data; HMO market penetration rates and an index of hospital market concentration, Herfindahl-Hirschman Index (HHI), were derived from national databases. Logistic and logarithmic regressions were used to examine the odds of having laparoscopic colectomy, effect of covariates on colectomy prices, and the differential price of laparoscopy.
Adoption of laparoscopy was highly sensitive to market forces, with a 10% increase in HMO penetration leading to a 10.3% increase in the likelihood of undergoing laparoscopic colectomy (Adjusted Odds Ratio (AOR): 1.109, 95% Confidence Interval: 1.062, 1.158), and a 10% increase in HHI resulting in 6.6% lower likelihood (AOR: 0.936 (0.880, 0.996)). Price models indicated that the price of laparoscopy was 7.6% lower than for open surgery (transformed coefficient (Coeff): 0.927 (0.895, 0.960)). A 10% increase in HMO penetration was associated with 1.6% lower price (Coeff: 0.985 (0.977, 0.992)), while a 10% increase in HHI was associated with 1.6% higher price (Coeff: 1.016 (1.006, 1.027), p < 0.001 for all comparisons).
Laparoscopy was significantly associated with lower hospital prices. Moreover,
Laparoscopic surgery may result in cost savings, while market pressures contribute to its adoption.
Colon Cancer; Surgery; Laparoscopy, Medical Prices
Reduced-intensity conditioning (RIC) regimens in cord blood transplant (CBT) are increasingly utilized for older patients and those with comorbidities. However, the optimal conditioning regimen has not yet been established and remains a significant challenge of this therapeutic approach. Anti-thymocyte globulin (ATG) has been incorporated into conditioning regimens in order to decrease the risk of graft failure; however, use of ATG is often associated with infusion reactions and risk of post-transplant complications. We report the results of a non-ATG-containing RIC regimen, where patients received 2Gy TBI unless they were considered to be at higher risk of graft failure, in which case they received 3Gy of TBI. Thirty patients underwent CBT using this protocol for high-risk hematological malignancies. There was only one case of secondary and no cases of primary graft failure. At one year, estimates of NRM, OS and PFS were 29%, 53% and 45%, respectively. The cumulative incidences of grade III–IV acute and chronic GVHD were 14% and 18%, respectively. In summary, results of this study demonstrate that this non-ATG-containing conditioning regimen provides a low incidence of graft failure without increasing regimen-related toxicity.
Umbilical cord blood transplant; Reduced-intensity conditioning regimen; Anti-thymocyte globuline
Human herpesvirus 6 (HHV-6) reactivation has been associated with acute graft-versus-host-disease (aGVHD), cytomegalovirus (CMV) reactivation, and mortality after allogeneic hematopoietic cell transplantation (HCT), but previous studies have yielded inconsistent results. We performed a large prospective study of allogeneic HCT recipients in order to more definitively define the relationships between HHV-6 and these important outcomes.
Plasma specimens were collected prospectively from 315 allogeneic HCT recipients and tested for HHV-6 DNA at baseline and twice-weekly for 12 weeks. Cox proportional hazards models were used to evaluate the time-dependent associations between HHV-6 reactivation and the targeted outcomes.
HHV-6 was detected in 111 (35%) of 315 patients at a median of 20 days after HCT. HHV-6 reactivation was associated with subsequent CMV reactivation [adjusted hazard ratio (aHR) 1.9, 95% confidence interval (CI) 1.3-2.8, p=0.002]. High-level HHV-6 (>1,000 HHV-6 DNA copies/mL) was associated with subsequent grades II-IV aGVHD (aHR 2.4, 95% CI 1.60-3.6), p<0.001). High-level HHV-6 reactivation was also associated with non-relapse mortality (aHR 2.7, 95% CI 1.2-6.3, p=0.02).
HHV-6 reactivation was independently and quantitatively associated with increased risk of subsequent CMV reactivation, aGVHD, and mortality after HCT. A randomized antiviral trial is warranted to establish causality between HHV-6 and these endpoints and to determine if reducing HHV-6 reactivation will improve outcome after HCT.
