Perioperative platelet reactivity over time in patients undergoing vascular surgery: An observational pilot study.

BACKGROUND: Despite Antiplatelet therapy (APT), cardiovascular patients undergoing revascularisation remain at high risk for thrombotic events. Individual response to APT varies substantially, resulting in insufficient protection from thrombotic events due to high on-treatment platelet reactivity (HTPR) in ≤40% of patients. Individual variation in platelet response impairs APT guidance on a single patient level. Unfortunately, little is known about individual platelet response to APT over time, timing for accurate residual platelet reactivity measurement, or the optimal test to monitor residual platelet reactivity. AIMS: To investigate residual platelet reactivity variability over time in individual patients undergoing carotid endarterectomy (CEA) treated with clopidogrel. METHODS: Platelet reactivity was determined in patients undergoing CEA in a prospective, single-centre, observational study using the VerifyNow (change in turbidity from ADP-induced binding to fibrinogen-coated beads), the VASP assay (quantification of phosphorylation of vasodilator-stimulated phosphoprotein), and a flow-cytometry-based assay (PACT) at four perioperative time points. Genotyping identified slow (CYP2C19*2 and CYP2C19*3) and fast (CYP2C19*17) metabolisers. RESULTS: Between December 2017 and November 2019, 50 patients undergoing CEA were included. Platelet reactivity measured with the VerifyNow (p = < .001) and VASP (p = .029) changed over time, while the PACT did not. The VerifyNow identified patients changing HTRP status after surgery. The VASP identified patients changing HTPR status after eight weeks (p = .018). CYP2C19 genotyping identified 13 slow metabolisers. CONCLUSION: In patients undergoing CEA, perioperative platelet reactivity measurements fluctuate over time with little agreement between platelet reactivity assays. Consequently, HTPR status of individual patients measured with the VerifyNow and VASP assay changed over time. Therefore, generally used perioperative platelet reactivity measurements seem unreliable for adjusting perioperative APT strategy.

Flight muscle and heart phenotypes in the high-flying ruddy shelduck.

Ruddy shelduck migrate from wintering grounds in lowland India and Myanmar to breeding grounds in central China and Mongolia, sustaining flight over the Himalayas, where oxygen availability is greatly reduced. We compared phenotypes of the pectoralis muscle and the ventricle of the heart from ruddy shelduck and common shelduck (a closely related low-altitude congener) that were raised in common conditions at sea level, predicting that oxidative capacity would be greater in ruddy shelduck to support high-altitude migration. Fibre-type composition of the pectoralis and the maximal activity of eight enzymes involved in mitochondrial energy metabolism in the pectoralis and heart, were compared between species. Few differences distinguished ruddy shelduck from common shelduck in the flight muscle, with the exception that ruddy shelduck had higher activities of complex II and higher ratios of complex IV (cytochrome c oxidase) and complex II when expressed relative to citrate synthase activity. There were no species differences in fibre-type composition, so these changes in enzyme activity may reflect an evolved modification in the functional properties of muscle mitochondria, potentially influencing mitochondrial respiratory capacity and/or oxygen affinity. Ruddy shelduck also had higher lactate dehydrogenase activity concurrent with lower pyruvate kinase and hexokinase activity in the left ventricle, which likely reflects an increased capacity for lactate oxidation by the heart. We conclude that changes in pathways of mitochondrial energy metabolism in the muscle and heart may contribute to the ability of ruddy shelduck to fly at high altitude.

Factor XII truncation accelerates activation in solution.

Essentials During contact system activation, factor XII is progressively cleaved by plasma kallikrein. We investigated the role of factor XII truncation in biochemical studies. Factor XII contains naturally occurring truncating cleavage sites for a variety of enzymes. Truncation of factor XII primes it for activation in solution through exposure of R353. SUMMARY: Background The contact activation system and innate immune system are interlinked in inflammatory pathology. Plasma kallikrein (PKa) is held responsible for the stepwise processing of factor XII (FXII). A first cleavage activates FXII (into FXIIa); subsequent cleavages truncate it. This truncation eliminates its surface-binding domains, which negatively regulates surface-dependent coagulation. Objectives To investigate the influence of FXII truncation on its activation and downstream kallikrein-kinin system activation. Methods We study activation of recombinant FXII variants by chromogenic assays, by FXIIa ELISA and western blotting. Results We demonstrate that FXII truncation primes it for activation by PKa in solution. We demonstrate this phenomenon in three settings. (i) Truncation at a naturally occurring PKa-sensitive cleavage site, R334, accelerates FXIIa formation in solution. A site-directed mutant FXII-R334A displays ~50% reduced activity when exposed to PKa. (ii) A pathogenic mutation in FXII that causes hereditary angioedema, introduces an additional plasmin-sensitive cleavage site. Truncation at this site synergistically accelerates FXII activation in solution. (iii) We identify new, naturally occurring cleavage sites in FXII that have so far not been functionally linked to contact system activation. As examples, we show that non-activating truncation of FXII by neutrophil elastase and cathepsin K primes it for activation by PKa in solution. Conclusions FXII truncation, mediated by either pathogenic mutations or naturally occurring cleavage sites, primes FXII for activation in solution. We propose that the surface-binding domains of FXII shield its activating cleavage site, R353. This may help to explain how the contact system contributes to inflammatory pathology.

