Association of AKAP6 and MIR2113 with cognitive performance in a population-based sample of older adults.

Genetic factors make a substantial contribution to inter-individual variability in cognitive function. A recent meta-analysis of genome-wide association studies identified two loci, AKAP6 and MIR2113, that are associated with general cognitive function. Here, we extend this previous research by investigating the association of MIR2113 and AKAP6 with baseline and longitudinal non-linear change across a broad spectrum of cognitive domains in a community-based cohort of older adults without dementia. Two single nucleotide polymorphisms (SNPs), MIR211-rs10457441 and AKAP6-rs17522122 were genotyped in 1570 non-demented older Australians of European ancestry, who were examined up to 4 times over 12 years. Linear mixed effects models were used to examine the association between AKAP6 and MIR2113 with cognitive performance in episodic memory, working memory, vocabulary, perceptual speed and reaction time at baseline and with linear and quadratic rates of change. AKAP6-rs17522122*T was associated with worse baseline performance in episodic memory, working memory, vocabulary and perceptual speed, but it was not associated with cognitive change in any domain. MIR2113-rs10457441*T was associated with accelerated decline in episodic memory. No other associations with baseline cognitive performance or with linear or quadratic rate or cognitive changes were observed for this SNP. These results confirm the previous finding that AKAP6 is associated with performance across multiple cognitive domains at baseline but not with cognitive decline, while MIR2113 primarily affects the rate at which memory declines over time.

The Convective Transport of Active Species in the Tropics (CONTRAST) Experiment.

The Convective Transport of Active Species in the Tropics (CONTRAST) experiment was conducted from Guam (13.5° N, 144.8° E) during January-February 2014. Using the NSF/NCAR Gulfstream V research aircraft, the experiment investigated the photochemical environment over the tropical western Pacific (TWP) warm pool, a region of massive deep convection and the major pathway for air to enter the stratosphere during Northern Hemisphere (NH) winter. The new observations provide a wealth of information for quantifying the influence of convection on the vertical distributions of active species. The airborne in situ measurements up to 15 km altitude fill a significant gap by characterizing the abundance and altitude variation of a wide suite of trace gases. These measurements, together with observations of dynamical and microphysical parameters, provide significant new data for constraining and evaluating global chemistry climate models. Measurements include precursor and product gas species of reactive halogen compounds that impact ozone in the upper troposphere/lower stratosphere. High accuracy, in-situ measurements of ozone obtained during CONTRAST quantify ozone concentration profiles in the UT, where previous observations from balloon-borne ozonesondes were often near or below the limit of detection. CONTRAST was one of the three coordinated experiments to observe the TWP during January-February 2014. Together, CONTRAST, ATTREX and CAST, using complementary capabilities of the three aircraft platforms as well as ground-based instrumentation, provide a comprehensive quantification of the regional distribution and vertical structure of natural and pollutant trace gases in the TWP during NH winter, from the oceanic boundary to the lower stratosphere.

APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer's disease.