The platelet receptor for von Willebrand factor (VWF), the glycoprotein Ib-IX (GPIb-IX) complex, mediates platelet adhesion at sites of vascular injury and transmits signals leading to platelet activation. VWF/GPIb-IX interaction sequentially activates the Src Family Kinase (SFK) Lyn, phosphoinositide 3-kinase (PI3K) and Akt, leading to activation of integrin αIIbβ3, and integrin-dependent stable platelet adhesion and aggregation. It remains unclear how Lyn activates the PI3K/Akt pathway following ligand binding to GPIb-IX.
Methods and Results
Using platelet-specific Rac1−/− mice and the Rac1 inhibitor NSC23766, we examined the role of Rac1 in GPIb-IX-dependent platelet activation. Rac1−/− mouse platelets and NSC23766-treated human platelets were defective in GPIb-dependent stable adhesion to VWF under shear stress, integrin activation, thromboxane A2 (TXA2) synthesis and platelet aggregation. Interestingly, GPIb-induced activation of Rac1 and the guanine nucleotide exchange factor (GEF) for Rac1,Vav, was abolished in both Lyn−/− and PP2-treated platelets but was unaffected by the PI3K inhibitor LY-294002, indicating that Lyn mediates activation of Vav and Rac1 independently of PI3K. Furthermore, GPIb-induced activation of Akt was abolished in Rac1-deficient platelets, suggesting that Rac1 is upstream of the PI3K/Akt pathway.
A Lyn/Vav/Rac1/PI3K/Akt pathway mediates VWF-induced activation of integrin αIIbβ3 to promote GPIb-IX-dependent platelet activation.
platelet; glycoprotein Ib-IX; platelet adhesion; von Willebrand factor; Rac1
In the Darwin region of Australia where melioidosis is highly endemic, only 11/354 (3%) healthy residents were seropositive by indirect hemagglutination assay, despite extensive exposure to Burkholderia pseudomallei. None developed melioidosis, but some described a prior self-limiting illness. This seropositivity rate is much lower than that seen in northeast Thailand, where melioidosis is similarly highly endemic, potentially reflecting important differences between these two locations in the epidemiology of melioidosis.
To evaluate feasibility and preliminary outcomes associated with sequential whole abdomen irradiation (WAI) as consolidative treatment following comprehensive surgery and systemic chemotherapy for advanced endometrial cancer.
We conducted a retrospective analysis of patients treated at our institution from 2000 to 2011. Inclusion criteria were stage III-IV endometrial cancer patients with histological proof of one or more sites of extra-uterine abdomen-confined disease, treated with WAI as part of multimodal therapy. Endpoints were feasibility, acute toxicity, late effects, recurrence-free survival (RFS) and overall survival (OS). Twenty patients were identified. Chemotherapy consisted of 3 to 6 cycles of a platinum-paclitaxel regimen in 18 patients. WAI was delivered using conventional technique to a median total dose of 27.5 Gy.
No grade 4 toxicities occurred during chemotherapy or radiotherapy. No radiation dose reduction was necessary. Three patients developed small bowel obstruction, all in the context of recurrent intraperitoneal disease. Kaplan-Meier estimates and 95% confidence intervals for RFS and OS at one year were 63% (38–80%) and 83% (56-94%) and at 3 years 57% (33-76%) and 62% (34-81%), respectively. On univariate Cox analysis, stage IVB and serous papillary (SP) histology were found to be statistically significantly (at the p = 0.05 level) associated with worse RFS and OS. The peritoneal cavity was the most frequent site of initial failure.
Consolidative WAI following chemotherapy is feasible and can be performed without interruption with manageable acute and late toxicity. Patients with endometrioid adenocarcinoma, especially stage FIGO III, had favorable outcomes possibly meriting prospective evaluation of the addition of WAI following chemotherapy in selected patients. Patients with SP do poorly and do not routinely benefit from this approach.