Feasibility study of a randomised controlled trial to compare (deferred) androgen deprivation therapy and cryotherapy in men with localised radiation-recurrent prostate cancer.

BACKGROUND: Salvage therapeutic options for biochemical failure after primary radiation-based therapy include radical prostatectomy, cryoablation, high-intensity focused ultrasound (HIFU), brachytherapy (for post-EBRT patients) and androgen deprivation therapy (ADT). ADT and salvage prostate cryoablation (SPC) are two commonly considered treatment options for RRPC. However, there is an urgent need for high-quality clinical studies to support evidence-based decisions on treatment choice. Our study aims to determine the feasibility of randomising men with RRPC for treatment with ADT and SPC. METHODS: The randomised controlled trial (CROP) was developed, which incorporated protocols to assess parameters relating to cryotherapy procedures and provide training workshops for optimising patient recruitment. Analysis of data from the recruitment phase and patient questionnaires was performed. RESULTS: Over a period of 18 months, 39 patients were screened for eligibility. Overall 28 patients were offered entry into the trial, but only 7 agreed to randomisation. The majority reason for declining entry into the trial was an unwillingness to be randomised into the study. 'Having the chance of getting cryotherapy' was the major reason for accepting the trial. Despite difficulty in retrieving cryotherapy temperature parameters from prior cases, 9 of 11 cryotherapy centres progressed through the Cryotherapists Qualification Process (CQP) and were approved for recruiting into the CROP study. CONCLUSIONS: Conveying equipoise between the two study arms for a salvage therapy was challenging. The use of delayed androgen therapy may have been seen as an inferior option. Future cohort studies into available salvage options (including prostate cryotherapy) for RRPC may be more acceptable to patients than randomisation within an RCT.

Localised amyloidosis of the glans penis presenting as a painless lump with progression after 10 years.

Primary amyloidosis of the genitourinary tract is uncommon, and isolated invasion of the glans penis is exceptionally rare Degos et al. (Bull Soc Fr Dermatol Syphiligr 68:159, 1961). We report a case of localised amyloidosis of the glans penis in a 40-year-old presenting as an asymptomatic penile mass which changed after 10 years prompting treatment. We believe this to be the longest interval recorded between clinical occurrence and histological diagnosis of primary penile amyloidosis.

Epithelioid haemangioma: a rare cause of painful erections and sleep deprivation.

Epithelioid haemangioma of the penis is a rare condition which usually presents a solid single nodule. We report a case in a 43-year-old man who presented with painful erections and sleep disturbance with two palpable penile nodules. Magnetic resonance imaging with an artificially induced erection revealed these as individual lesions, and local excision was successfully undertaken. Pathological diagnosis of epithelioid haemangioma was confirmed with positive staining for CD31. Although rare, penile epithelioid haemangioma should be considered as a differential in an atypical penile mass. Induction in of an artificial erection prior to MRI can aid diagnosis and treatment is typically with surgical excision.

Penile metastases treated with partial glansectomy and adjuvant radiotherapy 5 years after an initial diagnosis of rectal cancer.

A 61-year-old man with recurrent rectal carcinoma was referred to the urology clinic with two penile lesions. These had negatively affected his quality of life and he underwent a radical circumcision and proximal glansectomy with reconstruction. This case report examines the clinical presentation and surgical treatment of rectal carcinoma metastasising to the penis.

Lateral spine radiographs before androgen deprivation treatment detect a high incidence of undiagnosed vertebral fragility fractures in men with advanced prostate cancer.