Alzheimer's disease (AD) age of onset (ADAOO) varies greatly between individuals, with unique causal mutations suggesting the role of modifying genetic and environmental interactions. We analyzed ~50 000 common and rare functional genomic variants from 71 individuals of the 'Paisa' pedigree, the world's largest pedigree segregating a severe form of early-onset AD, who were affected carriers of the fully penetrant E280A mutation in the presenilin-1 (PSEN1) gene. Affected carriers with ages at the extremes of the ADAOO distribution (30s-70s age range), and linear mixed-effects models were used to build single-locus regression models outlining the ADAOO. We identified the rs7412 (APOE*E2 allele) as a whole exome-wide ADAOO modifier that delays ADAOO by ~12 years (ß=11.74, 95% confidence interval (CI): 8.07-15.41, P=6.31 × 10(-8), PFDR=2.48 × 10(-3)). Subsequently, to evaluate comprehensively the APOE (apolipoprotein E) haplotype variants (E1/E2/E3/E4), the markers rs7412 and rs429358 were genotyped in 93 AD affected carriers of the E280A mutation. We found that the APOE*E2 allele, and not APOE*E4, modifies ADAOO in carriers of the E280A mutation (ß=8.24, 95% CI: 4.45-12.01, P=3.84 × 10(-5)). Exploratory linear mixed-effects multilocus analysis suggested that other functional variants harbored in genes involved in cell proliferation, protein degradation, apoptotic and immune dysregulation processes (i.e., GPR20, TRIM22, FCRL5, AOAH, PINLYP, IFI16, RC3H1 and DFNA5) might interact with the APOE*E2 allele. Interestingly, suggestive evidence as an ADAOO modifier was found for one of these variants (GPR20) in a set of patients with sporadic AD from the Paisa genetic isolate. This is the first study demonstrating that the APOE*E2 allele modifies the natural history of AD typified by the age of onset in E280A mutation carriers. To the best of our knowledge, this is the largest analyzed sample of patients with a unique mutation sharing uniform environment. Formal replication of our results in other populations and in other forms of AD will be crucial for prediction, follow-up and presumably developing new therapeutic strategies for patients either at risk or affected by AD.

AAV serotype 2/1-mediated gene delivery of anti-inflammatory interleukin-10 enhances neurogenesis and cognitive function in APP+PS1 mice.

Brain inflammation is a double-edged sword. It is required for brain repair in acute damage, whereas chronic inflammation and autoimmune disorders are neuropathogenic. Certain proinflammatory cytokines and chemokines are closely related to cognitive dysfunction and neurodegeneration. Representative anti-inflammatory cytokines, such as interleukin (IL)-10, can suppress neuroinflammation and have significant therapeutic potentials in ameliorating neurodegenerative disorders such as Alzheimer's disease (AD). Here, we show that adeno-associated virus (AAV) serotype 2/1 hybrid-mediated neuronal expression of the mouse IL-10 gene ameliorates cognitive dysfunction in amyloid precursor protein+ presenilin-1 bigenic mice. AAV2/1 infection of hippocampal neurons resulted in sustained expression of IL-10 without its leakage into the blood, reduced astro/microgliosis, enhanced plasma amyloid-ß peptide (Aß) levels and enhanced neurogenesis. Moreover, increased levels of IL-10 improved spatial learning, as determined by the radial arm water maze. Finally, IL-10-stimulated microglia enhanced proliferation but not differentiation of primary neural stem cells in the co-culture system, whereas IL-10 itself had no effect. Our data suggest that IL-10 gene delivery has a therapeutic potential for a non-Aß-targeted treatment of AD.

Protective efficacy of a live attenuated anti-coccidial vaccine administered to 1-day-old chickens.

The efficacy of a live attenuated anti-coccidial vaccine, Paracox-5, administered to 1-day-old chicks was investigated by assessing protection against changes in weight gain following virulent challenge. Vaccinated birds were challenged independently 28 days later with each of the component species (Eimeria acervulina, Eimeria maxima, Eimeria mitis or Eimeria tenella), and protection was demonstrated against associated reduction in weight gain and lesion formation. In addition, an improvement in bird performance, in terms of feed conversion ratio, was also observed following vaccination. Furthermore, under conditions designed to more closely mimic those in the field and using hatchery spray administration, protection against a mixed virulent challenge introduced by 'seeder birds' was demonstrated evenly across a flock of broiler birds within 21 days after vaccination. These data demonstrate that Paracox-5 vaccine will protect broiler chickens against the adverse effects on performance induced by Eimeria spp.

Ultrasonography and abdominal radiography versus intravenous urography in investigation of urinary tract infection in men: prospective incident cohort study.