Whole abdomen irradiation; Advanced endometrial cancer; Chemotherapy; Radiotherapy
Variation in gene expression has been found to be important in disease susceptibility and pharmacogenomics. Local and distant expression quantitative trait loci (eQTLs) have been identified via genome-wide association study (GWAS); yet the functional analysis of these variants has been challenging. The aim of this study was to unravel the functional consequence of a gene with a local SNP with evidence for local and distant regulatory roles in cellular sensitivity to cisplatin, one of the most widely used chemotherapeutic drugs. To this end, we measured cellular susceptibility to cisplatin in 176 HapMap lymphoblastoid cell lines derived from Yoruba individuals from Ibadan, Nigeria. The 276 cytotoxicity-associated SNPs at the suggestive threshold of P ≤ 0.0001 were significantly enriched for eQTLs. Of these SNPs, we found one intronic SNP, rs17115814, that had a significant relationship with the expression level of its host gene, PRPF39 (P= 0.0007), and a significant correlation with the expression of over 100 distant transcripts (P ≤ 0.0001). Successful knockdown of PRPF39 expression using siRNA resulted in a significant increase in cisplatin resistance. We then measured the expression of 61 downstream targets after PRPF39 knockdown and found 53 gene targets had significant (P ≤ 0.05) expression changes. Included in the list of genes that significantly changed after PRPF39 knockdown were MAP3K4 and TFPD2, two important signaling genes previously shown to be relevant in cisplatin response. Thus, modulation of a local target gene identified through a GWAS was followed by a downstream cascade of gene expression changes resulting in greater resistance to cisplatin.
The Kir 6.1 Katp channel is believed to play an important role in ventricular repolarization as determined from both functional and genetic studies of the potassium inwardly-rectifying channel, subfamily J, member 8 (KCNJ8)-S422L missense mutation in patients with J-wave syndromes. Although Kir6.1 is also present in atrial tissue, it is unknown whether this channel modulates atrial repolarization and hence whether the S422L mutation portends a greater risk of atrial arrhythmias. This study sought to examine whether there was an increased frequency of the KCNJ8-S422L mutation among patients with atrial fibrillation (AF) and early repolarization (ER) as a possible novel susceptibility gene for AF.
Methods and results
A total of 325 lone AF probands were identified from the Vanderbilt AF Registry, a collection of clinical data and DNA from consented, consecutively enrolled participants. The coding regions of KCNJ8 were sequenced, and the patient's presenting electrocardiogram (ECG) was reviewed by two independent physicians for ER abnormalities. The KCNJ8-S422L mutation was identified in two AF probands while no other candidate gene variants were identified in these cases. Twenty-two (7%) patients were found to have ER on the ECG, including the two probands carrying the S422L variant. In one small AF kindred, the S422L variant co-segregated with AF and ER.
The KCNJ8-S422L variant is associated with both increased AF susceptibility and ER indicating a role for Kir 6.1 Katp channel in both ventricular and atrial repolarization.
Atrial fibrillation; Early repolarization; KCNJ8; Kir6.1; Mutation
The integrin family of cell adhesion receptors mediates bi-directional signaling: “inside-out” signaling activates the ligand binding function of integrins and “outside-in” signaling mediates cellular responses induced by ligand binding to integrins leading to cell spreading, retraction, migration, and proliferation. Integrin signaling requires both heterotrimeric G proteins and monomeric small G proteins. This review focuses on recent development in the roles of G proteins in integrin outside-in signaling. The finding of direct interaction between the heterotrimeric G protein subunit Gα13 and integrin β subunits reveals a new mechanism for integrin signaling, and also uncovers a crosstalk between the signaling pathways initiated by G protein-coupled receptors (GPCRs) and integrins. This crosstalk, which may be referred to as “inside-outside-in” signaling, dynamically regulates contractility and greatly promotes integrin outside-in signaling
Early implementation of programmatic colorectal cancer (crc) screening for average-risk individuals 50–74 years of age in Canada has used fecal occult blood tests [fts (guaiac or immunochemical)] and colonoscopy for follow-up of abnormal fts. This paper presents results of an evaluation of this crc screening.