PURPOSE: Baseline bone mineral density scanning in patients about to commence long-term androgen deprivation therapy for advanced/metastatic prostate cancer is reported to show a high incidence of osteoporosis and osteopenia. We investigated the incidence of existing spinal osteoporotic fractures in this population as this is known to be a risk factor for the development of treatment induced fractures. MATERIALS AND METHODS: Since 2003 we performed lateral thoracolumbar x-rays on all patients before androgen deprivation therapy for prostate cancer. The heights of T4-L5 vertebral bodies were measured, then reanalyzed by the Eastell method to define grade 1 or worse grade 2 vertebral crush fractures. We used a morphometric algorithm including an age stratified random sample of men with normal thoracolumbar x-rays to quantitatively assess fractures. RESULTS: A total of 202 patients with prostate cancer underwent thoracolumbar x-rays before androgen deprivation therapy. Of the patients 61.9% had 1 or more grade 1 and 60.9% had 1 or more grade 2 wedge fractures. In addition, 46.5% of patients had 1 or more grade 1 and 44.6% had greater than 1 grade 2 biconcavity fractures. Finally 63.9% of patients had 1 or more grade 1 and 47.8% had 1 or more grade 2 compression fractures. With conventional reporting 72.4% of patients had no bony abnormality, 14.9% had 1 and 12.7% multiple vertebral crush fractures. Bone mineral density was significantly less in patients with fracture(s) vs those with no abnormality (p<0.001). CONCLUSIONS: Routine reporting identifies a high incidence of spinal fractures before commencing androgen deprivation therapy, but this is much greater when quantitative assessment is applied. Thoracolumbar x-rays identify the risk of treatment induced fracture and allow baseline comparison in individuals who experience back pain on androgen deprivation therapy. We advocate more routine adoption of baseline thoracolumbar x-rays in patients with prostate cancer.

Referrals into a dedicated British penile cancer centre and sources of possible delay.

OBJECTIVE: To assess sources of delay in referral to a specialist Urology clinic for penile cancer. METHODS: Patients with penile cancer seen during the period December 2002 to December 2007 were identified from the unit's database. Information regarding presentation, diagnosis and pattern of referral was retrieved from records. Delay was defined as the time between the patient first noticing a penile lesion and date of first seeking medical advice, or additional time before being seen by a Urologist resulting from referral to another specialty. RESULTS: Of 100 patients, with a median age of 54 years (range 2-81 years), 19% were initially referred to other specialties (Genitourinary Medicine-13%, Dermatology-4%, Plastics 2%). Initial referrals to Genito-urinary Medicine and Dermatology resulted in mean delays of 6 and 3.5 months respectively, whereas the mean duration for patients to present to any medical practitioner from onset of symptoms was 5.8 months. Overall, 47% presented with locally advanced disease. CONCLUSION: Approximately one-fifth of patients with penile cancer are first referred to specialties other than Urology. This sometimes delays diagnosis, potentially affecting overall prognosis. The major source of delay, however, results from patient reluctance to seek medical advice. Thus, the greatest impact in this condition is likely to be achieved by increased public awareness and education.

Analysis using life tables of the major causes of death and the differences between country of birth groups in New South Wales, Australia.

OBJECTIVES: This study used life table methods to evaluate the potential effects of reduction in major disease mortality on life expectancy in New South Wales (NSW), and the differences in cause-specific mortality between country of birth groups. The total and partial elimination of major causes of death were examined to identify the high-risk groups for community-level health planning. STUDY DESIGN: Life tables were used to combine the mortality rates of the NSW population at different ages into a single statistical model. METHODS: Using abridged, multiple decrement and cause-elimination life tables with the mortality data for NSW in 2000-2002, broader disease groups were examined. Multiple decrement tables were generated by country of birth. The effect of the partial elimination of ischaemic heart disease (IHD) was also studied. RESULTS: This study found that Pacific-born men and women who reach their 30th birthday and eventually die from IHD are expected to live, on average, 10.8 and 5.8 years less, respectively, than average men and women in NSW. If IHD is eliminated as a cause of death, 7.5 years for males and 6.7 years for females would be added to life expectancy at birth. CONCLUSIONS: Life expectancy at birth is likely to be further increased by reducing deaths caused by diseases of the cardiovascular system, particularly among people aged over 65 years, by reducing malignant neoplasm deaths among those aged below 65 years, and by reducing deaths due to accidents, injury and poisoning, mainly among men aged 15-29 years. Further gains in life expectancy could be achieved with community-level educational programmes on lifestyle management and disease prevention.

Immediate dual energy X-ray absorptiometry reveals a high incidence of osteoporosis in patients with advanced prostate cancer before hormonal manipulation.

OBJECTIVE: To examine the incidence of osteoporosis in patients with advanced prostate cancer (using forearm densitometry) before commencing androgen deprivation therapy (ADT), as osteoporotic fractures are more frequent in patients with prostate cancer who have undergone either medical or surgical castration, because of rapid loss of bone mass. PATIENTS AND METHODS: In all, 174 patients (mean age 74.6 years, range 46-90) with advanced prostate cancer presented over 2 years. Their forearm bone densitometry values were compared with those from 106 age-matched controls (mean age 74.3 years, range 66-90). RESULTS: Of the 174 patients, 73 (42%) were osteoporotic (t score

Single bead characterization using analytical constructs: application to quality control of libraries.