OBJECTIVES: To compare ultrasonography and abdominal radiography with intravenous urography in the investigation of urinary tract infection in men. DESIGN: Prospective study in two hospital departments. Radiological procedures and urological assessments performed on different days by different clinicians SETTING: District general hospital. PARTICIPANTS: Consecutive series of men (n=114) referred to the department of urology for investigation of proved urinary tract infection. INTERVENTIONS: Ultrasonography and intravenous urography of renal tract and assessment of urinary flow rate. Clinical assessment, cystoscopy, urodynamic studies, and transrectal ultrasonography with biopsy. MAIN OUTCOME MEASURES: Sensitivity and specificity of ultrasonography and abdominal radiography compared with intravenous urography. RESULTS: Important abnormalities were seen in 53 of 100 fully evaluated patients, the most common being a poorly emptying bladder (34). The combination of plain radiographs of kidneys, ureter, and bladder and ultrasonography detected more abnormalities than intravenous urography alone. No important abnormality was missed by this combination (sensitivity 100% and specificity 93%). CONCLUSIONS: Ultrasonography with abdominal radiography is as accurate as intravenous urography in detecting important urological abnormalities in men presenting with urinary tract infection. This combination is safer than intravenous urography and should be the initial investigation for such patients. Additional determination of urinary flow rate is useful for the assessment of an incompletely emptying bladder.

Prospective analysis of a fever evaluation algorithm after major gynecologic surgery.

OBJECTIVE: We performed a prospective trial to evaluate the feasibility, accuracy, and safety of a postoperative fever algorithm that is based on symptoms and physical examination in an attempt to decrease the random use of urine cultures, blood cultures, and chest radiographs. STUDY DESIGN: Our fever algorithm consisted of assessing all febrile postoperative patients for signs and symptoms of infection. If none were present, no tests were ordered. RESULTS: Twenty-eight of 105 consecutive patients (27%) had postoperative fever after major gynecologic surgery. Three of 28 febrile patients (11%) were evaluated with tests according to the algorithm. Two of 28 febrile patients (7%) were evaluated in violation of the algorithm. Four febrile patients (14%) had documented infections. Two patients had infections within the first 30 days after discharge. Compared with our previous retrospective review, significantly fewer febrile patients were evaluated with testing with a significantly increased yield of positive test results. CONCLUSIONS: Our postoperative fever evaluation algorithm that is based on symptoms and physical examination is feasible, is safe, decreases random testing, and increases the yield of positive test results.

Survival after multimodality treatment for stage IIIC endometrial cancer.

OBJECTIVE: Our purpose was to review our results of multimodality treatment of lymph node metastasis in endometrial cancer (stage IIIC). STUDY DESIGN: All patients underwent surgical staging for endometrial cancer with complete pelvic and aortic lymphadenectomy. All macroscopic nodal metastases were resected. Patients with microscopic nodal metastasis received adjuvant teletherapy, whereas those with macroscopic nodal metastasis received chemotherapy (carboplatin AUC 5 and paclitaxel 135 mg/m2 every 3 weeks for 6 courses) followed by teletherapy. RESULTS: Twenty-one patients had stage IIIC disease, and one had stage IVB (inguinal nodal metastasis). Sixty-four percent of tumors were poorly differentiated. Fifty-five percent of patients had pelvic nodal metastasis only and 41% had macroscopic nodal metastasis. At a median follow-up of 3.8 years, 32% of patients had recurrence, all extrapelvic. Overall mean survival was 48 months and progression-free survival was 40 months. Overall survival for microscopic nodal metastasis was >60 months versus 35 months for macroscopic metastasis. Overall survival for pelvic nodal metastasis was 53 months versus 42 months for aorticinguinal metastasis. There were no complications from lymphadenectomy, a 22% chemotherapeutic toxicity, and a 14% radiation toxicity. CONCLUSION: Our surgical, chemotherapeutic, and radiation treatment protocol for stage IIIC endometrial cancer produced minimal toxicity and good survival.

The origins and biological significance of the coccidial lesions that occur in chickens vaccinated with a live attenuated anticoccidial vaccine.