Five Canadian provincial programs provided aggregated data for individuals with a first-round ft processed between January 1, 2009, and December 31, 2011.
The 104,750 people who successfully completed a first round of screening represented 16.1% of those who had access to the programs between January 1, 2009, and December 31, 2011 (mean age: 61.2 years; men: 61.4 years; women: 61.1 years). Of those participants, 4661 had an abnormal ft (4.4%). Uptake of colonoscopy within 180 days after an abnormal ft was 80.5%, ranging from 67.8% to 89.5% by program. The positive predictive value (ppv) for adenoma was 35.9% for guaiac ft and 50.6% for immunochemical ft. Adenoma and crc detection rates were, respectively, 16.9 and 1.8 per 1000 screened. Of invasive crcs detected, 64.6% were stage i or ii.
Considering the variation in characteristics and stage of implementation of each provincial program, the collaboration of the provinces leading to this report on the early performance of crc screening in Canada is a major milestone. Targets are met or nearly met for significant indicators such as ppv for adenoma and cancer detection rate. Participation is expected to increase as programs are fully implemented in the provinces. Additional effort may be needed to improve timely access to follow-up colonoscopy.
Colorectal cancer; screening programs; fecal occult blood test; guaiac; immunochemical; average risk
The use of neoadjuvant and adjuvant chemotherapy in soft tissue sarcomas is controversial. This is a report of long-term (≥5 years) follow-up in patients with high-grade, high-risk soft tissue sarcomas treated with neoadjuvant chemotherapy, preoperative radiotherapy (RT), and adjuvant chemotherapy.
Patients with high-grade soft tissue sarcoma ≥8 cm in diameter of the extremities and body wall received 3 cycles of neoadjuvant chemotherapy (mesna, doxorubicin, ifosfamide, and dacarbazine) and preoperative RT (44 grays administered in split courses), and 3 cycles of postoperative chemotherapy (mesna, doxorubicin, ifosfamide, and dacarbazine).
Sixty-four of 66 patients were analyzed. After chemotherapy and RT, 61 patients had surgery; 58 had R0 resections (5 amputations), and 3 had R1 resections. Ninety-seven percent experienced grade 3 or higher toxicity, including 3 deaths. These toxicities were short term. With a median follow-up of 7.7 years in surviving patients, the 5-year rates of locoregional failure (including amputation), and distant metastasis were 22.2% (95% confidence interval [CI], 11.8–32.6) and 28.1% (95% CI, 17.0–39.2). The most common site of metastasis was lung. Estimated 5-year rates of disease-free survival, distant disease-free survival, and overall survival were 56.1% (95% CI, 43.9–68.3), 64.1% (95% CI, 52.3–75.8), and 71.2% (95% CI, 60.0–82.5), respectively.
Although the toxicity was significant, it was limited in its course and for the most part resolved by 1 year. The long-term outcome was better than might be expected in such high-risk tumors.
sarcoma; neoadjuvant chemotherapy; radiation
Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT), Trichomonas vaginalis (TV) and Mycoplasma genitalium (MG) are established pathogens for human genital tract. However, the role of Ureaplasma urealyticum (UU) and Ureaplasma parvum (UP) in genital pathology is poorly unerstood. A prospective study to investigate the prevalence of above infections was performed on a cohort of 1,718 consecutive patients attending a Genitourinary Medicine (GUM) clinic. A previously published in-house real-time PCR assay, for the detection of CT DNA in genital swabs, was modified for this study. Two amplification reactions detected the DNAs of TV, NG, MG, CT, UU and UP in genital swabs from 4 (0.2%), 11 (0.6%), 17 (1%), 129 (8%), 282 (16%) and 636 (37%) patients, respectively. 594 (70%) of 848 women and 333 (38%) of 870 men were infected with at least one type of microorganism. Among 594 infected females, 485 (82%) had a single infection, 97 (16%) had a double infection, and 12 (2%) had a triple infection. Of the 333 infected men, 304 (91%) had a single infection, 27 (8%) had a double infection, and 2 (1%) had a triple infection. The prevalence of infection in both genders decreased with increasing age. The prevalence proportion of UP was significantly higher in women (54%) compared with men (18%). The high prevalence of UU and UP suggests that these bacteria are commensals of genital tract.