Analytical construct technology has been successfully applied to the single-bead analysis of a split-mix combinatorial library. Substrates can be released from the resin by conventional cleavage for biological screening. Alternatively, for the purpose of analysis and quality control, cleavage at an orthogonal construct linker produces an analytical fragment incorporating the substrate. This analytical fragmnent is highly sensitized to electrospray mass spectrometry (ESI-MS) and is easily identified by isotope labeling. The construct cleavage rendered readily visible even those compounds that clearly could not be seen by conventional cleavage and mass spectrometry analysis. A 1H NMR control experiment proved that the compounds cleaved conventionally were, however, present in the sample in good yield and purity. In view of the data obtained, we think that this is a significant and important step toward solving our current quality control problems.

Reporter resins for solid-phase chemistry.

[reaction: see text] An analytical construct resin, designed to aid the analysis of solid-phase chemistry, has been mixed in a small proportion with a conventional resin. The analytical construct ("reporter resin") contains two orthogonal linkers that allow cleavage of either the synthetic intermediates (at linker 2) or their analytically enhanced derivatives (at linker 1). The convenient and rapid monitoring of each step in the syntheses of representative library compounds was possible using small resin aliquots.

Projecting mammographic screens.

OBJECTIVE: The purpose of mammographic screening is to reduce mortality from breast cancer. This study describes a method for projecting the number of screens to be performed by a mammographic screening programme, and applies this method in the context of New South Wales, Australia. METHOD: The total number of mammographic screens was projected as the sum of initial screens and re-screens, and is based on projections of the population, rates of new recruitment, rates of attrition within the programme, and the mix of screening intervals. The baseline scenario involved: 70% participation of women aged 50-69 years, 90% return rate for the second and subsequent re-screens, 5% annual screens (95% biennial screens), and a specified population projection. The results were assessed with respect to variations in these assumptions. RESULTS: The projections were strongly influenced by: the rate of screening of the target age group; the proportion of women re-screened annually; and the rates of attrition within the programme. Although demographic change had a notable effect, there was little difference between different population projections. Standard assumptions about attrition within the programme suggest that the current target participation rates in NSW may not be achieved in the long term. CONCLUSIONS: A practical model for projecting mammographic screens for populations is described which is capable of forecasting the number of screens under different scenarios. IMPLICATIONS: Projections of mammographic screens provide important information for the planning and financing of equipment and personnel, and for testing the effects of variations in important operational parameters. Re-screening attrition is an important contributor to screening viability.

The effect of fasting or desmopressin before treatment on the concentration of mitomycin C during intravesical administration.

OBJECTIVE: To evaluate two methods of reducing the urine output during treatment (the most easily manipulated variable) in patients undergoing intravesical instillation with mitomycin C, where the concentration-time curve also depends upon dose, diluent volume, residual urine volume, and drug absorption and degradation. PATIENTS AND METHODS: The study comprised 20 consecutive patients undergoing a course of six weekly instillations of mitomycin C (40 mg in 40 mL for 1 h) for superficial bladder carcinoma. Urine production during treatment was calculated by adding the voided volume and ultrasonographically measured residual urine after treatment, and subtracting 40 mL; the patient's bladder was emptied before instillation. Before the first and second visit the patients were asked to drink normally. Before the third and fourth visit patients fasted for 6 h before treatment. For the fifth and sixth visit the patients had not fasted, but 200 microg of desmopressin was given orally 1 h before instillation. Any urinary side-effects were graded on a four-point scale. RESULTS: There were 17 patients with complete data; one patient failed to take desmopressin, one had detrusor instability and one developed chemical cystitis. The mean (SD) urine production in unprepared patients was 209 (123) mL, which decreased to 143 (80) mL (P = 0.039, t-test) after fasting and 103 (51) mL (P < 0.001) with desmopressin. This equates to a 20% increase in mean intravesical drug concentration with fasting and a 38% increase with desmopressin. Urinary side-effects were graded as mild in each group. CONCLUSION: Unprepared patients produce variable and often substantial volumes of urine during intravesical chemotherapy. There was a significant reduction in urine output after fasting or by administering desmopressin before instillation. These measures increase the area under the concentration-time curve for mitomycin C and potentially increase the efficacy of treatment.

Solid-phase reaction monitoring--chemical derivatization and off-bead analysis.

The aim of this review is to give a compendium of colorimetric assays and spectrophotometric-based quantification methods applicable to solid-phase organic chemistry. Comprehensive experimental details for commonly employed color tests performed on solid support will be documented.

Branch migration and the international dispersal of families.

This paper discusses the dispersal of facilities where family members migrate to different destination countries. Terminology for internationally dispersed families is proposed, and the term branch migration is suggested for the migration of related people from the same source country to different destination countries. Data from two 1993 surveys of senior secondary students show that 22% of Sydney students and 20% of Hong Kong students have relatives in two or more other countries. The data suggest that many Asian migrant families have branched between the US, Canada, Australia and other migrant-receiving nations. The causes and implications of the international dispersal of families are discussed.