The occurrence of vaccine-induced coccidial lesions in chicks vaccinated with a live attenuated anticoccidial vaccine is demonstrated. Healthy broiler chicks reared on litter to facilitate autoreinfection, but isolated from extraneous coccidial infections, were vaccinated when 8 days old with Paracox. Coccidial lesions were found in chicks between 5 and 23 days after vaccination; 24% of the 87 chicks sampled during 29 days had intestinal lesions of Eimeria acervulina, Eimeria maxima, Eimeria tenella or of undetermined species, mostly (19 out of 21) scored as 1 or 2 on the Johnson & Reid scale of 0 to 4. The other two positive birds had E. tenella lesions, each scored as 3. The lesions observed up to 5 days after vaccination were identified as primary (i.e. a host response to the first vaccinal life cycle) and those observed from 6 days onwards were designated as primary or secondary (i.e. a host response to the second and subsequent vaccinal life cycles) in origin. In the absence of extraneous coccidial infections, none of the lesions observed could have been due to non-vaccinal coccidial infections. No adverse effects on the health or growth rate of the chicks exhibiting primary or secondary lesions in response to vaccination with Paracox were apparent.

National Cancer Data Base/Surveillance Epidemiology and End Results: potential insensitive-measure bias.

OBJECTIVES: Abstraction of data from National Cancer Data Base (NCDB)/Surveillance Epidemiology and End Results (SEER) for reasons other than incidence, mortality, and patterns of care has risen. A potential problem with these data is that insensitive-measure bias can exist because of possible inaccuracies in hospital tumor registry staging. The purpose of this study is to assess the accuracy of tumor registry staging from six community hospitals. METHODS: Staging of 103 consecutive cancers operated on by a gynecologic oncologist (one of the authors) as a surgical consultant to a gynecologist or surgeon was reviewed. Hospital tumor registry staging forms were arbitrarily assigned to be completed by the nongynecologic oncologist versus the gynecologic oncologist by the medical records department. The authors reassessed cancer staging by medical chart review. The tumor registry staging was compared with the actual staging as determined by the authors. Major staging violations were defined as errors that would significantly change stage enough to alter prognosis or change recommended adjuvant treatment. All other violations were defined as minor. RESULTS: Twenty-eight (27%) cancers were staged by the gynecologic oncologist and 75 (73%) by nongynecologic oncologists. Eighty (78%) cancers were endometrial and 14 (13%) ovarian. Eighty-three (81%) tumors were stage I or II. Major staging violations occurred in 0% of cancers staged by the gynecologic oncologist and 22% (16/75) by a nongynecologic oncologist (P = 0.002). Minor staging violations occurred in 14% (4/28) of cancers staged by the gynecologic oncologist and 42% (32/75) by a nongynecologic oncologist (P = 0. 005). Minor violations were due to omission of histologic subtype and/or grade. CONCLUSION: The 22% major staging violation rate represents significant insensitive-measure bias. If additional studies produce similar results, abstraction of data from NCDB/SEER for reasons other than incidence, mortality, and patterns of care cannot be accepted as evidence-based scientific medicine.

Anticoccidial vaccination of broiler chickens in various management programmes: relationship between oocyst accumulation in litter and the development of protective immunity.

Paracox anticoccidial vaccine was administered to a 7-day-old flock of commercial broiler breeder stock subsequently reared to point-of-lay in the same house. For comparison, three subgroups of another flock of broiler breeders were also vaccinated with Paracox at 7 days of age, reared to 42 days and then transferred to new litter on another farm until point-of-lay. The first subgroup received no further treatment, but the second and third each received a second vaccination with Paracox, either immediately after transfer to the new litter or 42 days after transfer. Using an Eiomeria necatrix model, protective immunity was demonstrated by virulent challenge of samples of birds from all groups by the age of 37-40 days (30-33 days after the first vaccination), and was maintained to at least 122-125 days of age, whether the birds remained on the same litter or were transferred to another farm, and whether they received one or two anticoccidial vaccinations. Therefore, there is no disadvantage in transferring birds onto new litter 35 days after a single Paracox vaccination, nor is there any advantage in giving a second vaccination after such a transfer. Vaccinated birds seeded the new litter with oocysts, despite being clinically immune to coccidiosis. A supplementary laboratory experiment showed that birds vaccinated at 8 days of age passed almost no oocysts after a second vaccination at 43 days of age. This indicated that they were not only protected against clinical coccidiosis, but were almost solidly immune to a homologous infection 5 weeks after a single vaccination. Nevertheless, oocysts appeared in the litter of all four groups of commercial breeders throughout the trial, showing that wild-type heterologous infections occurred whether the birds were transferred to new litter or not, but these did not overwhelm the acquired protective immunity and cause clinical coccidiosis.