Neisseria gonorrhoeae; Chlamydia trachomatis; Trichomonas vaginalis; Mycoplasma genitalium; Ureaplasma urealyticu; Ureaplasma parvum; epidemiology; PCR
While several studies have reported a positive association between overall adiposity and heart failure (HF) risk, limited and inconsistent data are available on the relation between central adiposity and incident heart failure in older adults. We sought to examine the association between waist circumference and incident heart failure and assess whether sex modifies the relation between waist circumference and heart failure. Prospective study using data on 4861 participants of the Cardiovascular Health Study (1989 to 2007). Heart failure was adjudicated by a committee using information from medical records and medications. We used Cox proportional hazard models to compute hazard ratio. The mean age was 73.0 y for men and 72.3 y for women; 42.5% were men and 15.3% were African-Americans. Waist circumference was positively associated with an increased risk of HF: each standard deviation of waist circumference was associated with a 14% increased risk of HF (95% CI: 3% to 26%) in a multivariable model. There was not a statistically significant sex-by-waist circumference interaction (p=0.081). Body mass index was positively associated with incident HF [HR: 1.22 (95% CI: 1.15–1.29) per standard deviation increase of body mass index], however, this association was attenuated and became non-statistically significant upon additional adjustment for waist circumference [HR: 1.09 (95% CI: 0.99–1.21)]. In conclusion, a higher waist circumference is associated with an increased risk of heart failure independent of body mass index in community-living older men and women.
Epidemiology; heart failure; adiposity; risk factors
Although hematopoietic cell transplantation (HCT) arrests the cognitive decline in mucopolysaccharidosis type IH (Hurler syndrome, MPS IH), these children continue to have neuropsychological deficits as they age. Both compromised attention and effects on white matter have been observed in cancer patients who have had chemotherapy. Therefore, we explored the effects of disease and treatment on brain function in children with MPS I who have had HCT with those with attenuated MPS I treated with enzyme replacement therapy (ERT).
Subjects: 7 MPS IH participants at least 5 years post-HCT were compared with 7 attenuated participants who were treated with ERT. Measures: IQ, attention, spatial ability, and memory were assessed. Medical history and an unsedated MRI scan using diffusion tensor imaging (DTI) were acquired.
Despite clinically equivalent IQ and memory, children with MPS IH had poorer attention span than those with attenuated MPS I as well as decreased fractional anisotropy (FA) of the corpus callosum. A relationship between attention scores and FA was found in the MPS IH group but not the attenuated group. FA was also related to frequency of medical events.
In children with MPS IH, both the treatment and the disease affect attention functions associated with poor white matter integrity.
MPS I; hematopoietic cell transplant; attention span; cognition; diffusion tensor imaging; medical history
Homopolymers of β-lactams can be grown by surface-initiated polymerization. These surface-linked β-peptides are living polymers with the potential to be utilized as tunable, protease-resistant interfaces in multiphase structural composites where the characteristics of the interface influence bulk properties.
Guanidinohydantoin (Gh) is a hyperoxidized DNA lesion produced by oxidation of 8-oxo-7,8-dihydroguanine (8-oxoG). Previous work has shown that Gh is potently mutagenic both in vitro and in vivo coding for G → T and G → C transversion mutations. In this work, analysis by circular dichroism shows that the Gh lesion does not significantly alter the global structure of a 15-mer duplex, and that the DNA remains in the B-form. However, we find that Gh causes a large decrease in the thermal stability, decreasing the duplex melting temperature by ~ 17 °C relative to an unmodified duplex control. Using optical melting analysis and differential scanning calorimetry the thermodynamic parameters describing duplex melting were also determined. We find that the Gh lesion causes a dramatic decrease in the enthalpic stability of the duplex. This enthalpic destabilization is somewhat tempered by entropic stabilization yet Gh results in an overall decrease in thermodynamic stability of the duplex relative to a control which lacks DNA damage, with a ΔΔG° of −7 kcal/mol. These results contribute to our understanding of the consequences of hyperoxidation of G and provide insight into how the thermal and thermodynamic destabilization caused by Gh may influence replication and/or repair of the lesion.
addictions; cognitive-behavioral program; Web application; SMART Recovery; mutual self-help groups
Children with respiratory tract infections are the single most frequent patient group to make use of primary care health care resources. The use of antibiotics remains highly prevalent in young children, but can lead to antimicrobial resistance as well as reinforcing the idea that parents should re-consult for similar symptoms. One of the main drivers of indiscriminate antimicrobial use is the lack of evidence for, and therefore uncertainty regarding, which children are at risk of poor outcome. This paper describes the protocol for the TARGET cohort study, which aims to derive and validate a clinical prediction rule to identify children presenting to primary care with respiratory tract infections who are at risk of hospitalisation.
The TARGET cohort study is a large, multicentre prospective observational study aiming to recruit 8,300 children aged ≥3 months and <16 years presenting to primary care with a cough and respiratory tract infection symptoms from 4 study centres (Bristol, London, Oxford and Southampton). Following informed consent, symptoms, signs and demographics will be measured. In around a quarter of children from the Bristol centre, a single sweep, dual bacterial-viral throat swab will be taken and parents asked to complete a symptom diary until the child is completely well or for 28 days, whichever is sooner. A review of medical notes including clinical history, re-consultation and hospitalisations will be undertaken. Multivariable logistic regression will be used to identify the independent clinical predictors of hospitalisation as well as the prognostic significance of upper respiratory tract microbes. The clinical prediction rule will be internally validated using various methods including bootstrapping.
The clinical prediction rule for hospitalisation has the potential to help identify a small group of children for hospitalisation and a much larger group where hospitalisation is very unlikely and antibiotic prescribing would be less warranted. This study will also be the largest natural history study to date of children presenting to primary care with acute cough and respiratory tract infections, and will provide important information on symptom duration, re-consultations and the microbiology of the upper respiratory tract.
Cohort study; Children; Respiratory tract infections (RTIs); Primary care; Protocol; Throat swab
DNA is susceptible to alkylation damage by a number of environmental agents that modify the Watson-Crick edge of the bases. Such lesions, if not repaired, may be bypassed by Y-family DNA polymerases. The bypass polymerase Dpo4 is strongly inhibited by 1-methylguanine (m1G) and 3-methylcytosine (m3C), with nucleotide incorporation opposite these lesions being predominantly mutagenic. Further, extension following insertion of both correct and incorrect bases, introduces additional base substitution and deletion errors. Crystal structures of the Dpo4 ternary extension complexes with correct and mismatched 3′-terminal primer bases opposite the lesions reveal that both m1G and m3C remain positioned within the DNA template/primer helix. However, both correct and incorrect pairing partners exhibit pronounced primer terminal nucleotide distortion, being primarily evicted from the DNA helix when opposite m1G or misaligned when pairing with m3C. Our studies provide insights into mechanisms related to hindered and mutagenic bypass of methylated lesions and models associated with damage recognition by repair demethylases.
Chronological and replicative aging have been studied in yeast as alternative paradigms for post-mitotic and mitotic aging, respectively. It has been known for more than a decade that cells of the S288C background aged chronologically in rich medium have reduced replicative lifespan relative to chronologically young cells. Here we report replication of this observation in the diploid BY4743 strain background. We further show that the reduction in replicative lifespan from chronological aging is accelerated when cells are chronologically aged under standard conditions in synthetic complete medium rather than rich medium. The loss of replicative potential with chronological age is attenuated by buffering the pH of the chronological aging medium to 6.0, an intervention that we have previously shown can extend chronological lifespan. These data demonstrate that extracellular acidification of the culture medium can cause intracellular damage in the chronologically aging population that is asymmetrically segregated by the mother cell to limit subsequent replicative lifespan.
chronological lifespan; longevity; replication stress; replicative lifespan; yeast