The efficacy of levamisole, and a mixture of oxfendazole and levamisole, against the arrested stages of benzimidazole-resistant Haemonchus contortus and Ostertagia circumcincta in sheep.

Sheep were allowed to graze pasture that had been seeded with benzimidazole-resistant Haemonchus contortus and Ostertagia circumcincta in order to acquire a burden of arrested larvae. Following housing, sheep were dosed orally with either oxfendazole at a dose rate of 4.7 mg/kg (to confirm the benzimidazole-resistant status of the species of nematode), levamisole at a dose rate of 7.5 mg/kg, or an oxfendazole/levamisole mixture at a dose rate of 4.6 mg/kg oxfendazole and 8.1 mg/kg levamisole. The efficacies of the treatments were assessed by estimation of the arrested larval burden in the abomasum of each sheep, either at 10 or 11 days (oxfendazole and oxfendazole/levamisole mixture), or 12 or 13 days (levamisole), after treatment. Compared to the untreated controls, the protection afforded by a single dose of either levamisole or the oxfendazole/levamisole mixture was >99% against the arrested stages of both Haemonchus contortus and Ostertagia circumcincta. Treatment with oxfendazole confirmed the benzimidazole-resistance status of the two species.

High-performance liquid chromatographic method for sensitive determination of the alkylating agent CB1954 in human plasma.

A high-performance liquid chromatography (HPLC) method is described for the measurement of the weak alkylating agent CB1954 in human plasma. CB1954 can be used as an innocuous prodrug designed for activation by bacterial nitroreductases in strategies of gene-directed enzyme-prodrug therapy, and becomes activated to a potent bifunctional alkylating agent. The HPLC method involves precipitation and solvent extraction and uses Mitomycin C (MMC) as an internal standard, with a retention time for MMC of 5.85 +/- 0.015 min, and for CB1954 of 10.72 +/- 0.063 min. The limit of detection for CB1954 is 2.9 ng/ml, and this compares favourably with systems involving direct analysis of plasma (limit of detection 600 ng/ml, approximately). The method is now being used for pharmacokinetic measurements in plasma samples from cancer patients entering phase I clinical trials of CB1954. Results using serial plasma samples from one patient are presented. The patient was treated intravenously with CB1954 (6 mg/m2), and plasma clearance of the drug showed biphasic kinetics with alpha half-life 14.6 min, and beta half-life 170.5 min.

Vulvar metastases secondary to transitional cell carcinoma of the bladder. A case report.

BACKGROUND: Gynecologists are frequently asked to evaluate patients with vulvar lesions. Although the differential diagnosis of a vulvar lesion is varied, the main concern is to rule out a vulvar malignancy. Primary vulvar carcinoma is uncommon, and a metastatic cancer from an extragenital site involving the vulva is even more rare. CASE: A 78-year-old woman with a history of a transitional cell carcinoma (TCC) of the bladder presented with two painful vulvar lesions, which represented the first manifestation of metastatic disease. This is the fifth reported case of TCC from the bladder with metastases to the vulva. CONCLUSION: The differential diagnosis of a vulvar lesion, especially in a woman with a prior history of renal tract malignancy, should include metastatic lesions.

Immune responses of cattle to experimental anti-Fasciola hepatica vaccines.

Fasciola hepatica infection of cattle and sheep is an important cause of clinical disease and production losses, and is controlled at present by a combination of chemotherapy and management measures. However, the prospects for the control of F. hepatica infection by vaccination are good, and we have previously shown substantial protection of cattle against experimental challenge infection following immunisation with a combination of the purified fluke-derived enzymes cathepsin L1 (CATL 1), cathepsin L2 (CATL 2) and fluke-derived Hb fraction (FHB). This and other recent studies have also demonstrated fundamental differences between protective and non-protective immune responses to liver fluke infection. In this present study we have further analysed the response of animals to liver fluke challenge following experimental vaccination. Calves were vaccinated with either CATL 2 plus FHB, or CATL 1 plus CATL 2. Partial protection against challenge infection was achieved in both vaccinated groups, with the greatest level of protection (55 per cent reduction in fluke burdens) recorded in the group vaccinated with CATL 1 plus CATL 2. This latter group also showed the greater level of lymphocyte proliferation and the greater production of gamma-INF in response to stimulation with fluke antigen in vitro following challenge. These results are significant in our attempts to characterise the elements within the immune response to vaccination which are protective.

Correlation of specific antibody titre and avidity with protection in cattle immunized against Fasciola hepatica.

Cattle produce specific serum antibody mainly of the IgG1 isotype in response to infection with the liver fluke, Fasciola hepatica. In these animals a positive correlation between fluke-specific serum IgG1 levels and fluke-burden in non-immunized infected animals was observed. In contrast, immunization of cattle with a combination of the fluke-derived antigens cathepsin L2 (CL2) and fluke haemoglobin (FHb) in Freund's complete/incomplete adjuvant (FCA/FLA) induced a specific antibody response involving IgG2, as well as IgG1. These immunized animals also exhibited very high (72%) levels of protection against a subsequent challenge infection. When the vaccine was administered in FIA alone the specific antibody response, while still involving IgG1 and IgG2, was of lower magnitude (10-fold and 100-fold, respectively) and no significant reduction in fluke burden was observed following challenge. Nevertheless, in these animals, a strong IgG2 response was associated with low fluke burdens. These results provide further evidence of the non-protective nature of specific immune responses in cattle following F. hepatica infection, and demonstrate that vaccination can induce a qualitatively different, and protective, response.

Vaccination against Haemonchus contortus with denatured forms of the protective antigen H11.

As part of a systematic examination of the protective epitopes on H11, groups of sheep were vaccinated with preparations of purified H11 used untreated (group A), or progressively denatured (linearized) by incubation with sodium dodecyl sulphate (SDS) (group B) or by boiling with SDS in the presence of dithiothreitol (group C). All the sheep developed antibodies which bound to the untreated H11. When challenged with 10,000 infective larvae of Haemonchus contortus the mean levels of protection relative to the mean values for adjuvant controls were 99.8%, 85% and 79% for faecal egg counts and 95%, 79% and 54% for worm burden at post-mortem for groups A, B and C respectively. The H11-specific antibodies inhibited the microsomal aminopeptidase activity of H11 in vitro up to 80%. The levels of inhibition by sera from individual animals correlated with levels of protection with r2, of 0.69-0.87.

Duration of protective immunity against ovine haemonchosis following vaccination with the nematode gut membrane antigen H11.

To establish for how long protective antibody levels may be maintained, lambs were vaccinated with the gut membrane antigen H11 and challenged with Haemonchus contortus 14, 84, 126 or 168 days later. Compared to controls, mean faecal egg counts of vaccinated lambs were reduced by 97 per cent, 99 per cent, 92 per cent and 86 per cent respectively. Total worm burdens at postmortem five weeks after infection were reduced by 87 per cent, 94 per cent, 92 per cent and 62 per cent respectively. In vaccinated lambs, antibody levels to H11 peaked at about 60 days after the first vaccination and were maintained for the duration of the experiment. There was evidence of secondary antibody responses to H11 following challenge.